Faculty Profiles - Kyoko (Tsukiyama-)Kohara

Papers - Kyoko (Tsukiyama-)Kohara

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Soliman AM, Mahmoud HYAH, Amer MM, Mohamed S, Hifumi T, Tsukiyama-Kohara K, Tanaka T . First detection of Rickettsia japonica in Hyalomma dromedarii ticks infesting camels from Egypt: A call for enhanced surveillance of tick-borne pathogens. . Medical and veterinary entomology 2025.9Reviewed International journal

Akter L, Hashem MA, Kayesh MEH, Rakib TM, Rashid MHO, Maetani F, Tsukiyama-Kohara K . Correction: Elevated oncogene expressions in koala infected with multiple koala retrovirus subtypes: a preliminary study. . Virus genes 2025.8Reviewed International journal

Kayesh MEH, Kohara M, Tsukiyama-Kohara K . Toll-like Receptor (TLR) Response in Chikungunya Virus Infection: Mechanism of Activation, Immune Evasion, and Use of TLR Agonists in Vaccine Development. . Vaccines13 ( 8 ) 2025.8Reviewed International journal

Kayesh M.E.H., Kohara M., Tsukiyama-Kohara K. . Innate Immune Response to Powassan Virus Infection: Progress Toward Infection Control . Vaccines13 ( 7 ) 2025.7Reviewed International journal

Authorship：Lead author,　Last author,　Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Vaccines

Powassan virus is an emerging tick-borne flavivirus that poses a significant threat to human health. The outcome of Powassan virus infection is shaped by both viral factors and the host immune response. While this review aimed to examine the innate immune response, particularly toll-like receptor-mediated immune responses to Powassan virus, data specific to the immune response to Powassan virus remain scarce. Therefore, we focused on toll-like receptor responses to related flaviviruses to infer possible mechanisms of host response. Insights from both in vivo and in vitro studies are critical for guiding the development of effective therapeutic and preventive strategies. Currently, there are no clinically approved treatments or vaccines for Powassan virus, highlighting the urgent need for their development. We also highlight recent progress in POWV vaccine development, with an emphasis on the potential use of toll-like receptor agonists as adjuvants to enhance immunogenicity and improve vaccine efficacy.

DOI： 10.3390/vaccines13070754

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Akter L, Hashem MA, Kayesh MEH, Rakib TM, Rashid MHO, Maetani F, Kohara KT . Elevated oncogene expressions in koala infected with multiple koala retrovirus subtypes: a preliminary study. . Virus genes 2025.6Reviewed International journal

Sanada T, Tsukiyama-Kohara K, Kohara M . Genomic characterization of hepaciviruses and pegivirus in the northern tree shrew (Tupaia belangeri). . Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 105778 2025.6Reviewed International journal

Rashid MHO, Ezzikouri S, Soliman AM, Akter L, Momohara K, Hifumi T, Miyoshi N, Hishiki T, Abdel-Moneim AS, Kohara M, Tsukiyama-Kohara K . Drug repositioning: Identification of potent inhibitors of NS3 protease and NS5 RdRp for control of DENV infection. . Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie187 118104 2025.4Reviewed International journal

Rashid MHO, Yasui F, Sanada T, Kono R, Honda T, Kitab B, Akter L, Utsunomiya M, Sato R, Yoshida O, Hiasa Y, Oda Y, Goh Y, Miyazaki T, Kohara M, Tsukiyama-Kohara K . Immunogenicity of an Intranasal Dual (Core and Surface)-Antigen Vaccine Against Hepatitis B Virus Enhanced by Carboxyl-Vinyl Polymer Excipients. . Vaccines13 ( 5 ) 2025.4Reviewed International journal

Kayesh MEH, Kohara M, Tsukiyama-Kohara K . Effects of oxidative stress on viral infections: an overview. . Npj viruses3 ( 1 ) 27 2025.4Reviewed International journal

Akhter R, Hossain KA, Kitab B, Sakoda Y, Tsukiyama-Kohara K . Common host factors for internal ribosomal entry site-mediated translation of viral genomic RNA: An investigation in foot-and-mouth disease and classical swine fever viruses. . Virus research 199570 2025.4Reviewed International journal

Uno Y, Kawabata I, Ushirozako G, Tsukiyama-Kohara K, Ishizuka M, Mizukawa H, Murayama N, Yamazaki H . Exploration of functional cytochrome P450 4F enzymes in liver, intestine, and kidney from dogs, cats, pigs, and tree shrews and comparison of their metabolic capacities with human P450 4F2 and 4F12. . Biochemical pharmacology 116894 2025.3Reviewed International journal

Kayesh MEH, Kohara M, Tsukiyama-Kohara K . Toll-like receptor response to Zika virus infection: progress toward infection control. . Npj viruses3 ( 1 ) 20 2025.3Reviewed International journal

Rashid MHO, Kayesh MEH, Hashem MA, Hifumi T, Ogawa S, Miyoshi N, Tanaka Y, Kohara M, Tsukiyama-Kohara K . Adeno-associated virus 2 CRISPR/Cas9-mediated targeting of hepatitis B virus in tree shrews. . Virus research 199550 2025.2Reviewed International journal

Hifumi T., Tanaka Y., Tsukiyama-Kohara K., Miyoshi N. . Phyllodes tumor in the mammary gland of a northern tree shrew (Tupaia belangeri) . Journal of Veterinary Medical Science87 ( 4 ) 384 - 388 2025Reviewed International journal

Authorship：Lead author,　Last author,　Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Veterinary Medical Science

A rapidly growing mass was observed in the left third mammary gland of a 5-and-a-half-year-old intact female northern tree shrew (Tupaia belangeri). Histopathologically, the mass was composed of numerous irregularly dilated mammary ducts with a pericanalicular or intracanalicular pattern. These mammary ducts showed a leaf-like structure due to the proliferations of surrounding spindle-shaped neoplastic cells with moderate to severe nuclear atypia. We diagnosed this case as a phyllodes tumor in a mammary gland of a northern tree shrew (Tupaia belangeri), which closely resembled those occurring in the human breast histopathologically. To the best of our knowledge, this is the first report of a phyllodes tumor in the mammary gland of a northern tree shrew (Tupaia belangeri).

DOI： 10.1292/jvms.24-0444

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Soliman AM, Mahmoud HYAH, Amer MM, Mohamed S, Hifumi T, Tsukiyama-Kohara K, Tanaka T . First detection of Colpodella spp. in Rhipicephalus annulatus and molecular characterization of piroplasmids in southern Egypt. . Frontiers in veterinary science12 1617204 2025Reviewed International journal

Akter L, Hashem MA, Kayesh MEH, Hossain MA, Maetani F, Akhter R, Hossain KA, Rashid MHO, Sakurai H, Asai T, Hoque MN, Tsukiyama-Kohara K . A preliminary study of gene expression changes in Koalas Infected with Koala Retrovirus (KoRV) and identification of potential biomarkers for KoRV pathogenesis. . BMC veterinary research20 ( 1 ) 496 2024.10Reviewed International journal

Kayesh MEH, Hashem MA, Tsukiyama-Kohara K . Epidemiology, Transmission Mode, and Pathogenesis of Chlamydia pecorum Infection in Koalas (Phascolarctos cinereus): An Overview. . Animals : an open access journal from MDPI14 ( 18 ) 2024.9Reviewed International journal

Yao YG, Lu L, Ni RJ, Bi R, Chen C, Chen JQ, Fuchs E, Gorbatyuk M, Lei H, Li H, Liu C, Lv LB, Tsukiyama-Kohara K, Kohara M, Perez-Cruz C, Rainer G, Shan BC, Shen F, Tang AZ, Wang J, Xia W, Xia X, Xu L, Yu D, Zhang F, Zheng P, Zheng YT, Zhou J, Zhou JN . Study of tree shrew biology and models: A booming and prosperous field for biomedical research. . Zoological research45 ( 4 ) 877 - 909 2024.7Reviewed International journal

Uno Y, Tsukiyama-Kohara K, Ishizuka M, Mizukawa H, Murayama N, Yamazaki H . Investigation of functional cytochrome P450 4A enzymes in liver and kidney of pigs, cats, tree shrews, and dogs in comparison with the metabolic capacity of human P450 4A11. . Drug metabolism and disposition: the biological fate of chemicals 2024.7Reviewed International journal

Kayesh M.E.H., Kohara M., Tsukiyama-Kohara K. . Recent Insights into the Molecular Mechanisms of the Toll-like Receptor Response to Influenza Virus Infection . International Journal of Molecular Sciences25 ( 11 ) 2024.6Reviewed International journal

Authorship：Lead author,　Last author,　Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：International Journal of Molecular Sciences

Influenza A viruses (IAVs) pose a significant global threat to human health. A tightly controlled host immune response is critical to avoid any detrimental effects of IAV infection. It is critical to investigate the association between the response of Toll-like receptors (TLRs) and influenza virus. Because TLRs may act as a double-edged sword, a balanced TLR response is critical for the overall benefit of the host. Consequently, a thorough understanding of the TLR response is essential for targeting TLRs as a novel therapeutic and prophylactic intervention. To date, a limited number of studies have assessed TLR and IAV interactions. Therefore, further research on TLR interactions in IAV infection should be conducted to determine their role in host–virus interactions in disease causation or clearance of the virus. Although influenza virus vaccines are available, they have limited efficacy, which should be enhanced to improve their efficacy. In this study, we discuss the current status of our understanding of the TLR response in IAV infection and the strategies adopted by IAVs to avoid TLR-mediated immune surveillance, which may help in devising new therapeutic or preventive strategies. Furthermore, recent advances in the use of TLR agonists as vaccine adjuvants to enhance influenza vaccine efficacy are discussed.

