Abstract
Neutrophils are critical as the first-line defense against fungal pathogens. Yet, previous studies indicate that neutrophil function is complex during Cryptococcus neoformans (Cn) infection. To better understand the role of neutrophils in acute pulmonary cryptococcosis, we analyzed neutrophil heterogeneity by single-cell transcriptional analysis of immune cells in the lung of Cn-infected mice from a published dataset. We identified neutrophils by reference-based annotation and identified two distinct neutrophil subsets generated during acute Cn infection: A subset with an oxidative stress signature (Ox-PMN) and another with enhanced cytokine gene expression (Cyt-PMN). Based on gene regulatory network and ligand-receptor analysis, we hypothesize that Ox-PMNs interact with the fungus and generate ROS, while Cyt-PMNs are longer-lived neutrophils that indirectly respond to Cn-derived ligands and cytokines to modulate cell-cell communication with dendritic cells and alveolar macrophages. Based on the data, we hypothesized that, during in vivo fungal infection, there is a division of labor in which each activated neutrophil becomes either Ox-PMN or Cyt-PMN.
Highlights
Opportunistic fungal infections are a serious complication of immunosuppression in patients undergoing transplantation, patients with HIV-AIDS, and those with immunosuppression induced by leukemia or lymphoma [1]
We identified three major neutrophil subsets, termed clusters I-III (Figures 1A, B)
We focused on Ox-PMN (IIa) and CytPMN (IIb), which appear after Cryptococcus neoformans (Cn) infection and possess distinct gene expression profiles
Summary
Opportunistic fungal infections are a serious complication of immunosuppression in patients undergoing transplantation, patients with HIV-AIDS, and those with immunosuppression induced by leukemia or lymphoma [1]. Cryptococcus neoformans (Cn) is one of the pathogens with the highest disease burden and risk of complications. Inhaled from the environment, Cn begins as a primary pulmonary infectious agent and can disseminate through the vasculature to the central nervous system (CNS) resulting in meningoencephalitis [1]. Neutrophils are critical as the first-line of defense against fungal pathogens, effectively engulfing and killing Cn, arguably more efficacious than monocytes [2, 3]. Neutrophils produce the majority of reactive oxygen species (ROS) during cryptococcosis in attempts to control and clear the infection [4, 5]. Treatment with granulocyte colony-stimulating factor (G-CSF) decreased fungal
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