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Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus.
J Virol. 2019 03 15; 93(6)JV

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) infection can manifest as a mild illness, acute respiratory distress, organ failure, or death. Several animal models have been established to study disease pathogenesis and to develop vaccines and therapeutic agents. Here, we developed transgenic (Tg) mice on a C57BL/6 background; these mice expressed human CD26/dipeptidyl peptidase 4 (hDPP4), a functional receptor for MERS-CoV, under the control of an endogenous hDPP4 promoter. We then characterized this mouse model of MERS-CoV. The expression profile of hDPP4 in these mice was almost equivalent to that in human tissues, including kidney and lung; however, hDPP4 was overexpressed in murine CD3-positive cells within peripheral blood and lymphoid tissues. Intranasal inoculation of young and adult Tg mice with MERS-CoV led to infection of the lower respiratory tract and pathological evidence of acute multifocal interstitial pneumonia within 7 days, with only transient loss of body weight. However, the immunopathology in young and adult Tg mice was different. On day 5 or 7 postinoculation, lungs of adult Tg mice contained higher levels of proinflammatory cytokines and chemokines associated with migration of macrophages. These results suggest that the immunopathology of MERS-CoV infection in the Tg mouse is age dependent. The mouse model described here will increase our understanding of disease pathogenesis and host mediators that protect against MERS-CoV infection.IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) infections are endemic in the Middle East and a threat to public health worldwide. Rodents are not susceptible to the virus because they do not express functional receptors; therefore, we generated a new animal model of MERS-CoV infection based on transgenic mice expressing human DPP4 (hDPP4). The pattern of hDPP4 expression in this model was similar to that in human tissues (except lymphoid tissue). In addition, MERS-CoV was limited to the respiratory tract. Here, we focused on host factors involved in immunopathology in MERS-CoV infection and clarified differences in antiviral immune responses between young and adult transgenic mice. This new small-animal model could contribute to more in-depth study of the pathology of MERS-CoV infection and aid development of suitable treatments.

Authors+Show Affiliations

Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan. Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. Section of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan. Department of Tissue Physiology, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan nnagata@niid.go.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30626685

Citation

Iwata-Yoshikawa, Naoko, et al. "Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected With Middle East Respiratory Syndrome Coronavirus." Journal of Virology, vol. 93, no. 6, 2019.
Iwata-Yoshikawa N, Okamura T, Shimizu Y, et al. Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus. J Virol. 2019;93(6).
Iwata-Yoshikawa, N., Okamura, T., Shimizu, Y., Kotani, O., Sato, H., Sekimukai, H., Fukushi, S., Suzuki, T., Sato, Y., Takeda, M., Tashiro, M., Hasegawa, H., & Nagata, N. (2019). Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus. Journal of Virology, 93(6). https://doi.org/10.1128/JVI.01818-18
Iwata-Yoshikawa N, et al. Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected With Middle East Respiratory Syndrome Coronavirus. J Virol. 2019 03 15;93(6) PubMed PMID: 30626685.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus. AU - Iwata-Yoshikawa,Naoko, AU - Okamura,Tadashi, AU - Shimizu,Yukiko, AU - Kotani,Osamu, AU - Sato,Hironori, AU - Sekimukai,Hanako, AU - Fukushi,Shuetsu, AU - Suzuki,Tadaki, AU - Sato,Yuko, AU - Takeda,Makoto, AU - Tashiro,Masato, AU - Hasegawa,Hideki, AU - Nagata,Noriyo, Y1 - 2019/03/05/ PY - 2018/10/11/received PY - 2018/12/28/accepted PY - 2019/1/11/pubmed PY - 2019/11/20/medline PY - 2019/1/11/entrez KW - DPP4 KW - MERS-CoV KW - animal models KW - immunopathology KW - transgenic mouse JF - Journal of virology JO - J Virol VL - 93 IS - 6 N2 - Middle East respiratory syndrome coronavirus (MERS-CoV) infection can manifest as a mild illness, acute respiratory distress, organ failure, or death. Several animal models have been established to study disease pathogenesis and to develop vaccines and therapeutic agents. Here, we developed transgenic (Tg) mice on a C57BL/6 background; these mice expressed human CD26/dipeptidyl peptidase 4 (hDPP4), a functional receptor for MERS-CoV, under the control of an endogenous hDPP4 promoter. We then characterized this mouse model of MERS-CoV. The expression profile of hDPP4 in these mice was almost equivalent to that in human tissues, including kidney and lung; however, hDPP4 was overexpressed in murine CD3-positive cells within peripheral blood and lymphoid tissues. Intranasal inoculation of young and adult Tg mice with MERS-CoV led to infection of the lower respiratory tract and pathological evidence of acute multifocal interstitial pneumonia within 7 days, with only transient loss of body weight. However, the immunopathology in young and adult Tg mice was different. On day 5 or 7 postinoculation, lungs of adult Tg mice contained higher levels of proinflammatory cytokines and chemokines associated with migration of macrophages. These results suggest that the immunopathology of MERS-CoV infection in the Tg mouse is age dependent. The mouse model described here will increase our understanding of disease pathogenesis and host mediators that protect against MERS-CoV infection.IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) infections are endemic in the Middle East and a threat to public health worldwide. Rodents are not susceptible to the virus because they do not express functional receptors; therefore, we generated a new animal model of MERS-CoV infection based on transgenic mice expressing human DPP4 (hDPP4). The pattern of hDPP4 expression in this model was similar to that in human tissues (except lymphoid tissue). In addition, MERS-CoV was limited to the respiratory tract. Here, we focused on host factors involved in immunopathology in MERS-CoV infection and clarified differences in antiviral immune responses between young and adult transgenic mice. This new small-animal model could contribute to more in-depth study of the pathology of MERS-CoV infection and aid development of suitable treatments. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/30626685/Acute_Respiratory_Infection_in_Human_Dipeptidyl_Peptidase_4_Transgenic_Mice_Infected_with_Middle_East_Respiratory_Syndrome_Coronavirus_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30626685/ DB - PRIME DP - Unbound Medicine ER -