The Kotov lab broadly explores how cellular communication dictates pathogen clearance or susceptibility, with a primary focus on the innate immune response to Mycobacterium tuberculosis (Mtb) infection. We leverage mouse models to mimic key aspects of the human response to Mtb infection, with the hope that our research will uncover novel targets for host-directed cell therapies.
Ongoing work
Two hallmarks of tuberculosis disease progression in humans are the induction of the classically anti-viral type I interferon response and a heightened myeloid cell response (e.g. an increase in neutrophils). Using Mtb susceptible mice, we model these two aspects of human disease to move from the correlation observed in humans towards establishing causality and identifying the underlying mechanisms.
Type I interferon and tuberculosis
In a mouse model of type I interferon-driven Mtb susceptibility, we found that interstitial macrophages and plasmacytoid dendritic cells were the primary producers of type I interferon, and depletion of plasmacytoid dendritic cells restored bacterial control. These cell types are also the primary producers of type I interferon in non-human primates and plasmacytoid dendritic cells are found near tuberculosis granulomas in human lungs, demonstrating that our mouse model is informative for human disease. Ongoing work in the lab builds upon these initial findings by researching how plasmacytoid dendritic cells are recruited to infected lungs, what activates them upon their arrival, and exploring ways to shut down their type I interferon production during Mtb infection as a potential therapeutic strategy.
Myeloid cell exacerbation of tuberculosis disease
An increase in myeloid cell responses strongly correlates with tuberculosis disease progression in humans and is a common feature of all Mtb-susceptible mouse models, yet the mechanism by which myeloid cells promote progression is unknown. By comparing three susceptible mouse models, we identified that macrophage differentiation into unconventional Spp1+ macrophages was a commonality of susceptible mice and largely absent in Mtb-restrictive animals. A unique feature of the Spp1+ macrophages was their strong expression of immunosuppressive molecules, such as IL-1 receptor antagonist. We found that the presence of IL-1 receptor antagonist expressing Spp1+ macrophages during Mtb infection was conserved across mice, non-human primates, and humans. Furthermore, macrophage-specific, but not neutrophil-specific, deletion of IL-1 receptor antagonist was sufficient to rescue bacterial control in Mtb-susceptible mouse strains. Ongoing work builds upon these exciting findings by utilizing our mouse models to dissect Spp1+ macrophage differentiation as well as study the role of other immunosuppressive molecules during tuberculosis infection.