DOI： 10.3390/ijms25115909

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Ushirozako G, Murayama N, Tsukiyama-Kohara K, Yamazaki H, Uno Y . Novel tree shrew cytochrome P450 2Ds ( CYP2D8a and CYP2D8b ) are functional drug-metabolizing enzymes that metabolize bufuralol and dextromethorphan. . Drug metabolism and disposition: the biological fate of chemicals 2024.1Reviewed International journal

Uno Y, Makiguchi M, Ushirozako G, Tsukiyama-Kohara K, Shimizu M, Yamazaki H . Molecular and functional characterization of flavin-containing monooxygenases (FMO1-6) in tree shrews. . Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 109835 2024.1Reviewed International journal

Kayesh MEH, Nazneen H, Kohara M, Tsukiyama-Kohara K . An effective pan-serotype dengue vaccine and enhanced control strategies could help in reducing the severe dengue burden in Bangladesh-A perspective. . Frontiers in microbiology15 1423044 2024Reviewed International journal

Hasan MN, Rahman MM, Husna AA, Arif M, Iwanaga T, Tsukiyama-Kohara K, Jasineviciute I, Kato D, Nakagawa T, Miura N . Elevated expression of miR-301a and its functional roles in canine oral melanoma. . Veterinary and comparative oncology 2023.12Reviewed International journal

Uno Y, Minami Y, Tsukiyama-Kohara K, Murayama N, Yamazaki H . Identification of cytochrome P450 2C18 and 2C76 in tree shrews: P450 2C18 effectively oxidizes typical human P450 2C9/2C19 chiral substrates warfarin and omeprazole with less stereoselectivity. . Biochemical pharmacology 115990 2023.12Reviewed International journal

Ngwe Tun MM, Nwe KM, Balingit JC, Takamatsu Y, Inoue S, Pandey BD, Urano T, Kohara M, Tsukiyama-Kohara K, Morita K . A Novel, Comprehensive A129 Mouse Model for Investigating Dengue Vaccines and Evaluating Pathogenesis. . Vaccines11 ( 12 ) 2023.12Reviewed International journal

Kayesh MEH, Kohara M, Tsukiyama-Kohara K . Effects of neddylation on viral infection: an overview. . Archives of virology169 ( 1 ) 6 2023.12Reviewed International journal

Akter L, Hashem MA, Rakib TM, Rashid MHO, Hossain KA, Akhter R, Utsunomiya M, Kitab B, Hifumi T, Miyoshi N, Maetani F, Tsukiyama-Kohara K . Investigation of koala retrovirus in captive koalas with pneumonia and comparative analysis of subtype distribution. . Archives of virology168 ( 12 ) 298 2023.11Reviewed International journal

Ushirozako G, Murayama N, Tsukiyama-Kohara K, Yamazaki H, Uno Y . Tree shrew cytochrome P450 2E1 is a functional enzyme that metabolises chlorzoxazone and p-nitrophenol. . Xenobiotica; the fate of foreign compounds in biological systems 1 - 11 2023.11Reviewed International journal

Hossain KA, Akhter R, Rashid MHO, Akter L, Utsunomiya M, Kitab B, Mm N, Hishiki T, Kohara M, Morita K, Tsukiyama-Kohara K . Suppression of dengue virus replication by the French maritime pine extract Pycnogenol®. . Virus research 199244 2023.10Reviewed International journal

Okamoto R, Ito N, Ide Y, Kitab B, Sakoda Y, Tsukiyama-Kohara K . Development of short hairpin RNA expression vectors targeting the internal ribosomal entry site of the classical swine fever virus genomic RNA. . BMC biotechnology23 ( 1 ) 37 2023.9Reviewed International journal

Kenzaburo Yamaji, Sadahiro Iwabuchi, Yuko Tokunaga, Shinichi Hashimoto, Daisuke Yamane, Sakiko Toyama, Risa Kono, Bouchra Kitab, Kyoko Tsukiyama-Kohara*, Yosuke Osawa, Yukiko Hayashi, Tsunekazu Hishima, Chise Tateno, Kiminori Kimura, Takeshi Okanoue, Michinori Kohara . Molecular insights of a CBP/β-catenin-signaling inhibitor on nonalcoholic steatohepatitis-induced liver fibrosis and disorder . Biomedicine & Pharmacotherapy166 115379 2023.8Reviewed International coauthorship

Ushirozako G, Noda Y, Murayama N, Kawaguchi H, Tsukiyama-Kohara K, Yamazaki H, Uno Y . Newly Identified Tree Shrew Cytochrome P450 2A13 (CYP2A13) is Expressed in Liver and Lung and Encodes a Functional Drug-Metabolizing Enzyme Similar to Dog CYP2A13 and Pig CYP2A19. . Drug metabolism and disposition: the biological fate of chemicals 2023.5Reviewed International journal

Uno Y, Jikuya S, Noda Y, Oguchi A, Murayama N, Kawaguchi H, Tsukiyama-Kohara K, Yamazaki H . Newly identified cytochrome P450 3A genes of tree shrews and pigs are expressed and encode functional enzymes. . Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 109579 2023.5Reviewed International journal

Yoshida O, Akbar SMF, Imai Y, Sanada T, Tsukiyama-Kohara K, Miyazaki T, Kamishita T, Miyake T, Tokumoto Y, Hikita H, Tsuge M, Shimizu M, Al Mahtab M, Aguilar JC, Guillen G, Kohara M, Hiasa Y . Intranasal therapeutic vaccine containing HBsAg and HBcAg for patients with chronic hepatitis B; 18 months follow-up results of phase IIa clinical study. . Hepatology research : the official journal of the Japan Society of Hepatology 2023.3Reviewed International journal

Uno Y, Noda Y, Murayama N, Tsukiyama-Kohara K, Yamazaki H . Novel cytochrome P450 1 (CYP1) genes in tree shrews are expressed and encode functional drug-metabolizing enzymes. . Comparative biochemistry and physiology. Toxicology & pharmacology : CBP265 109534 2023.3Reviewed International journal

Kitab B, Tsukiyama-Kohara K . Regulatory Role of Ribonucleotide Reductase Subunit M2 in Hepatocyte Growth and Pathogenesis of Hepatitis C Virus. . International journal of molecular sciences24 ( 3 ) 2023.1Reviewed International journal

Kayesh MEH, Khalil I, Kohara M, Tsukiyama-Kohara K . Increasing Dengue Burden and Severe Dengue Risk in Bangladesh: An Overview. . Tropical medicine and infectious disease8 ( 1 ) 2023.1Reviewed International journal

Kayesh MEH, Kohara M, Tsukiyama-Kohara K . TLR agonists as vaccine adjuvants in the prevention of viral infections: an overview. . Frontiers in microbiology14 1249718 2023Reviewed International journal

Kayesh MEH, Kohara M, Tsukiyama-Kohara K . Epidemiology and Risk Factors for Acute Viral Hepatitis in Bangladesh: An Overview. . Microorganisms10 ( 11 ) 2022.11Reviewed International journal

Uno Y, Ushirozako G, Uehara S, Murayama N, Fujiki Y, Kawaguchi H, Tsukiyama-Kohara K, Yamazaki H . Newly identified tree shrew cytochrome P450 2B6 (CYP2B6) and pig CYP2B6b are functional drug-metabolising enzymes. . Xenobiotica; the fate of foreign compounds in biological systems 1 - 10 2022.11Reviewed International journal

Kayesh MEH, Hashem MA, Maetani F, Goto A, Nagata N, Kasori A, Imanishi T, Tsukiyama-Kohara K . Molecular Insights into Innate Immune Response in Captive Koala Peripheral Blood Mononuclear Cells Co-Infected with Multiple Koala Retrovirus Subtypes. . Pathogens (Basel, Switzerland)11 ( 8 ) 2022.8Reviewed International journal

Characterization of host factors associated with the internal ribosomal entry sites of foot-and-mouth disease and classical swine fever viruses. . 12 ( 1 ) 6709 2022.4Reviewed International coauthorship

Kayesh MEH, Kohara M, Tsukiyama-Kohara K . An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants. . Viruses13 ( 11 ) 2021.11Reviewed International journal

Kayesh MEH, Sanada T, Kohara M, Tsukiyama-Kohara K . Tree Shrew as an Emerging Small Animal Model for Human Viral Infection: A Recent Overview. . Viruses13 ( 8 ) 2021.8Reviewed International journal

Hashem MA, Kayesh MEH, Maetani F, Eiei T, Mochizuki K, Ochiai S, Ito A, Ito N, Sakurai H, Asai T, Tsukiyama-Kohara K . Koala retrovirus (KoRV) subtypes and their impact on captive koala (Phascolarctos cinereus) health. . Archives of virology166 ( 7 ) 1893 - 1901 2021.7Reviewed International journal

Makoto Saito1,*, Yasushi Itoh2,*, Fumihiko Yasui1,*, Tsubasa Munakata1, Daisuke Yamane1, Makoto Ozawa3, Risa Ito4, Takayuki Katoh4, Hirohito Ishigaki2, Misako Nakayama2, Shintaro Shichinohe2, Kenzaburo Yamaji1, Naoki Yamamoto1, Ai Ikejiri1, Tomoko Honda1, Takahiro Sanada1, Yoshihiro Sakoda5, Hiroshi Kida6, Le Thi Quynh Mai7, Yoshihiro Kawaoka8, Kazumasa Ogasawara2, Kyoko Tsukiyama-Kohara3,†, Hiroaki Suga4,†, and Michinori Kohara . Targeted macrocycles hamper hemagglutinin adsorption and fusion, and have antiviral effects in murine and macaque models of influenza . Nature Communications12 ( 1 ) 2654 2021.5Reviewed International coauthorship

Abounouh K. . Blocking neddylation elicits antiviral effect against hepatitis B virus replication . Molecular Biology Reports 2021Reviewed International journal

Takagi A, Amako Y, Yamane D, Kitab B, Tokunaga Y, El-Gohary A, Kohara M, Tsukiyama-Kohara K . Longer Poly(U) Stretches in the 3'UTR Are Essential for Replication of the Hepatitis C Virus Genotype 4a Clone in <i>in vitro</i> and <i>in vivo</i>. . Frontiers in microbiology12 764816 2021Reviewed International journal

Kayesh M.E.H. . Mammalian animal models for dengue virus infection: a recent overview . Archives of Virology167 ( 1 ) 31 - 44 2021Reviewed International journal

Mohammad Enamul Hoque Kayesh, Michinori Kohara, Kyoko Tsukiyama-Kohara . Toll-like Receptor Response to Human Immunodeficiency Virus Type 1 or Co-Infection with Hepatitis B or C Virus: An Overview. . International journal of molecular sciences24 ( 11 ) 2023.6Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors that play important roles in the early detection of pathogen-associated molecular patterns and shaping innate and adaptive immune responses, which may influence the consequences of infection. Similarly to other viral infections, human immunodeficiency virus type 1 (HIV-1) also modulates the host TLR response; therefore, a proper understanding of the response induced by human HIV-1 or co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), due to the common mode of transmission of these viruses, is essential for understanding HIV-1 pathogenesis during mono- or co-infection with HBV or HCV, as well as for HIV-1 cure strategies. In this review, we discuss the host TLR response during HIV-1 infection and the innate immune evasion mechanisms adopted by HIV-1 for infection establishment. We also examine changes in the host TLR response during HIV-1 co-infection with HBV or HCV; however, this type of study is extremely scarce. Moreover, we discuss studies investigating TLR agonists as latency-reverting agents and immune stimulators towards new strategies for curing HIV. This understanding will help develop a new strategy for curing HIV-1 mono-infection or co-infection with HBV or HCV.

