RSV Specific Responses in Viral Elimination &Disease

University Of Rochester, Rochester NY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Respiratory Syncytial Virus (RSV) infects most infants in their first year. Symptoms are normally mild, and the immune response clears the viral infection. In some cases RSV causes serious lower respiratory tract disease, including wheezing, and patients may require mechanical ventilation. Infants with severe initial infections have a high risk of subsequently developing asthma. Recipients of an unsuccessful vaccine developed worse disease when subsequently infected with natural RSV, and two died. Thus the immune system can normally deal with RSV infection, but the exact nature of the protective response is unknown. Several different T cell responses to infection have been defined by their associated cytokines. Type 1 responses (Interferon gamma, IFNgamma) help to cure infections by viruses and intracellular bacteria and parasites; and Type 2 responses (Interleukins 4 and 5) help to cure worm infections but also contribute to allergy and asthma. We propose that these two responses are differentially involved in clearance of RSV versus severe disease symptoms. Specifically, we hypothesize that Type 1 responses help to clear the viral infection, whereas Type 2 responses cause the immunopathology that mediates severe symptoms in some patients. We will test the first part of our model by analyzing the viral load and IFNgamma responses of T cells from RSV-infected infants at different times during primary infection. As only small volumes of blood are available from infants, we will use the single-cell Elispot and our new Fluorispot and Lysispot assays to measure cytokine secretion and cytotoxicity by RSV-specific T cells. We predict that at times when only some infants have cleared the virus, those infants will have higher IFNgamma responses than infants who still shed RSV. The second part of our hypothesis will be tested by measuring the numbers of cells secreting IL-4 and/or IL-5 in the acute and memory responses. We predict that Type 2 responses will be higher in those infants with severe symptoms, and that these will still be detectable in the memory response before the next RSV season. Definition of immune responses associated with severe symptoms and viral clearance should aid in the future design of immunotherapy and vaccines for RSV disease in infants.