Neutrophils induce zinc starvation response in Mycobacterium tuberculosis 9239

Abstract Description Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a pervasive global burden. TB is often chronic, during which remodeling and hibernation of Mtb ribosomes are induced in response to zinc starvation. Studies in both our and other laboratories link this ribosomal change with antibiotic tolerance in Mtb, although the origin of zinc starvation in the host remains unknown. Infiltrating neutrophils produce high levels of the metal micronutrient chelator calprotectin (S100). Here, we demonstrate a direct role of neutrophils and S100 in inducing zinc starvation response in Mtb persistence in mouse models of chronic TB. During acute infection with an Mtb ribosome remodeling reporter strain, neutrophils were ablated from C3Heb/FeJ mice by i.p. injection of anti-Ly6G Ab. Sustained neutrophil ablation was confirmed via flow cytometry in chronic phase infection. Confocal microscopy identified a significant reduction of Mtb ribosomal remodeling versus controls. In parallel inquiries, we also observed a significant reduction in ribosome remodeling in Mtb during chronic infection of BL/6 S100a9-/- mice. BL/6 S100a9-/- altered populations of key immune cells (eosinophils, macrophages, DCs) by flow cytometry, suggesting a broader role in shaping immune responses to Mtb infection in the chronic phase. Together, neutrophils induce ribosome remodeling and possibly ribosome hibernation in Mtb during chronic TB through the secretion of calprotectin. Funding Sources Supported by the APHL & funded by the CDC through Cooperative Agreement Number NU60OE000104 (CFDA #93.322), with additional support from (NIH: AI132422, NIH: AI163599). Additional support provided by the Wadsworth Immunology Core. S100A9-/- strain originally created by Thomas Vogl at the Institute of Immunology in Münster, Germany, was donated by Thomas Kehl-Fie of UIUC, Urbana-Champaign IL, USA. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)