DOI： 10.3390/ijms24119624

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Mohammad Enamul Hoque Kayesh, Md Abul Hashem, Takahiro Sanada, Bouchra Kitab, Md Haroon Or Rashid, Lipi Akter, Sayeh Ezzikouri, Shuko Murakami, Shintaro Ogawa, Yasuhito Tanaka, Michinori Kohara and Kyoko Tsukiyama-Kohara . Characterization of innate immune response to hepatitis B virus genotype F acute infection in tree shrew (Tupaia belangeri) model . Frontiers in Virology2 926831 2022.8Reviewed International coauthorship International journal

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers Media SA

Hepatitis B virus (HBV) infection is a global public health problem. The clinical outcomes of HBV infections are influenced by host as well as viral factors, including viral genotypes and subgenotypes. The interplay between HBV and host innate immunity remains unclear because of the lack of a suitable small animal model. Tree shrews (Tupaia belangeri) have been utilized as a useful animal model for hepatitis viruses such as hepatitis B and C viruses. In this study, we characterized acute infections by HBV genotype F (HBV-F) wild type (Wt) and mutant type (Mt) viruses in adult tree shrews. Serum alanine aminotransferase levels were measured before and post- infection 7 and 14 dpi. Both HBV-F-Wt and Mt were detected in the HBV-F-infected tree shrew serum and liver tissue at 7 and 14 dpi. We examined the intrahepatic expression patterns of Toll-like receptors (TLRs) (TLR1–9 mRNAs), cGAS, several transcription factors such as STAT1, STAT2, IRF7, HNF4, PD-L1, and cytokines, including IFN-β, IFN-γ, IL-6, and TNF-α in HBV-F Wt/Mt-infected tree shrews. When compared with uninfected animal group, significant suppression of TLR8 in HBV-F-Wt infected animals and significant suppression of PD-L1 in both HBV-F-Wt and Mt infected animals were observed. Thus, tree shrew can be a useful animal model to characterize HBV-F pathogenesis.

DOI： 10.3389/fviro.2022.926831

Md Abul Hashem, Mohammad Enamul Hoque Kayesh, Fumie Maetani, Atsushi Goto, Noriko Nagata, Aki Kasori, Tetsuya Imanishi, Kyoko Tsukiyama-Kohara . Subtype distribution and expression of the koala retrovirus in the Japanese zoo koala population. . Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases102 105297 - 105297 2022.8Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

We investigated the proviral copies and RNA expression in koala retrovirus (KoRV)-infected koalas. To ascertain any variation in viral load by institution, age, sex, or body condition score, we quantified KoRV proviral DNA and RNA loads in captive koalas (n = 37) reared in Japanese zoos. All koalas were positive for KoRV genes (pol, LTRs, and env of KoRV-A) in genomic DNA (gDNA), and 91.89% were positive for the pol gene in RNA. In contrast, the distribution rates of KoRV-B, KoRV-C, KoRV-D, and KoRV-F env genes in gDNA were 94.59%, 27.03%, 67.57%, and 54.05%, respectively. A wide inter-individual variation and/or a significant inter-institutional difference in proviral DNA (p < 0.0001) and RNA (p < 0.001) amounts (copies/103 koala β-actin copies) were observed in Awaji Farm England Hill Zoo koalas, which were obtained from southern koala populations, suggesting exogenous incorporation of KoRV in these koalas. Significant (p < 0.05) age differences were noted in KoRV RNA load (p < 0.05) and median total RNA load (p < 0.001), with loads higher in younger koalas (joeys and juveniles). Thus, the current study provides the distribution of KoRV subtypes in Japanese zoo koala populations and identifies several additional risk factors (sex, age, and body condition) associated with KoRV expression.

DOI： 10.1016/j.meegid.2022.105297

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Reverse vaccinology-based prediction of a multi-epitope SARS-CoV-2 vaccine and its tailoring to new coronavirus variants. . 2022.5Reviewed International coauthorship

Kayesh MEH, Kohara M, Tsukiyama-Kohara K. . Toll-like Receptor Response to Hepatitis C Virus Infection: A Recent Overview. . Int J Mol Sci.23 ( 10 ) 5475 2022.5Reviewed International coauthorship

Mohammad Enamul Hoque Kayesh, Michinori Kohara, Kyoko Tsukiyama-Kohara . Toll-like Receptor Response to Hepatitis C Virus Infection: A Recent Overview. . International journal of molecular sciences23 ( 10 ) 2022.5Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Hepatitis C virus (HCV) infection remains a major global health burden, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors that detect pathogen-associated molecular patterns and activate downstream signaling to induce proinflammatory cytokine and chemokine production. An increasing number of studies have suggested the importance of TLR responses in the outcome of HCV infection. However, the exact role of innate immune responses, including TLR response, in controlling chronic HCV infection remains to be established. A proper understanding of the TLR response in HCV infection is essential for devising new therapeutic approaches against HCV infection. In this review, we discuss the progress made in our understanding of the host innate immune response to HCV infection, with a particular focus on the TLR response. In addition, we discuss the mechanisms adopted by HCV to avoid immune surveillance mediated by TLRs.

DOI： 10.3390/ijms23105475

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Wahiba Ezzemani, Anass Kettani, Subrahmanyam Sappati, Kavya Kondaka, Hicham El Ossmani, Kyoko Tsukiyama-Kohara, Haya Altawalah, Rachid Saile, Michinori Kohara, Soumaya Benjelloun, Sayeh Ezzikouri . Reverse vaccinology-based prediction of a multi-epitope SARS-CoV-2 vaccine and its tailoring to new coronavirus variants. . Journal of biomolecular structure & dynamics 1 - 22 2022.5Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

The genome feature of SARS-CoV-2 leads the virus to mutate and creates new variants of concern. Tackling viral mutations is also an important challenge for the development of a new vaccine. Accordingly, in the present study, we undertook to identify B- and T-cell epitopes with immunogenic potential for eliciting responses to SARS-CoV-2, using computational approaches and its tailoring to coronavirus variants. A total of 47 novel epitopes were identified as immunogenic triggering immune responses and no toxic after investigation with in silico tools. Furthermore, we found these peptide vaccine candidates showed a significant binding affinity for MHC I and MHC II alleles in molecular docking investigations. We consider them to be promising targets for developing peptide-based vaccines against SARS-CoV-2. Subsequently, we designed two efficient multi-epitopes vaccines against the SARS-CoV-2, the first one based on potent MHC class I and class II T-cell epitopes of S (FPNITNLCPF-NYNYLYRLFR-MFVFLVLLPLVSSQC), M (MWLSYFIASF-GLMWLSYFIASFRLF), E (LTALRLCAY-LLFLAFVVFLLVTLA), and N (SPRWYFYYL-AQFAPSASAFFGMSR). The second candidate is the result of the tailoring of the first designed vaccine according to three classes of SARS-CoV-2 variants. Molecular docking showed that the protein-protein binding interactions between the vaccines construct and TLR2-TLR4 immune receptors are stable complexes. These findings confirmed that the final multi-epitope vaccine could be easily adapted to new viral variants. Our study offers a shortlist of promising epitopes that can accelerate the development of an effective and safe vaccine against the virus and its adaptation to new variants.Communicated by Ramaswamy H. Sarma.

DOI： 10.1080/07391102.2022.2075468

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Hashem MA, Kayesh MEH, Maetani F, Goto A, Nagata N, Kasori A, Imanishi T, Tsukiyama-Kohara K . Subtype distribution and expression of the koala retrovirus in the Japanese zoo koala population. . Infect Genet Evol. 105297 2022.5Reviewed International coauthorship

Yutaro Ide, Bouchra Kitab, Nobumasa Ito, Riai Okamoto, Yui Tamura, Takafumi Matsui, Yoshihiro Sakoda, Kyoko Tsukiyama-Kohara . Characterization of host factors associated with the internal ribosomal entry sites of foot-and-mouth disease and classical swine fever viruses. . Scientific reports12 ( 1 ) 6709 - 6709 2022.4Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Foot-and-mouth disease virus (FMDV) and classical swine fever virus (CSFV) possess positive-sense single-stranded RNA genomes and an internal ribosomal entry site (IRES) element within their 5'-untranslated regions. To investigate the common host factors associated with these IRESs, we established cell lines expressing a bicistronic luciferase reporter plasmid containing an FMDV-IRES or CSFV-IRES element between the Renilla and firefly luciferase genes. First, we treated FMDV-IRES cells with the French maritime pine extract, Pycnogenol (PYC), and examined its suppressive effect on FMDV-IRES activity, as PYC has been reported to have antiviral properties. Next, we performed microarray analysis to identify the host factors that modified their expression upon treatment with PYC, and confirmed their function using specific siRNAs. We found that polycystic kidney disease 1-like 3 (PKD1L3) and ubiquitin-specific peptidase 31 (USP31) were associated with FMDV-IRES activity. Moreover, silencing of these factors significantly suppressed CSFV-IRES activity. Thus, PKD1L3 and USP31 are host factors associated with the functions of FMDV- and CSFV-IRES elements.

DOI： 10.1038/s41598-022-10437-z

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Mohammad Enamul Hoque Kayesh, Md Abul Hashem, Michinori Kohara, Kyoko Tsukiyama-Kohara . In vivo Delivery Tools for Clustered Regularly Interspaced Short Palindromic Repeat/Associated Protein 9-Mediated Inhibition of Hepatitis B Virus Infection: An Update. . Frontiers in microbiology13 953218 - 953218 2022Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Chronic hepatitis B virus (HBV) infection remains a major global health problem despite the availability of an effective prophylactic HBV vaccine. Current antiviral therapies are unable to fully cure chronic hepatitis B (CHB) because of the persistent nature of covalently closed circular DNA (cccDNA), a replicative template for HBV, which necessitates the development of alternative therapeutic approaches. The CRISPR/Cas system, a newly emerging genome editing tool, holds great promise for genome editing and gene therapy. Several in vitro and/or in vivo studies have demonstrated the effectiveness of HBV-specific clustered regularly interspaced short palindromic repeat (CRISPR)/associated protein 9 (CRISPR/Cas9) systems in cleaving HBV DNA and cccDNA. Although recent advances in CRISPR/Cas technology enhance its prospects for clinical application against HBV infection, in vivo delivery of the CRISPR/Cas9 system at targets sites remains a major challenge that needs to be resolved before its clinical application in gene therapy for CHB. In the present review, we discuss CRISPR/Cas9 delivery tools for targeting HBV infection, with a focus on the development of adeno-associated virus vectors and lipid nanoparticle (LNP)-based CRISPR/Cas ribonucleoprotein (RNP) delivery to treat CHB. In addition, we discuss the importance of delivery tools in the enhancement of the antiviral efficacy of CRISPR/Cas9 against HBV infection.

