Innate inflammatory responses during pulmonary infections

National Institute Of Allergy And Infectious Diseases

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Abstract

Both effective vaccines and host directed therapeutic (HDT) strategies against M. tuberculosis (Mtb) infection require a better understanding of the cellular basis of protective immunity alongside the features that determine detrimental or protective inflammatory responses to tuberculosis (TB). The innate inflammatory response is a prime target for HDT and manipulation of innate immunity could have major inflammatory and immunoregulatory implications for host resistance. Eosinophils are phagocytic granulocytes that play an important effector role in type 2 immune responses, such as allergies and parasitic helminth infections. Their lineage-specific secondary granules contain cytotoxic cationic granular proteins (ECP, EDN, MBP and EPO) that have been shown to exhibit anti-microbial activity and cause tissue damage. Eosinophils contain preformed cytokines in their granules like TNF-, IL-1, IL-6, and IL-8 and pro-fibrogenic cytokines that can stimulate fibroblast proliferation, fibrotic and wound healing responses. In addition, lipid bodies, which form in response to eosinophil activation, contain a wide variety of leukotrienes, prostaglandins, and reactive oxygen species. Eosinophils have also been shown to play an important role in immunoregulation and homeostatic functions, including maintenance of long-lived plasma cells in the bone marrow and alternatively activated macrophages in adipose tissue. Eosinophils and their biological functions of have been studied primarily in the context of type 2 immunity, and the role of eosinophils during bacterial infections associated with classical cellular type 1 immunity, remains unexplored. Another barrier to our understanding of eosinophils in host resistance to TB is a paucity of data from the mouse model of Mtb infection. There are likely two major contributing factors to be considered for this: 1) Mtb infection primarily causes a type I immune response, and eosinophils are rare in numbers compared to neutrophils in the lungs of Mtb infected mice the pathology of Mtb infected mouse lungs and human lungs is vastly different. Therefore, we systematically characterized the pulmonary granulocyte response after Mtb infection across multiple species, including zebrafish, rhesus macaques, mice and humans and found that eosinophils are an integral component of the innate cellular response to Mtb infection in tissues. We show in two experimental animal models that pulmonary eosinophil accumulation precedes influx of neutrophils and other innate circulating immune cells, suggesting that eosinophils may be the very first circulating immune cells detecting and responding to initial Mtb infection of AM. Importantly, we report that eosinophils play a protective role and contribute to host resistance against Mtb infection as both dblGata and PHIL eosinophil deficient mouse lines exhibited highly significant decreases in survival after LD and HD aerosol Mtb exposure. We currently investigating the underlying molecular mechanisms promoting eosinophil migration into the lung after Mtb infection. Our previous work characterized how two major innate cytokine pathways, IL-1, and type I interferons, respectively, play pivotal yet opposing roles in governing host resistance versus disease in the murine model of Mtb infection. They do this by intersecting the eicosanoid lipid network. We found that IL-1 and type I IFNs potently counter-regulate each others inflammatory and cellular programs during Mtb infection, with IL-1 being required for host resistance while type I IFNs contribute to disease progression. This cross-talk is of functional importance because mice doubly deficient in Il1r1,Ifnar1-/- are partially protected while Il1r1-/- singly deficient animals succumb rapidly to Mtb aerosol challenge. Interestingly, IL-1 induced prostaglandin E2 (PGE2) is also able to potently inhibit type I IFNs in a dose dependent manner. These data highlighted and provided proof-of-concept that the crosstalk of IL-1 and type I IFN provides a valuable target for host-directed therapies of Mtb and plays a major role during infection in mice. Moreover, we measured and analyzed cytokines, chemokines, and lipid mediators of the IL-1, type IFN and eicosanoid axis in a prospective cohort of Chinese individuals infected with M. tuberculosis. We are currently investigating the exact nature of IL-1 and type I IFN induced cell death mechanisms, lipid regulation and host resistance pathways during tuberculosis. Excessive inflammasome activation associated with IL-1 production was observed in Mtb infected nonhuman primate granulomas after checkpoint inhibitor blockade. An important pathogenicity factor is the subcellular localization of Mtb. Mtb can translocate from the phago-lysosome to the cytosol, a process exclusively described for virulent mycobacteria infecting macrophages in vitro. Our knowledge about this phenomenon in vivo is limited. It is in this context that we showed that in IL-1R1 deficient lungs, Mtb bacilli are differentially escaped to the cytosol of infected cell compared to infected cells from WT control mice. We show that in vivo, mycobacteria locate in the cytosol, but only when the immune system is deficient in. For example, in mice low numbers of cytosolic mycobacteria are present. Importantly, when immunity is impaired, as is the case in Scid mice, lacking T and B cells, and IL-1R1 knockout mice, substantial numbers of cytosolic bacteria are detectable. Il1r1-/- deficient mice infected with Mtb display increased cytosolic bacteria in vivo in infected pulmonary macrophages, arguing that both innate and adaptive immune mechanisms protect against Mtb translocation into cytosol. The cytosolic localization of mycobacteria is controlled by IL-1R1-mediated host resistance to M. tuberculosis infection.