Innate inflammatory responses during pulmonary infections

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Effective vaccines and host-directed therapeutic (HDT) strategies against M. tuberculosis (Mtb) infection necessitate a deeper understanding of the cellular basis of protective immunity. They also require insights into the aspects influencing detrimental or beneficial inflammatory responses to tuberculosis (TB). The innate inflammatory response, a prime target for HDT, holds significant inflammatory and immunoregulatory implications for host resistance. Eosinophils, phagocytic granulocytes crucial to type 2 immune responses, store cytotoxic cationic granular proteins in their lineage-specific secondary granules. These proteins, including ECP, EDN, MBP, and EPO, display anti-microbial activity and can cause tissue damage. These cells also contain preformed cytokines and pro-fibrogenic cytokines, stimulating fibroblast proliferation, fibrotic, and wound healing responses. Despite the critical role eosinophils play in immunoregulation and homeostatic functions, their role during bacterial infections associated with type 1 immunity remains underexplored. An additional hindrance to understanding the role of eosinophils in host resistance to TB is a lack of data from the mouse model of Mtb infection.To address this, we systematically characterized the pulmonary granulocyte response after Mtb infection across multiple species. Our findings showed that eosinophils are integral to the innate cellular response to Mtb infection. Notably, we reported that eosinophils contribute to host resistance against Mtb infection. In addition, we found that oxysterols, cholesterol derivatives that can bind the chemotactic receptor GPR183, selectively recruited eosinophils into the lungs of Mtb infected mice and nonhuman primates and showed that eosinophils may be ther earliest cells from circulation to recognize Mtb infection of alveolar macropahges. This work was published in 2022 in Cell Reports. Our earlier work detailed the pivotal yet contrasting roles of two major innate cytokine pathways, IL-1 and type I interferons, in governing host resistance versus disease in the mouse model of Mtb infection. We found a dynamic crosstalk between these pathways, with IL-1 required for host resistance and type I IFNs contributing to disease progression. In addition to the cross-talk between IL-1 and type I IFN, the subcellular localization of Mtb is another important pathogenicity factor. We showed that IL-1R1 deficient lungs harbor more Mtb bacilli in the cytosol than in infected cells from WT control mice. The neutrophil, the most studied granulocyte subset during Mtb infection, has a complex role in host resistance to Mtb infection. Recent research focused on their disease-promoting properties as they provide a niche for Mtb to survive despite being the most common Mtb-containing phagocytes in the airways of active TB patients. We now propose a Tipping-point model for TB disease exacerbation, suggesting that neutrophils play a key role after the initial loss of disease tolerance or bacterial control. This work is published in Current Opinion in Immunology in 2023.