DOI： 10.3389/fmicb.2022.953218

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Mohammad Enamul Hoque Kayesh, Michinori Kohara, Kyoko Tsukiyama-Kohara . Toll-Like Receptor Response to Hepatitis B Virus Infection and Potential of TLR Agonists as Immunomodulators for Treating Chronic Hepatitis B: An Overview. . International journal of molecular sciences22 ( 19 ) 2021.9Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Chronic hepatitis B virus (HBV) infection remains a major global health problem. The immunopathology of the disease, especially the interplay between HBV and host innate immunity, is poorly understood. Moreover, inconsistent literature on HBV and host innate immunity has led to controversies. However, recently, there has been an increase in the number of studies that have highlighted the link between innate immune responses, including Toll-like receptors (TLRs), and chronic HBV infection. TLRs are the key sensing molecules that detect pathogen-associated molecular patterns and regulate the induction of pro- and anti-inflammatory cytokines, thereby shaping the adaptive immunity. The suppression of TLR response has been reported in patients with chronic hepatitis B (CHB), as well as in other models, including tree shrews, suggesting an association of TLR response in HBV chronicity. Additionally, TLR agonists have been reported to improve the host innate immune response against HBV infection, highlighting the potential of these agonists as immunomodulators for enhancing CHB treatment. In this study, we discuss the current understanding of host innate immune responses during HBV infection, particularly focusing on the TLR response and TLR agonists as immunomodulators.

DOI： 10.3390/ijms221910462

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Islam Abbadi, Mustapha Lkhider, Bouchra Kitab, Khalid Jabboua, Imane Zaidane, Asmaa Haddaji, Sabrine Nacer, Aya Matsuu, Pascal Pineau, Kyoko Tsukiyama-Kohara, Soumaya Benjelloun, Sayeh Ezzikouri . Non-primate hepacivirus transmission and prevalence: Novel findings of virus circulation in horses and dogs in Morocco. . Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases93 104975 - 104975 2021.9Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Non-primate hepacivirus (NPHV) is a homolog of hepatitis C virus and has been isolated from dogs and horses. Data on NPHV prevalence and distribution are not complete, and there is a particular lack of reports from the African continent. The present study represents the first investigation of NPHV prevalence in horses and dogs in North Africa. Blood was collected from 172 horses and 36 dogs at different locations in Morocco, and screened for NPHV RNA using nested PCR targeting 5'UTR and NS3 regions and analyzed for anti-NPHV NS3 antibody using a Gaussia luciferase immunoprecipitation system-to determine seroprevalence. Eight sequences of the NS3 region isolated from positive serum samples were targeted for phylogenetic analysis. Horses and dogs showed respective NPHV RNA positivity rates of 10.5% and 5.5%, and seroprevalences of 65.7% and 8.33%. Juvenile horses appeared more susceptible to infection, with a 23.5% NHPV RNA positivity rate. Seropositivity was more extensive in mares than stallions (77.14% vs. 46.27%, p < 0.0001). Phylogenetically, that NPHV NS3 genes isolated from horses and dog are clustered together. The NPHV strains we detected showed no correlation with geographic location within Morocco. In conclusion, Moroccan horses showed much evidence of previous and/or current NPHV infection, with young age and female sex as noted potential risk factors. Interestingly, NPHV is circulating in dogs as well as horses, suggesting that it has crossed species barriers and that horses and dogs are potential vectors by which an ancestor to hepatitis C virus was transmitted into human populations.

DOI： 10.1016/j.meegid.2021.104975

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ケアシュ・モハメド, 尼子豊, ハシェム・モハメド, 山本直樹, 杉山真也, 溝上雅史, 小原道法, 小原恭子 . B型肝炎ウイルスcccDNAを標的としたCRISPR/Cas9システムの生体内送達法の開発 . 日本癌学会総会記事80回 [J3 - 5] 2021.9Reviewed International journal

Honda T, Gomi S, Yamane D, Yasui F, Yamamoto T, Munakata T, Itoh Y, Ogasawara K, Sanada T, Yamaji K, Yasutomi Y, Tsukiyama-Kohara K, Kohara M. . Development and Characterization of a Highly Sensitive NanoLuciferase-Based Immunoprecipitation System for the Detection of Anti-Influenza Virus HA . mSphere6 ( 3 ) e1342-20 2021.5Reviewed

Tomoko Honda, Sumiko Gomi, Daisuke Yamane, Fumihiko Yasui, Takuya Yamamoto, Tsubasa Munakata, Yasushi Itoh, Kazumasa Ogasawara, Takahiro Sanada, Kenzaburo Yamaji, Yasuhiro Yasutomi, Kyoko Tsukiyama-Kohara, Michinori Kohara . Development and Characterization of a Highly Sensitive NanoLuciferase-Based Immunoprecipitation System for the Detection of Anti-Influenza Virus HA Antibodies. . mSphere6 ( 3 ) 1 - 14 2021.5Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Antibody detection is crucial for monitoring host immune responses to specific pathogen antigens (Ags) and evaluating vaccine efficacies. The luciferase immunoprecipitation system (LIPS) was developed for sensitive detection of Ag-specific antibodies in sera from various species. In this study, we describe NanoLIPS, an improved LIPS assay based on NanoLuciferase (NLuc), and employ the assay for monitoring antibody responses following influenza virus infection or vaccination. We generated recombinant influenza virus hemagglutinin (HA) proteins tagged with N-terminal (N-NLuc-HA) or C-terminal (C-NLuc-HA) NLuc reporters. NLuc-HA yielded an at least 20-fold higher signal-to-noise ratio than did a LIPS assay employing a recombinant HA-Gaussia princeps luciferase (GLuc) fusion protein. NanoLIPS-based detection of anti-HA antibodies yielded highly reproducible results with a broad dynamic range. The levels of antibodies against C-NLuc-HA generated by mice vaccinated with recombinant vaccinia virus DIs strain expressing an influenza virus HA protein (rDIs-HA) was significantly correlated with the protective effect elicited by the rDIs-HA vaccine. C-NLuc-HA underwent glycosylation with native conformations and assembly to form a trimeric structure and was detected by monoclonal antibodies that detect conformational epitopes present on the globular head or stalk domain of HA. Therefore, NanoLIPS is applicable for evaluating vaccine efficacy. We also showed that C-NLuc-HA is applicable for detection of HA-specific antibodies in sera from various experimental species, including mouse, cynomolgus macaque, and tree shrew. Thus, NanoLIPS-based detection of HA offers a simple and high-sensitivity method that detects native conformational epitopes and can be used in various experimental animal models.IMPORTANCE Influenza virus HA-specific antibodies can be detected via the hemagglutination inhibition (HI) assay, the neutralization (NT) assay, and the enzyme-linked immunosorbent assay (ELISA). However, these assays have some drawbacks, including narrow dynamic range and the requirement for large amounts of sera. As an alternative to an ELISA-based method, luciferase immunoprecipitation system (LIPS) was developed. We focused on NanoLuciferase (NLuc), which has a small size, higher intensity, and longer stability. In this study, we developed a technically feasible and highly sensitive method for detecting influenza virus-specific antibodies using a NLuc-tagged recombinant HA protein produced in mammalian cells. HA with a C-terminal NLuc extension (C-NLuc-HA) was glycosylated and formed trimeric complexes when expressed in mammalian cells. Furthermore, C-NLuc-HA was recognized not only by monoclonal antibodies that bind to the globular head domain but also by those that bind to the stalk domain. We also demonstrated that the data obtained by this assay correlate with the protection of an experimental vaccine in animal models.

DOI： 10.1128/mSphere.01342-20

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Makoto Saito, Yasushi Itoh, Fumihiko Yasui, Tsubasa Munakata, Daisuke Yamane, Makoto Ozawa, Risa Ito, Takayuki Katoh, Hirohito Ishigaki, Misako Nakayama, Shintaro Shichinohe, Kenzaburo Yamaji, Naoki Yamamoto, Ai Ikejiri, Tomoko Honda, Takahiro Sanada, Yoshihiro Sakoda, Hiroshi Kida, Thi Quynh Mai Le, Yoshihiro Kawaoka, Kazumasa Ogasawara, Kyoko Tsukiyama-Kohara, Hiroaki Suga, Michinori Kohara . Macrocyclic peptides exhibit antiviral effects against influenza virus HA and prevent pneumonia in animal models. . Nature communications12 ( 1 ) 2654 - 2654 2021.5Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Most anti-influenza drugs currently used, such as oseltamivir and zanamivir, inhibit the enzymatic activity of neuraminidase. However, neuraminidase inhibitor-resistant viruses have already been identified from various influenza virus isolates. Here, we report the development of a class of macrocyclic peptides that bind the influenza viral envelope protein hemagglutinin, named iHA. Of 28 iHAs examined, iHA-24 and iHA-100 have inhibitory effects on the in vitro replication of a wide range of Group 1 influenza viruses. In particular, iHA-100 bifunctionally inhibits hemagglutinin-mediated adsorption and membrane fusion through binding to the stalk domain of hemagglutinin. Moreover, iHA-100 shows powerful efficacy in inhibiting the growth of highly pathogenic influenza viruses and preventing severe pneumonia at later stages of infection in mouse and non-human primate cynomolgus macaque models. This study shows the potential for developing cyclic peptides that can be produced more efficiently than antibodies and have multiple functions as next-generation, mid-sized biomolecules.

DOI： 10.1038/s41467-021-22964-w

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Toll-Like Receptor and Cytokine Responses to Infection with Endogenous and Exogenous Koala Retrovirus, and Vaccination as a Control Strategy . Curr Issues Mol Biol. 43 ( 1 ) 52 - 64 2021.4Reviewed International coauthorship

Md Abul Hashem1, 2, 3, Mohammad Enamul Hoque Kayesh1, 2, 4, Fumie Maetani5, Taiki Eiei5, Kyoya Mochizuki5, Shinsaku Ochiai5, Ayaka Ito5, Nanao Ito5, Hiroko Sakurai5, Takayuki Asai5 and Kyoko Tsukiyama-Kohara . Koala retrovirus (KoRV) subtypes and their impact on captive koala (Phascolarctos cinereus) health . Archives of Virologyaccepted 2021.4Reviewed

Mohammad Enamul Hoque Kayesh 1,2 , Md Abul Hashem 1,3,4 and Kyoko Tsukiyama-Kohara . Toll-Like Receptor Expression Profiles in Koala (Phascolarctos cinereus) Peripheral Blood Mononuclear Cells Infected with Multiple KoRV Subtypes . 11 983 2021.4Reviewed

Mohammad Enamul Hoque Kayesh, Md Abul Hashem, Kyoko Tsukiyama-Kohara . Toll-Like Receptor Expression Profiles in Koala (Phascolarctos cinereus) Peripheral Blood Mononuclear Cells Infected with Multiple KoRV Subtypes. . Animals : an open access journal from MDPI11 ( 4 ) 2021.4Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Toll-like receptors (TLRs), evolutionarily conserved pattern recognition receptors, play an important role in innate immunity by recognizing microbial pathogen-associated molecular patterns. Koala retrovirus (KoRV), a major koala pathogen, exists in both endogenous (KoRV-A) and exogenous forms (KoRV-B to J). However, the expression profile of TLRs in koalas infected with KoRV-A and other subtypes is yet to characterize. Here, we investigated TLR expression profiles in koalas with a range of subtype infection profiles (KoRV-A only vs. KoRV-A with KoRV-B and/or -C). To this end, we cloned partial sequences for TLRs (TLR2-10 and TLR13), developed real-time PCR assays, and determined TLRs mRNA expression patterns in koala PBMCs and/or tissues. All the reported TLRs for koala were expressed in PBMCs, and variations in TLR expression were observed in koalas infected with exogenous subtypes (KoRV-B and KoRV-C) compared to the endogenous subtype (KoRV-A) only, which indicates the implications of TLRs in KoRV infection. TLRs were also found to be differentially expressed in koala tissues. This is the first report of TLR expression profiles in koala, which provides insights into koala's immune response to KoRV infection that could be utilized for the future exploitation of TLR modulators in the maintenance of koala health.

