The omics of gender-specific MERS-CoV severity in a transgenic mouse model
Neeltje van Doremalen1, Natarajan Bhanu2, RanRan Wu2, Benjamin Garcia2, Angela Rasmussen3, Vincent Munster1
1Virus Ecology Unit, National Institutes of Health, Hamilton, MT
2Department of Biochemistry and Biophysics, Perelman School of Medicine, Philadelphia, PA
3Center for Infection and Immunity, Columbia University Mailman School of Public Health, New York, NY
Middle East respiratory syndrome coronavirus (MERS-CoV) has caused 2,220 infections since 2012 with a 36% case-fatality rate. Severity of disease varies and depends on gender; literature meta-analysis revealed male gender is a predictor of increased risk of death. We hypothesize that gender-dependent differences can be found in host response to MERS-CoV infection. We developed a transgenic mouse model which expresses human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV, in all tissue. In this study, we inoculated mice with a lethal dose, sublethal dose or no MERS-CoV. Six mice/group were sacrificed daily, and tissues were collected for transcriptomic, proteomic and metabolic analyses. In lung tissue, viral RNA, mRNA and infectious virus could be detected from 1 dpi and 2 dpi for lethal and sublethal dose groups, respectively. No viral RNA or infectious virus was found in control groups. Significant differences in viral RNA load between genders were only found at 5 dpi in mice infected with a sublethal dose of MERS-CoV. No significant differences could be found in viral mRNA load or infectious virus in any group. Lung homogenates yielded 3344 hits in total. In both male and female mice, changes in protein expression with a sublethal dose of MERS-CoV from 1-5 dpi were minimal. However, both male and female mice infected with a lethal dose of MERS-CoV showed a prominent upregulation of a cluster of 507 and 532 proteins respectively. In addition, another 2180 in male and 1046 proteins in female were downregulated by 5 dpi. The enrichment of the gene ontology categories differed indicating significant gender differences in the response independent of virus titer in tissue. This data will be used to identify host response signatures which can distinguish between gender differences associated with MERS-CoV disease. This study was funded by the Defense Advanced Research Projects Agency.