The clinical symptoms of a virus infection are often defined by the cell types the virus infects. Key determinants of cell tropism include entry receptor availability, strength of the cellular innate immune response, and presence of cell intrinsic pro- or anti-viral factors. However, with the advent of large-scale, multi “omics” technologies, a new paradigm has emerged, which is that the same biological process may not be uniform across cell populations that have otherwise been defined as identical. It is also increasingly appreciated that cues from the tissue microenvironment and interactions within cellular “neighborhoods” influence cell identity. The role of cellular heterogeneity as a factor for defining virus cell tropism is not well-understood and therefore represents a critical knowledge gap.

Our lab seeks to understand how complex relationships between cells within a susceptible host influence the capacity of a given cell type to support virus infection, disseminate, and ultimately, cause disease. We use mouse models of arthritogenic alphavirus infections, a mosquito-borne human pathogen, along with in vitro infection models, tissue imaging, and bioinformatics approaches to address our research questions. Currently, we have two lines of investigation in the lab.

Monocytes are circulating, myeloid-lineage cells that orchestrate immune responses across diverse inflammatory stimuli. Due to their remarkable plasticity and capacity to be rapidly deployed during infection, monocytes represent an ideal cell target for viruses to exploit for replication. Our previous work showed that Chikungunya virus (CHIKV), a prototypic arthritogenic alphavirus, productively infects skin-infiltrating Ly6Chi monocytes which, in turn, enhances CHIKV infection of several non-hematopoietic cell types in the skin (Holmes AC et al., Cell Reports, 2024). These pro-viral, cooperative interactions between monocytes and their stromal niches promote CHIKV particle dissemination to the bloodstream via the efferent lymph. Unexpectedly, in contrast to the skin, lymph node-associated monocytes are largely refractory to CHIKV infection. Our aim is to define the mechanisms that drive monocyte heterogeneity in CHIKV and other arthritogenic alphavirus infections.

We have also recently shown that endothelial cell interactions with platelet-derived growth factor alpha+ (PDGFRa+) mesenchymal cells increase local vascular permeability within musculoskeletal tissues during CHIKV infection in a manner that is dependent on vascular endothelial growth factor (VEGF) signaling. Decreased endothelial barrier integrity promotes virus dissemination directly from the infected tissue to the bloodstream, bypassing the lymphatics (Holmes AC et al., submitted, https://doi.org/10.64898/2026.10.06.757040). Similar to monocytes, infection of PDGFRa+ cells also enhances endothelial cell infection. Our aims are to: (1) define the molecular events that underlie the VEGF signaling cascade during arthritogenic alphavirus infections; (2) determine the mechanism by which endothelial cells receive VEGF signals from the infected tissue microenvironment; and (3) determine how virus disseminates across the vasculature.

Our long-term goal is to develop a comprehensive understanding of arthritogenic alphavirus cell tropism interactions to both better understand disease pathogenesis and for the rational design of precise, effective anti-viral therapeutics.