DOI： 10.3390/ani11040983

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Nagai M, Okabayashi T, Akagami M, Matsuu A, Fujimoto Y, Hashem MA, Mekata H, Nakao R, Matsuno K, Katayama Y, Oba M, Omatsu T, Asai T, Nakagawa K, Ito H, Madarame H, Kawai K, Ito T, Nonaka N, Tsukiyama-Kohara K, Inoshima Y, Mizutani T, Misawa N. . Metagenomic identification, sequencing, and genome analysis of porcine hepe-astroviruses (bastroviruses) in porcine feces in Japan . Infect Genet Evol.88 104664 2021.3Reviewed

Makoto Nagai, Tamaki Okabayashi, Masataka Akagami, Aya Matsuu, Yoshikazu Fujimoto, Md Abul Hashem, Hirohisa Mekata, Ryo Nakao, Keita Matsuno, Yukie Katayama, Mami Oba, Tsutomu Omatsu, Tetsuo Asai, Keisuke Nakagawa, Hiroshi Ito, Hiroo Madarame, Kazuhiro Kawai, Toshihiro Ito, Nariaki Nonaka, Kyoko Tsukiyama-Kohara, Yasuo Inoshima, Tetsuya Mizutani, Naoaki Misawa . Metagenomic identification, sequencing, and genome analysis of porcine hepe-astroviruses (bastroviruses) in porcine feces in Japan. . Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases88 104664 - 104664 2021.3Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Recently, hepe-astrovirus-like RNA viruses named bastroviruses (BastVs), have been found in human, pig, bat, and rat fecal samples. In this study, we determined nearly complete genome sequences of four BastVs in the feces of healthy pigs. Genetic characterization revealed that these porcine BastVs (PBastVs) and BastVs from other animals including humans, had the same genome organization, that is, they contained three predicted conserved domains of viral methyltransferase, RNA helicase, and RdRp in the nonstructural ORF1 and the astrovirus capsid domain in the structural ORF2. Phylogenetic analyses using RNA-dependent RNA polymerase and the capsid region revealed that PBastVs branched with bat and rat BastVs; however, the groups formed by each host were distantly related to human BastVs. Pairwise amino acid sequence comparison demonstrated that PBastVs shared 95.2-98.6% and 76.1-95.5% sequence identity among each other in the ORF1 and ORF2 regions, respectively; the sequence identities between PBastVs and BastVs from other animals were 21.4-42.5% and 9.1-20.6% in the ORF1 and ORF2 regions, respectively. This suggested that BastVs were derived from a common ancestor but evolved independently in each host population during a prolonged period. Putative recombination events were identified in the PBastV genome, suggesting that PBastVs gain sequence diversity and flexibility through recombination events. In an analysis of previously obtained metagenomic data, PBastV sequence reads were detected in 7.3% (23/315) of fecal samples from pigs indicating that PBastVs are distributed among pig populations in Japan.

DOI： 10.1016/j.meegid.2020.104664

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Suzuki Y, Onuma H, Sato R, Sato Y, Hashiba A, Maeki M, Tokeshi M, Kayesh MEH, Kohara M, Tsukiyama-Kohara K, Harashima H. . Lipid nanoparticles loaded with ribonucleoprotein-oligonucleotide complexes synthesized using a microfluidic device exhibit robust genome editing and hepatitis B virus inhibition. . 330 67 - 71 2021.2Reviewed

Yuichi Suzuki, Haruno Onuma, Risa Sato, Yusuke Sato, Akari Hashiba, Masatoshi Maeki, Manabu Tokeshi, Mohammad Enamul Hoque Kayesh, Michinori Kohara, Kyoko Tsukiyama-Kohara, Hideyoshi Harashima . Lipid nanoparticles loaded with ribonucleoprotein-oligonucleotide complexes synthesized using a microfluidic device exhibit robust genome editing and hepatitis B virus inhibition. . Journal of controlled release : official journal of the Controlled Release Society330 61 - 71 2021.2Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

The clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) system has considerable therapeutic potential for use in treating a wide range of intractable genetic and infectious diseases including hepatitis B virus (HBV) infections. While non-viral delivery technologies for the CRISPR/Cas system are expected to have clinical applications, difficulties associated with the clinically relevant synthesis of formulations and the poor efficiency of delivery severely hinder therapeutic genome editing. We report herein on the production of a lipid nanoparticle (LNP)-based CRISPR/Cas ribonucleoprotein (RNP) delivery nanoplatform synthesized using a clinically relevant mixer-equipped microfluidic device. DNA cleavage activity and the aggregation of Cas enzymes was completely avoided under the optimized synthetic conditions. The optimized formulation, which was identified through 2 steps of design of experiments, exhibited excellent gene disruption (up to 97%) and base substitution (up to 23%) without any apparent cytotoxicity. The addition of negative charges to the RNPs by complexing single-stranded oligonucleotide (ssON) significantly enhanced the delivery of both Cas9 and Cpf1 RNPs. The optimized formulation significantly suppressed both HBV DNA and covalently closed circular DNA (cccDNA) in HBV-infected human liver cells compared to adeno-associated virus type 2 (AAV2). These findings represent a significant contribution to the development of CRISPR/Cas RNP delivery technology and its practical applications in genome editing therapy.

DOI： 10.1016/j.jconrel.2020.12.013

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Mohammad Enamul Hoque Kayesh, Michinori Kohara, Kyoko Tsukiyama-Kohara . Recent Insights Into the Molecular Mechanism of Toll-Like Receptor Response to Dengue Virus Infection. . Frontiers in microbiology12 744233 - 744233 2021Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Dengue is the most prevalent and rapidly spreading mosquito-borne viral disease caused by dengue virus (DENV). Recently, DENV has been affecting humans within an expanding geographic range due to the warming of the earth. Innate immune responses play a significant role in antiviral defense, and Toll-like receptors (TLRs) are key regulators of innate immunity. Therefore, a detailed understanding of TLR and DENV interactions is important for devising therapeutic and preventive strategies. Several studies have indicated the ability of DENV to modulate the TLR signaling pathway and host immune response. Vaccination is considered one of the most successful medical interventions for preventing viral infections. However, only a partially protective dengue vaccine, the first licensed dengue vaccine CYD-TDV, is available in some dengue-endemic countries to protect against DENV infection. Therefore, the development of a fully protective, durable, and safe DENV vaccine is a priority for global health. Here, we demonstrate the progress made in our understanding of the host response to DENV infection, with a particular focus on TLR response and how DENV avoids the response toward establishing infection. We also discuss dengue vaccine candidates in late-stage development and the issues that must be overcome to enable their success.

DOI： 10.3389/fmicb.2021.744233

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CD4, CD8b, and Cytokines Expression Profiles in Peripheral Blood Mononuclear Cells Infected with Different Subtypes of KoRV from Koalas (Phascolarctos cinereus) in a Japanese Zoo. . Viruses12 ( 12 ) 1415 2020.12

Mohammad Enamul Hoque Kayesh, Md Abul Hashem, Fumie Maetani, Taiki Eiei, Kyoya Mochizuki, Shinsaku Ochiai, Ayaka Ito, Nanao Ito, Hiroko Sakurai, Takayuki Asai, Kyoko Tsukiyama-Kohara . CD4, CD8b, and Cytokines Expression Profiles in Peripheral Blood Mononuclear Cells Infected with Different Subtypes of KoRV from Koalas (Phascolarctos cinereus) in a Japanese Zoo. . Viruses12 ( 12 ) 2020.12Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Koala retrovirus (KoRV) poses a major threat to koala health and conservation, and currently has 10 identified subtypes: an endogenous subtype (KoRV-A) and nine exogenous subtypes (KoRV-B to KoRV-J). However, subtype-related variations in koala immune response to KoRV are uncharacterized. In this study, we investigated KoRV-related immunophenotypic changes in a captive koala population (Hirakawa zoo, Japan) with a range of subtype infection profiles (KoRV-A only vs. KoRV-A with KoRV-B and/or -C), based on qPCR measurements of CD4, CD8b, IL-6, IL-10 and IL-17A mRNA expression in unstimulated and concanavalin (Con)-A-stimulated peripheral blood mononuclear cells (PBMCs). Although CD4, CD8b, and IL-17A expression did not differ between KoRV subtype infection profiles, IL-6 expression was higher in koalas with exogenous infections (both KoRV-B and KoRV-C) than those with the endogenous subtype only. IL-10 expression did not significantly differ between subtype infection profiles but did show a marked increase-accompanying decreased CD4:CD8b ratio-in a koala with lymphoma and co-infected with KoRV-A and -B, thus suggesting immunosuppression. Taken together, the findings of this study provide insights into koala immune response to multiple KoRV subtypes, which can be exploited for the development of prophylactic and therapeutic interventions for this iconic marsupial species.

DOI： 10.3390/v12121415

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Ezzikouri S, Nourlil J, Benjelloun S, Kohara M, Tsukiyama-Kohara K. . Coronavirus disease 2019-Historical context, virology, pathogenesis, immunotherapy, and vaccine development. . Hum Vaccin Immunother. 16 ( 12 ) 2992 - 3000 2020.12Invited Reviewed

Kayesh MEH, Amako Y, Hashem MA, Murakami S, Ogawa S, Yamamoto N, Hifumi T, Miyoshi N, Sugiyama M, Tanaka Y, Mizokami M, Kohara M, Tsukiyama-Kohara K. . Development of an in vivo delivery system for CRISPR/Cas9-mediated targeting of hepatitis B virus cccDNA . Virus Research290 198191 2020.12Reviewed

Sayeh Ezzikouri, Jalal Nourlil, Soumaya Benjelloun, Michinori Kohara, Kyoko Tsukiyama-Kohara . Coronavirus disease 2019-Historical context, virology, pathogenesis, immunotherapy, and vaccine development. . Human vaccines & immunotherapeutics16 ( 12 ) 2992 - 3000 2020.12Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

The current Coronavirus Disease 2019 (COVID-19) pandemic is causing great alarm around the world. The pathogen for COVID-19 - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - is the seventh known coronavirus to cause pneumonia in humans. While much remains unknown about SARS-CoV-2, physicians and researchers have begun to publish relevant findings, and much evidence is available on coronaviruses previously circulating in human and animal populations. In this review, we situate COVID-19 in its context as a transboundary viral disease, and provide a comprehensive discussion focused on the discovery, spread, virology, pathogenesis, and clinical features of this disease, its causative coronaviral pathogen, and approaches to combating the disease through immunotherapies and other treatments and vaccine development. An epidemiological survey revealed a potentially large number of asymptomatic SARS-CoV-2 carriers within the population, which may hamper efforts against COVID-19. Finally, we emphasize that vaccines against SARS-CoV-2, which may be developed by 2021, will be essential for prevention of COVID-19.

