NIH Research Festival
Pneumocystis is an opportunistic fungal pathogen that causes asymptomatic infection in immunocompetent hosts but life-threatening pneumonia (PCP) in immunosuppressed hosts. Understanding immune mechanisms by which Pneumocystis is cleared will give valuable insights into strategies for reducing risk of PCP.
We used a co-housing exposure model of mouse Pneumocystis infection to determine gene expression levels of host cells from the lungs of immunocompetent (C57BL/6) mice. We applied single-cell RNA sequencing combined with flow cytometry, qPCR, ELISA, and pathway analyses, to better characterize host immune responses during infection.
We observed a peak in Pneumocystis organism load at day 35 post-infection. All infected mice cleared Pneumocystis and developed anti-Pneumocystis antibodies. CD4+ T cells increased at days 35 and 42 post-infection, primarily involving Th1-effector cells during clearance. An IFN‚ÄêŒ≥ centered cytokine signaling pathway was identified at peak of infection. The top differentially expressed genes in infected mice included pro-inflammatory cytokines IL-21 and CXCL9, co-stimulatory molecule Ox-40 (CD134), and regulatory genes CTLA4, LY6A, and IRF4.
These data support a CD4 Th1 cell-driven response in immunocompetent hosts and suggest that a regulated IFN‚ÄêŒ≥‚Äêrich milieu is necessary to enhance phagocytosis of Pneumocystis organisms by macrophages, leading to efficient clearance of Pneumocystis without the development of severe symptoms. More research on the roles of B cells, epithelial cells, and endothelial cells will help to further elucidate the diverse host-pathogen interactions required to prevent PCP in immunosuppressed hosts.
Scientific Focus Area: RNA Biology
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