Chikungunya virus (CHIKV) is a reemerging alphavirus that recently spread throughout the world via its mosquito vectors. The virus has high potential to inflict significant morbidity and mortality worldwide, including the U.S., with initial transmissions reported in Florida. Older adults are particularly sensitive to severe CHIKV disease (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 of highly debilitating arthritis/arthralgia for months and years. While we are beginning to understand CHIKV pathogenesis and immunity, we are far from even scratching the surface on the mechanisms of age-related vulnerability 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 dysfunction of the immune response to CHIKV infection. We found an increase in TGF?, concomitant with qualitative and quantitative impairments in B and T cell responses which failed to clear the virus. We showed that anti-TGF? antibody blockade could prevent the age-related increase in CHIKV disease severity, reduce joint pathology and improve production of neutralizing antibodies. TGF? was also elevated and neutralizing Ab reduced in older humans suffering from CHIKV, making our model potentially directly relevant to older adults. Here, we propose to dissect mechanisms that lead to dysregulated TGF? production and to elucidate how TGF? contributes to increased pathology and decreased CHIKV control. Our central hypothesis is that that in old CHIKV-infected mice, increased TGF? dysregulates type 1 (T1) immunity against CHIKV by acting upon 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 suboptimal adaptive 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 pave the way for immune interventions against CHIKVD/chronic arthritis in older adults.
At the end of the support period, our experiments should provide detailed insights into pathogenesis and immunity against CHIKV in old organisms, providing clues on why older individuals suffer disproportionally from CHIKV diseases. Together with other studies in humans, these experiments will pave way to specific immune interventions against CHIKV arthritis in older adults.