DOI： 10.1080/21645515.2020.1787068

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Elmessaoudi-Idrissi M, Tsukiyama-Kohara K, Nourlil J, Kettani A, Windisch MP, Kohara M, Malik YS, Dhama K, Benjelloun S, Ezzikouri S. . Structure-guided discovery approach identifies potential lead compounds targeting M pro of SARS-CoV-2 . Virusdisease 2020.11Reviewed

Sayeh Ezzikouri, Jalal Nourlil, Kyoko Tsukiyama-Kohara, Michinori Kohara, Hicham El Ossmani, Marc P Windisch, Soumaya Benjelloun . Nanobodies: an unexplored opportunity to combat COVID-19. . Journal of biomolecular structure & dynamics 1 - 3 2020.11Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). This virus is capable of human-to-human transmission, and is spreading rapidly round the globe, with markedly high fatality rates. Unfortunately, there are neither vaccines nor specific therapies available to combat it, and the developments of such approaches depend on pursuing multiple avenues in biomedical science. Accordingly, in this paper we highlight one such avenue-nanobodies-for potential utility in therapeutic and diagnostic interventions to combat COVID-19.Communicated by Ramaswamy H. Sarma.

DOI： 10.1080/07391102.2020.1845801

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Kayesh MEH, Hashem MA, Tsukiyama-Kohara K. . Koala retrovirus epidemiology, transmission mode, pathogenesis, and host immune response in koalas (Phascolarctos cinereus): a review. . Arch Virol. 165 ( 11 ) 2409 - 2417 2020.11Invited Reviewed

Ezzikouri S, Nourlil J, Tsukiyama-Kohara K, Kohara M, El Ossmani H, Windisch MP, Benjelloun S. . Nanobodies: an unexplored opportunity to combat COVID-19 . J Biomol Struct Dyn.10 1 - 3 2020.11Reviewed

Mohammad Enamul Hoque Kayesh, Md Abul Hashem, Kyoko Tsukiyama-Kohara . Koala retrovirus epidemiology, transmission mode, pathogenesis, and host immune response in koalas (Phascolarctos cinereus): a review. . Archives of virology165 ( 11 ) 2409 - 2417 2020.11Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Koala retrovirus (KoRV) is a major threat to koala health and conservation. It also represents a series of challenges across the fields of virology, immunology, and epidemiology that are of great potential interest to any researcher in the field of retroviral diseases. KoRV is a gammaretrovirus that is present in both endogenous and exogenous forms in koala populations, with a still-active endogenization process. KoRV may induce immunosuppression and neoplastic conditions such as lymphoma and leukemia and play a role in chlamydiosis and other diseases in koalas. KoRV transmission modes, pathogenesis, and host immune response still remain unclear, and a clear understanding of these areas is critical for devising effective preventative and therapeutic strategies. Research on KoRV is clearly critical for koala conservation. In this review, we provide an overview of the current understanding and future challenges related to KoRV epidemiology, transmission mode, pathogenesis, and host immune response and discuss prospects for therapeutic and preventive vaccines.

DOI： 10.1007/s00705-020-04770-9

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Hashem MA, Maetani F, Kayesh MEH, Eiei T, Mochizuki K, Ito A, Sakurai H, Asai T, Tsukiyama-Kohara K. . Transmission of koala retrovirus from parent koalas to a joey in a Japanese zoo. . Journal of Virolgy94 ( 11 ) e0019-20 2020.5Reviewed

Chi Hai-Ying, Yuuki Tanaka, Tatsuro Hifumi, Ko-ichiro Shoji, Mohammad Enamul Hoque Kayesh, Md Abul Hashem, Bouchra Kitab, Takahiro Sanada, Tomoko Fujiyuki, Misako Yoneda, Hitoshi Hatai, Akira Yabuki, Noriaki Miyoshi, Chieko Kai, Michinori Kohara, Kyoko Tsukiyama-Kohara . Pathological and genetic aspects of spontaneous mammary gland tumor in Tupaia belangeri (Tree shrew) . PLoS One15 ( 5 ) e0233232 2020.5Reviewed

Sayeh Ezzikouri, Mohammad Enamul Hoque Kayesh, Soumaya Benjelloun, Michinori Kohara and Kyoko Tsukiyama-Kohara . Targeting host innate and adaptive immunity to achieve the functional cure of chronic hepatitis B . Vaccines8 ( 2 ) E216 2020.5Reviewed

Mohammad Enamul Hoque Kayesh 1,2 , Md Abul Hashem 1, Bouchra Kitab 1 and Kyoko Tsukiyama-Kohara . Pathogenesis and Immune Response Caused by Vector-Borne and Other Viral Infections in a Tupaia Model . microorganism 2019.12Invited Reviewed

Sanada T, Yamamoto N, Kayesh MEH, Tsukiyama-Kohara K, Hasegawa H, Miyazaki T, Takano JI, Shiogama Y, Yasutomi Y, Goh Y, Yoshida O, Hiasa Y, Kohara M. . Intranasal vaccination with HBs and HBc protein combined with carboxyl vinyl polymer induces strong neutralizing antibody, anti-HBs IgA, and IFNG response. . Biochem Biophys Res Commun.520 ( 1 ) 86 - 92 2019.11Reviewed

Takahiro Sanada, Naoki Yamamoto, Mohammad Enamul Hoque Kayesh, Kyoko Tsukiyama-Kohara, Hideki Hasegawa, Takashi Miyazaki, Jun-Ichiro Takano, Yumiko Shiogama, Yasuhiro Yasutomi, Yasumasa Goh, Osamu Yoshida, Yoichi Hiasa, Michinori Kohara . Intranasal vaccination with HBs and HBc protein combined with carboxyl vinyl polymer induces strong neutralizing antibody, anti-HBs IgA, and IFNG response. . Biochemical and biophysical research communications520 ( 1 ) 86 - 92 2019.11Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Hepatitis B virus (HBV) infection causes acute and chronic hepatitis, which is a major public health concern worldwide. Immunization methods incorporating hepatitis B surface-small (HBs-S) antigen and hepatitis B core antigen (HBc) have been proposed as candidate therapeutic vaccines, but the elimination of existing HBV infection remains a challenge. To enhance the efficacy of HBs and HBc vaccination, we investigated HBs-large (HBs-L) as an immunogen, and carboxyl vinyl polymer (CVP) as an excipient. HBs-S or HBs-L, in combination with HBc antigen, was administered subcutaneously (without CVP) or intranasally (with or without CVP) for the evaluation of immune response in the tree shrew, which is considered to be a suitable small animal model of HBV infection. Immunization with HBs-L antigen by either route induced a rapid IgG response. Intranasal immunization with HBs-S or HBs-L and HBc formulated with CVP strongly induced neutralizing antibody activity, IgA response, and HBc-specific expression of the interferon gamma-encoding gene. These data indicated the potential of HBs-L and HBc intranasal immunization with CVP, not only as a therapeutic vaccine, but also as a prophylactic vaccine candidate.

DOI： 10.1016/j.bbrc.2019.09.072

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Hashem MA, Kayesh MEH, Yamato O, Maetani F, Eiei T, Mochizuki K, Sakurai H, Ito A, Kannno H, Kasahara T, Amano Y, Tsukiyama-Kohara K. . Coinfection with koala retrovirus subtypes A and B and its impact on captive koalas in Japanese zoos. . Arch Virol. 164 ( 11 ) 2735 - 2745 2019.11Reviewed

Md Abul Hashem, Mohammad Enamul Hoque Kayesh, Osamu Yamato, Fumie Maetani, Taiki Eiei, Kyoya Mochizuki, Hiroko Sakurai, Ayaka Ito, Hiroki Kannno, Tatsuya Kasahara, Yusuke Amano, Kyoko Tsukiyama-Kohara . Coinfection with koala retrovirus subtypes A and B and its impact on captive koalas in Japanese zoos. . Archives of virology164 ( 11 ) 2735 - 2745 2019.11Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Koala retrovirus (KoRV) is unique among endogenous retroviruses because its endogenization is still active. Two major KoRV subtypes, KoRV-A and B, have been described, and KoRV-B is associated with disease and poses a health threat to koalas. Here, we investigated the co-prevalence of KoRV-A and KoRV-B, detected by type-specific PCR and sequencing, and their impact on the health of koalas in three Japanese zoos. We also investigated KoRV proviral loads and found varying amounts of genomic DNA (gDNA) in peripheral blood mononuclear cells (PBMCs). We found that 100% of the koalas examined were infected with KoRV-A and 60% (12/20) were coinfected with KoRV-B. The KoRV-A sequence was highly conserved, whereas the KoRV-B sequence varied among individuals. Interestingly, we observed possible vertical transmission of KoRV-B in one offspring in which the KoRV-B sequence was similar to that of the father but not the mother. Moreover, we characterized the KoRV growth patterns in concanavalin-A-stimulated PBMCs isolated from KoRV-B-coinfected or KoRV-B-uninfected koalas. We quantified the KoRV provirus in gDNA and the KoRV RNA copy numbers in cells and culture supernatants by real-time PCR at days 4, 7, and 14 post-seeding. As the study population is housed in captivity, a longitudinal study of these koalas may provide an opportunity to study the transmission mode of KoRV-B. In addition, we characterized KoRV isolates by infecting tupaia cells. The results suggested that tupaia may be used as an infection model for KoRV. Thus, this study may enhance our understanding of KoRV-B coinfection and transmission in the captive koalas.

