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

Topological characterization of the host response shows spatio-temporal transcriptomic differences between MERS-CoV strains Human Calu-3 2B4 cells were infected with one of two different MERS-CoV strains, MERS-CoV SA 1 or MERS-CoV Eng 1, or with icSARS-CoV, and cell lysates were harvested throughout the infection course for microarray analysis. We first characterized topological differences of the whole transcriptome on Euclidean metric space for the collection of 93 samples (mock, MERS-CoV SA 1, MERS-CoV Eng 1 and icSARS-CoV) using recent methods from computational topology, including persistence homology [15, 16] . Many data reduction methods rely on embedding high-dimensional data into two dimensions. Multi-dimensional scaling (MDS), for example, calculates coordinates for a 2-dimensional embedding of the experimental data by minimizing the deviation between embedded and original data (Kruskal stress). Persistence homology, on the other hand, performs computation of topological invariants in the dimension of the original dataset and is, unlike MDS, more stable under perturbation. To assess global kinetic dissimilarities across different CoV infections, we calculated topological differences between MERS-CoV SA 1, MERS-CoV Eng 1 and icSARS-CoV, each grouped throughout all time points and with data set-matched mock samples. The kinetics of the host response refers to the spread of infected samples relative to mock samples over time. There were large topological differences between MERS-CoV Eng 1 and icSARS-CoV (score: 2.42), and between MERS-CoV SA 1 and icSARS-CoV (score: 2.18), and moderate differences between MERS-CoV Eng 1 and MERS-CoV SA 1 (score: 0.29) (Methods and Table 1) .