Interrogating inflammatory responses to SARS-CoV-2 infection in vivo

National Institute Of Allergy And Infectious Diseases

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Abstract

During the Coronavirus Disease 2019 (COVID-19) pandemic we felt obligated to leverage our more than a decade long experience performing reproducible and insightful in vivo experiments, with a focus on lung innate immune responses to respiratory pathogens under high containment conditions, to contribute in a meaningful way to the global efforts to better understand this emerging pathogen. Exposure to Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) leads to highly variable outcomes in patients. While many individuals exposed to SARS-CoV-2 remain asymptomatic or experience flu-like symptoms, the lungs of patients suffering from severe COVID-19 present with pneumonia and significant tissue damage which can lead to acute respiratory distress syndrome (ARDS) and even death. This deterioration is caused not only by the cytopathic virus itself but also dysregulated host immune responses. Co-morbidities, sex, age, host genetics and vaccine status are known to affect disease severity, but exactly how the inflammatory milieu of the lung at the time of SARS-CoV-2 exposure impacts the control of viral replication remains poorly understood. Understanding the complex host response to SARS-CoV-2 infection in the lung, especially early after initial exposure and before onset of disease-associated complications is critically important to determine which immune parameters have to be carefully regulated to prevent inflammation-associated disease and limit viral replication. We leverage our expertise in inflammatory cytokines and pulmonary pathophysiology and our high-containment research environment to investigate the infected host’s cellular innate immune mechanisms that contribute to pathogenesis during SARS-CoV-2 infection. Our research is focused on the very earliest innate immune responses to viral infection in the lung, with an emphasis on how the inflammatory microenvironment, prior pulmonary exposure history and underlying inflammatory conditions in the lung may directly impact initial innate control of viral replication and disease trajectories. SARS-CoV-2 infection leads to vastly divergent clinical outcomes ranging from asymptomatic infection to fatal COVID-19 disease. In FY2025 we demonstrated that immune events in the mouse lung closely preceding SARS-CoV-2 infection, very significantly impact and shape subsequent viral control. Importantly, we identified key innate immune pathways required to limit viral replication, including the receptors recognizing infection and viruses such as Toll-like receptor (TLR) 3, TLR2, Melanoma Differentiation-Associated gene 5 (MDA5), membrane pore forming molecules such as Gasdermin D and E and innate cytokines such as type I interferons and TNF. Moreover, a diverse set of pulmonary inflammatory stimuli, including resolved antecedent respiratory infections with both viral and bacterial pathogen potently limited viral replication in the lungs of mice. For example, prior infections with S. aureus or influenza, ongoing pulmonary Mycobacterium tuberculosis infection, but also non-infectious sterile inflammation, such as ovalbumin/alum-induced asthma, and even airway administration of defined TLR ligands and recombinant cytokines, all establish a protective antiviral state in the lung that restricted SARS-CoV-2 replication upon exposure. We also were able to demonstrate that in addition to the known antiviral properties of type I interferons, the broadly inducible inflammatory cytokines Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1), a cytokine our laboratory has studied for over 15 years, potently preconditioned the lungs for enhanced viral control early after exposure. Collectively, our work demonstrated that SARS-CoV-2 may indeed benefit from an immunologically quiescent lung microenvironment and suggests that the heterogeneity in pulmonary inflammation that precedes or accompanies SARS-CoV-2 exposure may be a potentially important contributing factor to the population-wide variability observed in COVID-19 disease outcomes. 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