DOI： 10.1007/s00705-019-04392-w

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PubMed

Sanada T, Tsukiyama-Kohara K, Shin-I T, Yamamoto N, Kayesh MEH, Yamane D, Takano JI, Shiogama Y, Yasutomi Y, Ikeo K, Gojobori T, Mizokami M, Kohara M. . Construction of complete Tupaia belangeri transcriptome database by whole-genome and comprehensive RNA sequencing. . Sci Rep. 9 ( 1 ) 12372 2019.8Reviewed

Takahiro Sanada, Kyoko Tsukiyama-Kohara, Tadasu Shin-I, Naoki Yamamoto, Mohammad Enamul Hoque Kayesh, Daisuke Yamane, Jun-Ichiro Takano, Yumiko Shiogama, Yasuhiro Yasutomi, Kazuho Ikeo, Takashi Gojobori, Masashi Mizokami, Michinori Kohara . Construction of complete Tupaia belangeri transcriptome database by whole-genome and comprehensive RNA sequencing. . Scientific reports9 ( 1 ) 12372 - 12372 2019.8Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

The northern tree shrew (Tupaia belangeri) possesses high potential as an animal model of human diseases and biology, given its genetic similarity to primates. Although genetic information on the tree shrew has already been published, some of the entire coding sequences (CDSs) of tree shrew genes remained incomplete, and the reliability of these CDSs remained difficult to determine. To improve the determination of tree shrew CDSs, we performed sequencing of the whole-genome, mRNA, and total RNA and integrated the resulting data. Additionally, we established criteria for the selection of reliable CDSs and annotated these sequences by comparison to the human transcriptome, resulting in the identification of complete CDSs for 12,612 tree shrew genes and yielding a more accurate tree shrew genome database (TupaiaBase: http://tupaiabase.org ). Transcriptome profiles in hepatitis B virus infected tree shrew livers were analyzed for validation. Gene ontology analysis showed enriched transcriptional regulation at 1 day post-infection, namely in the "type I interferon signaling pathway". Moreover, a negative regulator of type I interferon, SOCS3, was induced. This work, which provides a tree shrew CDS database based on genomic DNA and RNA sequencing, is expected to serve as a powerful tool for further development of the tree shrew model.

DOI： 10.1038/s41598-019-48867-x

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PubMed

Matsui T, Handa Y, Kanda T, Tsukiyama-Kohara K. . Silencing of the foot-and-mouth disease virus internal ribosomal entry site by targeting relatively conserved region among serotypes. . Virus Genes. 2019.7Reviewed

Kitab B, Satoh M, Ohmori Y, Munakata T, Sudoh M, Kohara M, Tsukiyama-Kohara K . Ribonucleotide reductase M2 promotes RNA replication of hepatitis C virus by protecting NS5B protein from hPLIC1-dependent proteasomal degradation. . J. Biol. Chem.294 ( 15 ) 5759 - 5773 2019.4Reviewed

Sanada T, Yasui F, Honda T, Kayesh MEH, Takano JI, Shiogama Y, Yasutomi Y, Tsukiyama-Kohara K, Kohara M. . Avian H5N1 influenza virus infection causes severe pneumonia in the Northern tree shrew (Tupaia belangeri). . Virology529 101 - 110 2019.3Reviewed

Kayesh MEH, Yamato O, Rahman MM, Hashem MA, Maetani F, Eiei T, Mochizuki K, Sakurai H, Tsukiyama-Kohara K. . Molecular dynamics of koala retrovirus infection in captive koalas in Japan. . Arch. Virol.164 ( 3 ) 757 - 765 2019.3Reviewed

Takahiro Sanada, Fumihiko Yasui, Tomoko Honda, Mohammad Enamul Hoque Kayesh, Jun-Ichiro Takano, Yumiko Shiogama, Yasuhiro Yasutomi, Kyoko Tsukiyama-Kohara, Michinori Kohara . Avian H5N1 influenza virus infection causes severe pneumonia in the Northern tree shrew (Tupaia belangeri). . Virology529 101 - 110 2019.3Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Avian-origin influenza viruses like H5N1 and H7N9 often cause severe symptoms with high mortality in humans. Animal models are useful for clarification of the mechanisms of pathogenicity of these infections. In this study, to expand the potential utility of the Northern tree shrew (Tupaia belangeri) for influenza virus infection, we assessed the pathogenicity of H5N1 and H7N9 avian influenza viruses in tupaia. Infectious virus was detected continuously from nasal, oral, tracheal, and conjunctival swab samples in the animals infected with these viruses. H5N1 influenza virus infection of tupaia caused severe diffuse pneumonia with fever and weight loss. In contrast, H7N9 influenza virus infection caused focal pneumonia. The severity of pneumonia was correlated with proinflammatory cytokine transcript levels. These results indicated that tupaia can be another suitable animal model for avian influenza virus research.

DOI： 10.1016/j.virol.2019.01.015

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PubMed

Kitab, B., Kohara, M., Tsukiyama-Kohara, K. . Experimental in vitro and in vivo systems for studying the innate immune response during dengue virus infections. . Arch Virol.163 ( 7 ) 1717 - 1726 2018.7Reviewed

Kyoko Tsukiyama-Kohara, Michinori Kohara . Hepatitis C Virus: Viral Quasispecies and Genotype . International Journal of Molecular Sciences19 ( 23 ) 1 - 8 2017.12Invited Reviewed

Kyoko Tsukiyama-Kohara, Michinori Kohara . Hepatitis C Virus: Viral Quasispecies and Genotypes. . International journal of molecular sciences19 ( 1 ) 2017.12Reviewed International journal

Language：English Publishing type：Research paper (scientific journal)

Hepatitis C virus (HCV) mainly replicates in the cytoplasm, where it easily establishes persistent infection, resulting in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Due to its high rate of mutation, HCV forms viral quasispecies, categorized based on the highly variable regions in the envelope protein and nonstructural 5A protein. HCV possesses seven major genotypes, among which genotype 1 is the most prevalent globally. The distribution of HCV genotypes varies based on geography, and each genotype has a different sensitivity to interferon treatment. Recently-developed direct-acting antivirals (DAAs), which target viral proteases or polymerases, mediate drastically better antiviral effects than previous therapeutics. Although treatment with DAAs has led to the development of drug-resistant HCV mutants, the most recently approved DAAs show improved pan-genomic activity, with a higher barrier to viral resistance.

DOI： 10.3390/ijms19010023

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PubMed

Nze-Nkogue C, Horie M, Fujita S, Inoue E, Akomo-Okoue EF, Ozawa M, Ngomanda A, Yamagiwa J, Tsukiyama-Kohara K. . Identification and molecular characterization of novel primate bocaparvoviruses from wild western lowland gorillas of Moukalaba-Doudou National Park, Gabon. . Infect Genet Evol.53 30 - 37 2017.9Reviewed

Chimene NZE NKOGUE . Epidemiological study of viruses infecting western lowland gorillas in Moukalaba-Doudou National Park (Gabon) . 2017.9Reviewed

Kayesh MEH, Ezzikouri S, Chi H, Sanada T, Hayashi, Y., Rebbani, K., Kitab, B., Matuu, A., Miyoshi, N., Hishima, T., Kohara, M., Tsukiyama-Kohara, K. . Oxidative Stress and Immune Responses During Hepatitis C Virus Infection in Tupaia belangeri. . Scientific Reports7 ( 1 ) 9848 - 9861 2017.8Reviewed

Kayesh ME*, Kitab B*, Sanada T, Hayasaka D, Morita K, Kohara M, Tsukiyama-Kohara K . Susceptibility of tupaia cells to dengue virus infection and their initial immune response. . Infection Genetics and Evolution51 203 - 210 2017.7Reviewed

KAYESH MEH, EZZIKOURI S, CHI H, SANADA T, YAMAMOTO N, KITAB B, HARAGUCHI T, MATUYAMA R, NKOGUE CN, HATAI H, MIYOSHI N, MURAKAMI S, TANAKA Y, TAKANO J, SHIOGAMA Y, YASUTOMI Y, KOHARA M, TSUKIYAMA-KOHARA K. . Interferon-β response is impaired by hepatitis B virus infection in Tupaia belangeri. . VIRUS RESEARCH237 47 - 57 2017.6Reviewed

Tokunaga Y, Osawa Y, Ohtsuki T, Hayashi Y, Yamaji K, Yamane D, Hara M, Munekata K, Tsukiyama-Kohara K, Hishima T, Kojima S, Kimura K, Kohara M. . Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model. . Sci Rep.7 ( 1 ) 325 2017.3Reviewed

Chime`ne Nze Nkogue, Masayuki Horie, Shiho Fujita, Michiko Ogino, Yuki Kobayashi, Keijiro Mizukami, Tatsunori Masatani, Sayeh Ezzikouri, Aya Matsuu, Tetsuya Mizutani, Makoto Ozawa, Osamu Yamato, Alfred Ngomanda, Juichi Yamagiwa, Kyoko Tsukiyama-Kohara . Molecular epidemiological study of adenovirus infecting western lowland gorillas and humans in and around Moukalaba-Doudou National Park (Gabon) . Virus Genes52 ( 5 ) 671 - 678 2016.10Reviewed

Sayeh Ezzikouri, Fatima Zahra Jadid, Salsabil Hamdi, Kyoko Tsukiyama-Kohara, Soumaya Benjelloun . Supplementation of Pycnogenol to conventional treatment may improve type 2 diabetes-associated with Hepatitis C Therapy . Journal of Clinical and Translational Hepatology4 ( 3 ) 228 - 233 2016.9Reviewed

Takahisa Kouwaki, Yoshimi Fukushima, Takuji Daito, Naoki Yamamoto, Edin J Mifsud, Chean Ring Leong, Kyoko Tsukiyama-Kohara, Michinori Kohara, Misako Matsumoto, Tsukasa Seya, Hiroyuki Oshiumi . Exosome RNA Released by Hepatocytes Regulates Innate Immune Responses to Hepatitis B Virus Infection . Frontiers in Immunology7 335 2016.8Reviewed

Hai-Ying C, Nagano K, Ezzikouri S, Yamaguchi C, Kayesh ME, Rebbani K, Kitab B, Nakano H, Kouji H, Kohara M, Tsukiyama-Kohara K. . Establishment of an intermittent cold stress model using Tupaia belangeri and evaluation of compound C737 targeting neuron-restrictive silencer factor. . Exp. Anim.65 ( 3 ) 285 - 292 2016.7Reviewed

Rebban, K & iTsukiyama-Kohara, K. . HCV-Induced Oxidative Stress: Battlefield-Winning Strategy . Oxidative Medicine and Cellular Longevity2016 ( 2016 ) 7425628 2016.5Invited Reviewed

Kanda T, Ozawa M, Tsukiyama-Kohara K . IRES-mediated translation of foot-andmouth disease virus (FMDV) in cultured cells derived from FMDV-susceptible and -insusceptible animals . BMC Veterinary Research12 66 2016.3Reviewed

Sanada, T., Tsukiyama-Kohara, K., Yamamoto, N., Ezzikouri, S., Benjelloun, S., Murakami, S., Tanaka, Y., Tateno, C., Kohara, M. . Property of hepatitis B virus replication in tupaia belangeri hepatocytes . BBRC8 ( 469 ) 229 - 235 2016.1Reviewed

