Project summary: This K08 proposal describes a 5-year research and training plan that will facilitate the transition of Chintan Gandhi, MD to an independent researcher in the field of lung innate immunity and host defense. Dr. Gandhi is establishing himself as a basic and translational researcher focusing on innate immune responses to respiratory infections with a focus on the respiratory syncytial virus (RSV). Although RSV is the leading cause of mortality due to viral respiratory illnesses in children worldwide, there are no virus-specific treatments or vaccines currently available. This is partly due to an incomplete understanding of the interaction between the virus and the immature host immune system. Age at initial infection and male sex are independent risk factors for RSV severity. Surfactant protein A (SP-A), an innate immune protein, regulates phagocytic and inflammatory functions of alveolar macrophages (AMs) through the surfactant protein-A-receptor 210 (SP- R210). SP-A genetic variants and low levels of SP-A are associated with RSV severity. Dr. Gandhi reported associations of young age and the 1A0 variant of SFTPA2 (SFTPA2-1A0) with RSV severity in children. The focus of this proposal is to investigate the underlying mechanisms of those associations using a humanized transgenic neonatal mouse model of RSV carrying the SFTPA2-1A0 variant. The central hypothesis is that SP- A genetic variants and male sex converge to dysregulate the SP-A/SP-R210 pathway in neonatal AMs leading to delayed RSV clearance and excessive inflammation. The central hypothesis will be tested via the following Specific Aims: 1) determine how SFTPA2-1A0 regulates in vivo AM differential responses to RSV in male and female pups, and 2) elucidate mechanisms of the SFTPA2-1A0 mediated dysfunction of SP-A/SP-R210 pathway in RSV clearance and define in vivo therapeutic effects of exogenous SP-A in neonatal RSV infection. These studies will yield important information about the SP-A/SP-R210 signaling as a novel pathway in RSV severity and will also determine if SP-A, its receptor, SP-R210, or the modulation of the SP-A/SP-R210 pathway may be future therapeutic targets for RSV infection. During the award period, Dr. Gandhi will continue to develop his expertise in immunology, molecular biology, and genetics. In addition, Dr. Gandhi will develop skills in flow cytometry and microscopic approaches to study viral dynamics. A multidisciplinary mentorship team has been assembled to ensure the success of this project, and includes expertise in virus biology, pathogenesis, and development of novel antiviral agents (Dr. Lukacher); lung cell purification, culture protocols, and advanced life imaging techniques (Dr. Chroneos); and mechanisms of sex differences in neonatal pulmonary diseases (Dr. Lingappan). The mentorship team will guide Dr. Gandhi in meeting his training objectives through direct research experience, formal didactics, and participation in career development opportunities. The research described in this proposal is innovative and will be a substantive addition to the knowledge gap and will help Dr. Gandhi to become an independent R01-funded investigator.

Narrative Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants with a global disease burden of 64 million cases and 160,000 deaths with healthcare costs estimated at $365-$585 million per year. The objective of the current research proposal is to elucidate the role of human SP-A genetic variant and sex in RSV severity and to get insight into the mechanisms of host factors that govern the severity of RSV disease. This will lead to the development of novel approaches and individualized therapeutic options for severe RSV infection.