kara-misel@uiowa.edu
Mentor: Priya Issuree, PhD
Lab Room: 503 EMRB
Lab Phone: 319-335-3668

Fate of Francisella tularensis-infected human neutrophils

Francisella tularensis (Ft) is a Gram-negative facultative intracellular bacterium and the causative agent of the disease tularemia. This pathogen infects a variety of cell types including macrophages and neutrophils. Neutrophils are short-lived and are inherently programmed to undergo apoptosis ~ 24 hours after release into the circulation. Rapid clearance of dying neutrophils by macrophages, a process called efferocytosis, prevents release of toxic cell components and drives resolution of inflammation via effects on macrophage polarization state and cytokine production. Our published data demonstrate that Ft significantly delays neutrophil apoptosis but the fate of these cells is unknown. Exposure of phosphatidlyserine (PS) on the surface of apoptotic cells is an ‘eat me’ signal that favors efferocytosis. As PS is low on Ft-infected neutrophils, we predicted that interaction of these cells with human monocyte-derived macrophages (MDMs) would be impaired. In marked contrast, we found that MDMs interacted more avidly with infected neutrophils than the aged, uninfected controls. After uptake, Ft infected neutrophils evaded trafficking to lysosomes and instead acted as Trojan horses with live Ft escaping from PMN-laden efferosomes to replicate in MDM cytosol. Current studies are focused on analyses of MDM polarization and cytokine secretion and identification of receptors that mediate binding and uptake of aged and infected neutrophils. Candidates of interest are being evaluated using blocking antibodies in conjunction with microscopy and a multicolor flow cytometry assay and include complement receptors (CR1, CR3, CR4) and the vitronectin receptor (v3) as well as calreticulin and scavenger receptors and the ‘don’t eat me’ molecule CD47. Results of these studies will advance understanding of how Ft evades the host immune system to persist and cause life-threatening infection.

Krysan DJ, Zhai B, Beattie SR, Misel KM, Wellington M, Lin X. Host Carbon Dioxide Concentration Is an Independent Stress for Cryptococcus neoformans That Affects Virulence and Antifungal Susceptibility. mBio. 2019; 10(4):e01410-19.