Obesity-Associated Changes in Immune Cell Dynamics During Alphavirus Infection Revealed by Single Cell Transcriptomic Analysis

Summary Obesity induces diverse changes in host immunity, resulting in worse disease outcomes following infection with various pathogens, including arthritogenic alphaviruses. However, the impact of obesity on the functional landscape of immune cells during arthritogenic alphavirus infection remains unexplored. Here, we used single-cell RNA sequencing (scRNA-seq) to dissect the blood and tissue immune responses to Mayaro virus (MAYV) infection in lean and obese mice. Footpad injection of MAYV caused significant shifts in immune cell populations and induced robust expression of interferon response and proinflammatory cytokine genes and related pathways in both blood and tissue. In MAYV-infected lean mice, analysis of the local tissue response revealed a unique macrophage subset with high expression of IFN response genes that was not found in obese mice. This was associated with less severe inflammation in lean mice. These results provide evidence for a unique macrophage population that may contribute to the superior capacity of lean mice to control arthritogenic alphavirus infection. Graphical abstract Highlights Obesity worsens disease outcomes following arthritogenic alphavirus infection. Arthritogenic alphavirus infection causes significant shifts in immune cell populations in the blood and footpad. Blood monocytes from lean mice had higher expression of interferon response genes at the later stage of infection. Footpads in lean mice have an expanded population of F4/80lo macrophages with an intense interferon response gene signature before and after alphavirus infection that is not found in obese mice. Macrophages in obese mice express lower levels of interferon response genes, have a unique necroptosis signature, and higher F4/80 expression.