Cytokine systems approach demonstrates differences in innate and pro-inflammatory host responses between genetically distinct MERS-CoV isolates

Selinger, Christian; Tisoncik-Go, Jennifer; Menachery, Vineet D; Agnihothram, Sudhakar; Law, G Lynn; Chang, Jean; Kelly, Sara M; Sova, Pavel; Baric, Ralph S; Katze, Michael G

At present, nonhuman primates serve as the best available model of MERS-CoV pathogenesis, with animals developing moderate clinical disease and signs of histopathologic changes in the lung [33, 34] . While there is no current small-animal model of MERS infection, immunocompromised mice transduced with an adenoviral vector expressing human DPP4 show increased susceptibility to MERS-CoV infection [35] . In a separate study, a variant of Pipistrellus bat coronavirus (BtCoV) strain HKU5 expressing the SARS-CoV spike (S) glycoprotein ectodomain (BtCoV HKU5-SE) resulted in enhanced morbidity and acute changes in lung histopathology in aged BALB/c mice following mouse adaptation [36] . The present cytokine systems approach provides valuable insight into differences of cellular antiviral responses to distinct MERS-CoV strains. In line with these observations, reversal of infection gene signatures that can attenuate viral replication or enhance innate immune responses to the most highly pathogenic MERS-CoV strain could be investigated in this model system. We are beginning to better understand that different MERS-CoV strains can result in variable host responses, as observed with the recent clinical study by Faure and colleagues [12] . The patients infected with MERS-CoV SA 1 and MERS-CoV Eng 1 had both a fatal outcome, with the MERS-CoV SA 1-infected patient succumbing to infection within 11 days after admission, 18 days to death following initial symptoms [1] . The MERS-CoV Eng 1 patient on the other hand had an initially transient illness and then rapidly declined to a severe acute respiratory distress syndrome remaining in this state for 9 months before death [2] . Having an efficient innate immune response likely dictates a patient's disease progression and would thus be a primary goal for in silico drug predictions, which could then be tested Ingenuity Pathway Analysis was used to determine the top 20 Upstream Regulators. z-scores for predicted upstream regulators (|z| >2) at each time point are shown. z >2 predicts activation of the upstream regulator. z < -2 predicts inhibition of the upstream regulator. The Activation z-score was used to rank the Upstream Regulator based on the "Inhibited" status (darker cells indicated more significant "Inhibited" status of Upstream Regulator). Upstream Regulators in bold indicates enrichment of DNA-binding motifs (human) via TRANSFAC promoter analysis intersected DE genesets for MERS-CoV Eng 1 and MERS-CoV SA 1 at either 18 or 24 hpi (q-value of 10 -7 ).