Anti-PD-L1 treatment improves infection outcomes in a lethal model of Coccidioides 4317

Description Coccidioidomycosis, or Valley Fever, is an emerging pulmonary infection caused by inhalation of Coccidioides fungi that are native to the arid soils of the southwestern US. Cases of Coccidioides infection are expected to rise as climate change expands the geographic region where the fungus thrives. Most cases are asymptomatic and resolve spontaneously, although a subset of patients develop severe, chronic, and/or disseminated disease, which can persist for life. T cells play a well-defined role in protective immunity, however the mechanisms that lead to insufficient T cell responses during severe infection remain under described. Previously, we performed a transcriptomic analysis of disease progression in the lungs over time using a mouse model of lethal infection coupled with single cell RNA sequencing (scRNAseq). Our data revealed a massive influx of multiple myeloid cell populations, including a large neutrophil population expressing high levels of PD-L1, a molecule which plays a well-known role in suppression of T cell responses during other chronic infections. PD-L1 blockade resulted in a modest but significant improvement in survival following lethal infection in mice. scRNAseq analyses of lungs from anti-PD-L1 treated mice to reveal the mechanisms of improved infection outcome are ongoing. These data suggest that myeloid populations may actively inhibit T cell responses during severe infection, and immunomodulation of these interactions can boost protective immunity. Funding Sources This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Security, LLC, Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. Funding was provided by internal Lawrence Livermore National Laboratory Directed Research and Development funds (22-ERD-010 to D.R.W. and 24-ERD-025 to N.R.H.) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)