AbstractChikungunya virus (CHIKV) is a reemerging alphavirus that recently spread throughout the world via itsmosquito vectors. The virus has high potential to inflict significant morbidity and mortality worldwide includingthe U.S. with initial transmissions reported in Florida. Older adults are particularly sensitive to severe CHIKVdisease (CHIKVD) which includes fever rash joint pain and sometimes involvement of parenchymal organs(liver brain kidney). Moreover CHIKVD tends to persist in many particularly older subjects in the form ofhighly debilitating arthritis/arthralgia for months and years. While we are beginning to understand CHIKVpathogenesis and immunity we are far from even scratching the surface on the mechanisms of age-relatedvulnerability to CHIKV.We recently developed a mouse model which recapitulates age-related clinical outcomes observed in CHIKV-infected elderly humans and used it to begin to elucidate mechanisms underlying the age-related dysfunctionof the immune response to CHIKV infection. We found an increase in TGF concomitant with qualitative andquantitative impairments in B and T cell responses which failed to clear the virus. We showed that anti-TGFantibody blockade could prevent the age-related increase in CHIKV disease severity reduce joint pathologyand improve production of neutralizing antibodies. TGF was also elevated and neutralizing Ab reduced inolder humans suffering from CHIKV making our model potentially directly relevant to older adults. Here wepropose to dissect mechanisms that lead to dysregulated TGF production and to elucidate how TGFcontributes to increased pathology and decreased CHIKV control. Our central hypothesis is that that in oldCHIKV-infected mice increased TGF dysregulates type 1 (T1) immunity against CHIKV by actingupon soluble factors Th1 B and perhaps Th17 cells. This hypothesis and related questions and sub-hypotheses will be tested in the following Aims: SA1. To test the roles of T and B cell-intrinsic and extrinsic (environmental) factors in suboptimaladaptive responses of old mice to CHIKV. SA2. To examine whether and how elevated TGF acts directly on old adaptive immune cells. These experiments will provide detailed insights into pathogenesis and immunity against CHIKV and pavethe way for immune interventions against CHIKVD/chronic arthritis in older adults.