Khadija Rhebbani, Kyoko Tsukiyama-Kohara . DHCR24:A Novel HCC Biomaker at a Glance . Clinical Microbiology4 ( 6 ) 1000228 2015.12Invited Reviewed

Masatani T, Ozawa M, Yamada K, Ito N, Horie M, Matsuu A, Okuya K, Tsukiyama-Kohara K, Sugiyama M, Nishizono A. . Contribution of the interaction between rabies virus P protein and IKKε to the inhibition of type I interferon induction signaling. . J Gen. Virol. 2015.12Reviewed

Ohtsuki T, Kimura K, Tokunaga Y, Tsukiyama-Kohara K, Tateno C, Hayashi Y, Hishima T, Kohara M. . M2 macrophages play critical roles in progression of inflammatory liver disease in hepatitis C virus transgenic mice. . J Virol.14 ( 90 ) 307 - 309 2015.10Reviewed

Okuya K, Kawabata T, Nagano K, Tsukiyama-Kohara K, Kusumoto I, Takase K, Ozawa M. . Isolation and characterization of influenza A viruses from environmental water at an overwintering site of migratory birds in Japan. . Arch Virol. 2015.9Reviewed

Full genome sequences of torque teno sus virus strains that coinfected a pig with postweaning multisystemic wasting syndrome in Japan: implications for genetic diversity. . 2015.9Reviewed

Miura R, Kooriyama T, Yoneda M, Takenaka A, Doki M, Goto Y, Sanjoba C, Endo Y, Fujiyuki T, Sugai A, Tsukiyama-Kohara K, Matsumoto Y, Sato H, Kai C. . Efficacy of Recombinant Canine Distemper Virus Expressing Leishmania Antigen against Leishmania Challenge in Dogs. . PLoS Negl Trop Dis.10 ( 9 ) e0003914 2015.7Reviewed

Matsuu A, Hobo S, Ando K, Sanekata T, Sato F, Endo Y, Amaya T, Osaki T, Horie M, Masatani T, Ozawa M, Tsukiyama-Kohara K . Genetic and serological surveillance for non-primate hepacivirus inhorses in Japan . Veterinary Microbiologyin press 2015.6Reviewed

Sayeh Ezzikouri, Kiminori Kimura, Hajime Sunagozaka, Shuichi Kaneko, Kazuaki Inoue, Tomohiro Nishimura, Tsunekazu Hishima, Michinori Kohara, and Kyoko Tsukiyama-Kohara . Serum DHCR24 auto-antibody as a new biomarker for progression of hepatitis C . EBioMedicine2 604 - 612 2015.4Reviewed

Makoto Saito, Takashi Takano, Tomohiro Nishimura, Michinori Kohara, Kyoko Tsukiyama-Kohara . 3β-Hydroxysterol Δ24-reductase on the Surface of Hepatitis C Virus-related Hepatocellular Carcinoma Cells can be a Target for Molecular Targeting Therapy . PLoS One e0124197 2015.4Reviewed

Ozawa M, Matsuu A, Yonezawa K, Igarashi M, Okuya K, Kawabata T, Ito K, Tsukiyama-Kohara K, Taneno A, Deguchi E. . Efficient isolation of Swine influenza viruses by age-targeted specimen collection. . J Clin Microbiol. 201553 ( 4 ) 1331 - 1338 2015.4Reviewed

新井　正明 . Establishment of evaluation systems of antiviral agents for hepatitis C virus and analysis of cyclophilin inhibitors as anti-HCV drugs . 2015.3Reviewed

Ezzikouri S, Nishimura T, Kohara M, Benjelloun S, Kino Y, Inoue K, Matsumori A, Tsukiyama-Kohara K . Inhibitory Effects of PycnogenolR on Hepatitis C Virus Replication . Antiviral Research113 93 - 102 2015.1Reviewed

Takenaka A, Yoneda M, Seki T, Uema M, Kooriyama T, Nishi T, Fujita K, Miura R, Tsukiyama-Kohara K, Sato H, Kai C. . Characterization of two recent Japanese field isolates of canine distemper virus and examination of the avirulent strain utility as an attenuated vaccine. . Vet Microbiol. 174 ( 42067 ) 372 - 381 2014.12Reviewed

Kyoko Tsukiyama-Kohara and Michinori Kohara . Tupaia belangeri as an experimental animal model for viral infection . Experimental Animal63 ( 4 ) 367 - 374 2014.10Reviewed

Mohammad Zare-Bidaki, Kyoko Tsukiyama-Kohara, Mohammad Kazemi Arababadi . Toll like receptor 4 and hepatitis B infection; molecular mechanisms and pathogenesis . Viral Immunology27 ( 7 ) 321 - 326 2014.9Reviewed

Ezzikouri S, Ozawa M, Kohara M, Elmdaghri N, Benjelloun S, Tsukiyama-Kohara K. . Recent insights into hepatitis B virus-host interactions. . J Med Virol.86 ( 6 ) 925 - 932 2014.6Reviewed

Arai M, Tsukiyama-Kohara K, Takagi A, Tobita Y, Inoue K, Kohara M. . Resistance to cyclosporin A derives from mutations in hepatitis C virus nonstructural proteins. . Biochem Biophys Res Commun.448 ( 1 ) 56 - 62 2014.5Reviewed

Kasama Y, Mizukami T, Kusunoki H, Peveling-Oberhag J, Nishito Y, Ozawa M, Kohara M, Mizuochi T, Tsukiyama-Kohara K. . B-Cell-Intrinsic Hepatitis C Virus Expression Leads to B-Cell-Lymphomagenesis and Induction of NF-κB Signalling. . PLos One9 ( 3 ) e91373 2014.3Reviewed

勝目朝夫 . Preclinical evaluation of an anti-interleukin 6 receptor antibody for Castleman's disease and a serene palmitoyltransferase inhibitor as an antiviral agent for hepatitis C virus . 2014.3Reviewed

Katsume A, Tokunaga Y, Hirata Y, Munakata T, Saito M, Hayashi H, Okamoto Y, Kusanagi I, Fujiwara S, Klumpp K, Tsukiyama-Kohara K, El-Gohary A, Sudoh M, Kohara M . A serine palmitoyltransferase inhibitor blocks hepatitis C virus replication in human hepatocytes . Gastroenterology145 865 - 873 2013.10Reviewed

Kyoko Tsukiyama-Kohara, Asao Katsume,Kazuhiro Kimura, Masayuki Saito, and MichinoriKohara . 4E-BP1 regulates the differentiation of white adipose tissue . Genes to Cells18 ( 7 ) 602 - 607 2013.7Reviewed

Nakagawa S, Hirata Y, Kameyama T, Tokunaga Y,Nishito Y, Yano J, Ochiya T, Tateno C, MizokamiM, Tsukiyama-Kohara K, Inoue K, Yoshiba M,Takaoka A, Kohara M. . Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virusinfection. . PLoS Onee59611 2013.3Reviewed

Salem NE, Saito M, Kasama Y, Ozawa M,Kawabata T, Harada S, Suda H, Asonuma K, El-Gohary A, Tsukiyama-Kohara, K. . Genomic polymorphisms in 3β-hydroxysterol Δ24-reductase promoter sequences. . Microbiol. Immunol.57 179 - 184 2013.3Reviewed

S. Sekiguchi, K. Kimura, T. Chiyo, T. Ohtsuki, Y. Tobita, Y. Tokunaga, F. Yasui, K. Tsukiyama-Kohara, T. Wakita, T. Tanaka, M. Miyasaka, K. Mizuno, Y. Hayashi, T. Hishima, K. Matsushima and M. Kohara . Immunization with a recombinant vaccinia virus that encodes nonstructural proteins of the hepatitis C virus suppresses viral protein levels in mouse liver. . Pros Onee51656 2012.11Reviewed

K. Inoue, K. Tsukiyama-Kohara, C. Matsuda, M. Yoneyama, T. Fujita, S. Kuge, M. Yoshiba, and *M. Kohara. . Impairment of interferon regulatory factor-3 activation by hepatitis C virus core protein basic amino acid region 1. . Biochem. Biophys. Res. Com. 428 494 - 499 2012.10Reviewed

Saito M, Kohara M, *Tsukiyama-Kohara K. . Hepatitis C virus promotes expression of the 3β-hydroxysterol δ24-reductase through Sp1. . Journal of Medical Virology84 ( 5 ) 733 - 746 2012.5Reviewed

Y. Kasama, M. Saito, T. Takano, T. Nishimura, M. Satoh, Z. Wang, S.N. E. S. Ali, S. Harada, M. Kohara, and *K. Tsukiyama-Kohara. . Translocase of outer mitochondrial membrane 70 induces interferon response and is impaired by hepatitis C virus NS3. . Virus Research 163 ( 1 ) 405 - 409 2012.1Reviewed

M. Satoh, M. Saito, T.Takano, Y. Kasama, T. Nishimura, Y. Nishito, Y. Hirata, M. Arai, M. Sudoh, C. Kai, M. Kohara and *K. Tsukiyama-Kohara . Monoclonal antibody 2-152a suppresses hepatitis C virus infection thorough betaine/GABA transporter-1. . Journal of Infectious Diseses204 1172 - 1180 2011.10Reviewed

T. Takano, *K. Tsukiyama-Kohara, M. Hayashi, Y. Hirata, M. Satoh, C. Tateno, Y. Hayashi, T. Hishima, N. Funata, M. Sudo, and M. Kohara. . Augmentation of DHCR24 expression by hepatitis C virus infection facilitates viral replication in hepatocytes. . Journal of Hepatology55 512 - 521 2011.8Reviewed

Y. Kasama, M. Satoh, M. Saito, S. Okada, C. Kai and *K. Tsukiyama-Kohara. . Evaluation of a recombinant measles virus as the expression vector of hepatitis C virs envelope proteins. . World Journal of Vaccine1 98 - 103 2011.8Reviewed

K. Tsukiyama-Kohara, S. Sekiguchi, Y. Kasama, N. E. S. Ali, K. Machida and M. Kohara . Hepatitis C virus-related lymphomagenesis in a mouse model. . ISRN Hematology2011 2011.6Reviewed

T. Takano, M. Kohara, M. Kasama, T. Nishimura, M. Saito, C. Kai and *K. Tsukiyama-Kohara . Translocase of outer mitochondrial membrane 70 expression is induced by hepatitis C virus and is related to the apoptotic response. . Journal of Medical Virology83 801 - 809 2011.3Reviewed

Selective translation of the measles virus nucleocapsid mRNA by la protein. Y. Inoue, H. Sato, K. Fujita, K. Tsukiyama-Kohara, M.Yoneda, and *C. Kai. . Selective translation of the measles virus nucleocapsid mRNA by la protein. . Front. Microbiol. 2 173 2011.1Reviewed

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Papers - Kyoko (Tsukiyama-)Kohara