Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus

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 CD3positive 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. FIG 9 Histopathological changes in the lungs of human dipeptidyl peptidase 4 (hDPP4)-transgenic mice inoculated with MERS-CoV. Representative histopathological images of the lungs from 25-week-old Tg2 mice at 1, 3, 5, 7, 14, and 35 days post-MERS-CoV infection. Images in the left (A, D, G, J, M, and P) and right (C, F, I, L, O, and R) columns show time-dependent recruitment of inflammatory cells to the lung. Marked inflammatory cell infiltration was noted at 7 days postinoculation (dpi) in panels J and L. Images in the middle column (B, E, H, K, N, and Q) show immunohistochemical staining for MERS-CoV antigen (Ag). Scale bars: 100 m (left and middle columns), 50 m (right column), and 20 m (insets of middle...

Animal models for emerging coronavirus: progress and new insights

“…Similar to the model by Agrawal et al, activated innate immune cells accumulated in the lungs after MERS-CoV infection. Recently, Yoshikawa et al observed the cytokine storm in a newly generated hDPP4-transgenic mouse [37].…”

Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection

“…MERS-CoV does not replicate in wild-type mice because of differences in the receptor binding domain of DPP4 (31)(32)(33). To overcome this, many groups, including ours, have developed transgenic mice that express human DPP4 (34)(35)(36)(37)(38)(39). In our model, exons 2-25 of mouse DPP4 were replaced with the human DPP4 sequence (DPP4 H/M ) (34).…”

The characteristics of hDPP4 transgenic mice subjected to aerosol MERS coronavirus infection via an animal nose‐only exposure device

“…Previous studies showed that transgenic mice expressing the human DPP4 (hDPP4) receptor could be infected intranasally with MERS-CoV and developed acute pneumonia. [13][14][15] Therefore, hDPP4 transgenic mice were selected for exposure to MERS-CoV-containing aerosols using an animal nose-only exposure device.…”