Thursday, May 9, 2024
5/9/2024
Abstract. Why 5-10% of people develop tuberculosis (TB) after Mycobacterium tuberculosis (Mtb) infection is largely unknown. Th1 immunity is the dominant mechanism of control. In contrast, how type 2 immunity affects immunity to TB is a clinically important knowledge gap. Th2 immune responses are elicited by helminths parasites, and half of the 180 million school age children in Sub-Saharan Africa are estimated to be infected with helminths. Chronic helminth infection induces Th2 and Tregs, both which inhibit Th1 immunity, and impair BCG efficacy. IL-4, IL-5, and IL-13 are the canonical cytokines of Th2 cells. These cytokines are also produced by innate cells including eosinophils and mast cells. We discovered that BCG vaccination worsens subsequent Mtb infection in CC040 mice and is associated with the emergence of IL-4-producing cells in the lung. Our overarching hypothesis is that IL-4 production in CC040 mice permits Mtb growth and exacerbates disease in BCG vaccinated mice. While the mouse has been outstanding in developing immunological concepts that translate into humans, standard inbred strains lack the genetic diversity of people. Th1 immunity develops following Mtb infection in C57BL/6 (B6) mice, the “go to” strain for immunologists. However, B6 mice poorly model other immune responses including Th2 and Th17 responses, and MAIT cells. To address the short- comings of the murine TB model, we are using Collaborative Cross (CC) mice to study mechanisms of vaccine-induced immunity against TB. CC mice are derived from eight founder strains that include wild-derived mice. The breeding schemes captured >90% of the diversity present in the Mus species and led to the creation of ~70 CC strains. In one of these, the CC040 strain, we detect a clinically relevant phenotype that is not detected in traditional mouse models (i.e., B6). Using the CC040 mouse strain, we will ask how IL-4 affects vaccine-induced protection against Mtb infection. We will determine which cell types produce IL-4 and whether IL-4 is induced by BCG and/or Mtb infection. Next, we will measure how immunity is altered in an IL-4-sufficient environment by performing scRNAseq of lung cells from IL-4-sufficient or depleted CC040 mice, following BCG vaccination and Mtb infection. Two strategies will be used to determine how IL-4 affects vaccine-induced protection against Mtb infection. Whether IL-4 is detrimental to BCG-mediated protection and heightens the susceptibility of CC040 mice to TB will be tested by depletion of IL-4 or IL-4-producing cells. Another approach will use genetic segregation and mapping analysis to determine the role of IL-4 signaling and identify genetic susceptibility loci specifically driving IL-4-enhanced Mtb disease. New insights into how mast cells and eosinophils affect TB susceptibility are changing the way we view immunity to mycobacteria. Clinical and epidemiological data indicates that IL-4 production during chronic helminth infection could impair BCG efficacy and immunity to TB. The CC040 strain will be an important tool to unravel how IL-4 and IL-4 producing cells affect immunity to Mtb.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
