The severity of Middle East respiratory syndrome in human dipeptidyl peptidase 4 (DPP4)-bearing transgenic mice
Naoko Iwata-Yoshikawa1, Tadashi Okamura2, Makoto Takeda3, Hideki Hasegawa1, and Noriyo Nagata1 *
1Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
2Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
3Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.
Middle East respiratory syndrome coronavirus (MERS-CoV) infection has a wide clinical spectrum, ranging from asymptomatic infection to severe acute respiratory disease and death. The mechanisms underlying the variability in disease severity in MERS are still unclear. To understand the pathogenesis of MERS-CoV and to develop vaccines and therapeutic agents, we produced a transgenic (Tg) mouse line overexpressing human dipeptidyl peptidase 4 (hDPP4), a cellular receptor for MERS-CoV, under the control of an endogenous promoter. The Tg mice were then backcrossed to Th1-prone C57BL/6 (Tg-B6) and Th2-dominant BALB/c mice (Tg-BALB). These Tg mice showed high expression of hDPP4; indeed, the expression profile was similar to that of human tissues, including high expression in the kidney and lung. Intranasal inoculation of young and adult mice on both Tg backgrounds with MERS-CoV led to non-lethal infection of the lower respiratory tract and pathological evidence of acute multifocal interstitial pneumonia with transient body weight loss within 7 days of infection. Virus replication in the lungs peaked on days 1-3 post-infection (p.i.) in the Tg-B6 mouse, after which the virus was rapidly cleared. High levels of IP-10, MIG, MCP-1, MIP-1α, IL-6, IL-10, and IFN-γ were detected in the lungs of infected Tg-B6 mice on days 5-7 p.i. Molecular and pathological evidence of disease was not observed in any other organs, including the brain. Although further study of the immune system of the Tg-BALB/c mice is required, our results suggest that age and genetic background have no effect on outcomes after MERS-CoV infection in mice.