Long-term impact of persistent parainfluenza virus infection

Seasonal respiratory RNA viruses, including human parainfluenza viruses (HPIVs) infect every child and can reinfect individuals later in life. Globally, HPIVs are responsible for 725,000 hospitalizations and >34,000 deaths per year with HPIV1 being the major cause of croup. In addition to acute complications, severe disease from HPIV infection early in life associates with the development of chronic lung pathologies, including asthma, impacting a large fraction of the adult population. Based on observations in immunocompromised patients, persistence of respiratory RNA viruses is suspected to drive the development and maintenance of these chronic lung diseases. However, respiratory RNA virus persistence in immunocompetent hosts remains largely understudied. Studies on the mechanisms and consequences of persistent RNA virus infections are critical to expand our understanding of the biology, ecology, and evolution of common viruses of clinical importance and may reveal solutions to debilitating chronic illnesses. Infection of mice with the murine parainfluenza virus type 1 (best known as Sendai virus; SeV) results in acute disease and virus clearance that is followed by the development of expanding pathology with characteristics of type 2 inflammation, similar to what is observed during asthma in humans. Using immunocompetent mice, we recently demonstrated the persistence of viral proteins and viral RNA in a subset of hematopoietic cells infiltrating the lung. Persistently infected cells were found long after the acute infection was cleared. We also showed that cells expressing persistent viral proteins had transcriptomic signatures consistent with pathogenic chronic inflammation. Importantly, ablation of cells exposed to the virus significantly decreased the severity of chronic lung inflammation, suggesting that viral persistence is a key factor in the establishment and maintenance of chronic post-viral lower respiratory tract disease. Here, we will use this murine model to determine where and how the virus persists in hematopoietic cells (Aim 1). We will also study the long-term impact of SeV infection in the structural cells of the upper and lower respiratory tracts (Aim 2), and we will further explore the long-term impact of parainfluenza virus infection on chronic post-viral disease and susceptibility to future viral infections (Aim 3). Overall, our studies will advance our understanding of the mechanism mediating the establishment and maintenance of persistent viral products, as well as the long-term impact of parainfluenza virus infection on the host’s health. We expect that knowledge gained from these studies will be applicable to other RNA respiratory viral infections that affect every child, including respiratory syncytial virus, human metapneumovirus, and rhinoviruses. Project Number: 1R01AI188900-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Carolina Lopez | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $596,115 | Activity Code: R01 | Study Section: Viral Pathogenesis and Immunity Study Section [VPI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18890001A1