Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children with approximately 125,000 hospitalizations per year in the United States and over 3 million worldwide. There is currently no licensed RSV vaccine with only costly prophylactic treatments available. Severe RSV-induced disease is associated with increased levels of pro-inflammatory cytokines, especially in otherwise healthy infants. Therefore, by understanding the factors that modulate RSV-induced inflammation in the lung, new therapies can be developed to inhibit inflammation leading to less severe disease and faster recovery times.

Previous work in the Varga lab has demonstrated that RSV strains differentially induce inflammatory cytokines such as IL-6 and inflammasome-associated IL-1β leading to priming of a pathogenic Th17 response. My research seeks to identify the mechanism by which RSV strains differentially activate the inflammasome and lead to increased disease severity. Currently, my work has shown that as few as three amino acid changes in a region of the F protein likely to interact with host cell receptors significantly increases inflammasome activation and production of pro-inflammatory cytokines. Reversion of these amino acids to a sequence from an RSV strain associated with less severe disease abolished increases in IL-6 and IL-1β protein production. Thus, gaining a better understanding of this poorly understood mechanism of RSV immunopathology initiated by the innate immune response may have broad implications for many pathogens and lead to development of better therapeutic targets.
 

Bibliography

Soto JA, Stephens LM, Waldstein KA, Canedo-Marroquín G, Varga SM, Kalergis AM. Current Insights in the Development of Efficacious Vaccines Against RSV. Front Immunol. 2020 Jul 17;11:1507. doi: 10.3389/fimmu.2020.01507. PMID: 32765520; PMCID: PMC7379152.

Stephens LM, Ross KA, Waldstein KA, Legge KL, McLellan JS, Narasimhan B, Varga SM. Prefusion F-Based Polyanhydride Nanovaccine Induces Both Humoral and Cell-Mediated Immunity Resulting in Long-Lasting Protection against Respiratory Syncytial Virus. J Immunol. 2021 May 1;206(9):2122-2134. doi: 10.4049/jimmunol.2100018. Epub 2021 Apr 7. PMID: 33827894; PMCID: PMC8062305.

Waldstein KA, Yi J, Cho MM, Mudumbai R, Wu X, Varga SM, Xu W. Use of compressed sensing to expedite high-throughput diagnostic testing for COVID-19 and beyond. medRxiv [Preprint]. 2021 Aug 10:2021.08.09.21261669. doi: 10.1101/2021.08.09.21261669. PMID: 34401889; PMCID: PMC8366810.

Stephens LM, Ross KA, Waldstein KA, Legge KL, McLellan JS, Narasimhan B, Varga SM. Prefusion F-Based Polyanhydride Nanovaccine Induces Both Humoral and Cell-Mediated Immunity Resulting in Long-Lasting Protection against Respiratory Syncytial Virus. J Immunol. 2021 May 1;206(9):2122-2134. doi: 10.4049/jimmunol.2100018. Epub 2021 Apr 7. PMID: 33827894; PMCID: PMC8062305.