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

Innate immune and pro-inflammatory responses to MERS-CoV remains poorly understood. Human cell culture models of MERS infection have shown a deficiency in interferon (IFN) induction and innate immune responses, which may in part result from multiple mechanisms of MERS-CoV regulation of host antiviral responses. In addition to accessory protein 4a (p4a), the MERS-CoV viral papain-like protease (PLpro) can also block IFN-β induction, as well as downregulate expression of CCL5 and CXCL10 pro-inflammatory cytokine genes [5, 6] . Siu and colleagues showed that the block in IFN production is in part the result of MERS-CoV p4a interaction with cellular dsRNA-binding protein PACT that interferes with the activation of RIG-I-like receptors RIG-I and MDA5 [7] . In A549 lung epithelial cells and human bronchus and lung tissue ex vivo cultures, MERS-CoV SA 1 failed to induce significant expression differences of IFNB1 and TNF genes relative to mock throughout the 72 hour infection course [8] . The delay of IFN-β expression in response to MERS-CoV was also observed in Calu-3 airway cells [9] . In a separate study, the expression of a panel of interferon-responsive genes, including DDX58 (encoding RIG-I), IL1B, and CXCL10, was undetectable in human airway epithelial (HAE) cultures infected with MERS-CoV SA 1, despite efficient viral replication [10] . However, pre-treatment of HAE cells with recombinant IFN-α or IFN-λ suppressed MERS-CoV SA 1 replication, indicating viral sensitivity to innate immune responses [10] .