Innate inflammatory responses during pulmonary infections

National Institute Of Allergy And Infectious Diseases

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Abstract

Pathogens serve as an exquisite tool to probe the body’s immune system and gain fundamental insight into the general functions of inflammatory lipid mediators and cytokines. Research in the IIIU is based on the hypothesis that during chronic inflammatory reactions, including chronic pathogen driven diseases like tuberculosis, distinct arms of innate inflammatory responses establish counter regulatory cytokine and lipid mediator networks that ultimately determine health. This hypothesis led to the development of a Tipping-point model of disease exacerbation, which is currently the underlying conceptual framework of many ongoing projects in the lab. More specifically, our research is focused on inflammatory responses in the lung, a critical mucosal-barrier tissue exposed to both environmental and pathogenic insults. Innate immune cells interact with structural cells in the lungs to promote cooperative tissue immunity that facilitates disease tolerance of the organ itself but also system-wide, affecting immunometabolism and overall health. This innate regulation of protective inflammatory responses is important to prevent dysregulated detrimental responses that promote disease and greatly impair host resistance. Interleukin-1 (IL-1) plays a critical role in pulmonary tissue immunity during chronic pulmonary disease caused by Mycobacterium tuberculosis (Mtb) and we have now extended these findings to acute inflammatory conditions such as viral infections. Exposure to viruses, including Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) leads to highly variable outcomes in patients. While many individuals exposed to the virus remain asymptomatic or experience flu-like symptoms, the lungs of patients suffering from severe disease present with pneumonia and significant tissue damage which can lead to acute respiratory distress syndrome and even death. This deterioration is caused not only by the cytopathic virus itself but also dysregulated host immune responses. We demonstrated that pulmonary IL-1 pre-conditioning in mice, prior to viral infection, created a potent antiviral state mice and significantly interfered with viral replication in the lung tissue. Importantly, and like what we have previously described during chronic lung infections with Mtb, this IL-1 mediated control of the pathogen required a cooperative immune response in the tissue between bone marrow derived immune cells and structural stroma cells. Our findings may help in the design of preventative therapeutics that improve and activate our natural antiviral responses in the respiratory system prior to infection. This work was published in Science Immunology in December 2024. Baker PJ, Bohrer AC, Castro E, Amaral EP, Snow-Smith M, Torres-Juarez F, Gould ST, Queiroz ATL, Fukutani ER, Jordan CM, Khillan JS, Cho K, Barber DL, Andrade BB, Johnson RF, Hilligan KL and Mayer-Barber KD* The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication. Science Immunology (2024) Dec. doi: https://doi.org/10.1101/2024.03.27.58688