Through our genomics-based approach, we found (i) topological differences in the kinetics and magnitude of the host response to MERS-CoV SA 1 and MERS-CoV Eng 1, with (i) a precursory host response in MERS-CoV Eng 1-infected cells, (ii) differential expression of innate immune and pro-inflammatory responsive genes between MERS-CoV Eng 1 and MERS-CoV SA 1 that may be associated with downstream effects of IFN, TNF and IL-1α signaling, and (iii) a predicted activation for STAT3 mediating gene expression relevant for epithelial cell remodeling in MERS-CoV Eng 1 infection. Here, TNF is linked to infection.