Neutrophil-driven mucosal dysfunction in SIV/malaria co-infection

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PROJECT SUMMARY/ABSTRACT With more than 37 million people living with HIV (PLWH) and an additional 1.7 million new infections per year, HIV remains one of the world’s most devastating diseases. Moreover, in 2018, infection with malaria was reported to have reached 228 million cases worldwide and to have caused over 405,000 deaths. Although advances have been made in reducing the incidence of both HIV and malaria, the risk of infection with either disease is still great, especially in resource-limited countries. Importantly, as HIV and malaria are endemic to similar areas, the geographical overlap constitutes a great risk for co-infection, fueling the transmission and pathogenesis of both diseases. HIV and malaria have each been shown to cause gastrointestinal (GI) pathologies, including disruption of the epithelial barrier and elevated microbial translocation. These disease characteristics are highly associated with risk of morbidity and mortality; however, the underlying biological mechanisms by which they occur remain unclear. Previous work suggested that inflammatory neutrophils accumulate, are hyperactivated, and have prolonged survival capabilities in the GI tract during SIV/HIV infection. Additionally, prior studies demonstrated that alterations in neutrophil function associates with malaria pathogenesis. However, the role of neutrophils in mucosal dysfunction and risk for morbidity and mortality in the context of HIV/malaria co-infection has not been established. Our global hypothesis is that malaria co-infection of SIV-infected rhesus macaques will result in increased neutrophil accumulation and hyperactivity in the GI tract, which will lead to elevated immune activation, epithelial barrier dysfunction and microbial translocation. In the proposed project, we aim to longitudinally assess neutrophil kinetics and function throughout malaria infection of SIV-infected rhesus macaques. Additionally, we will characterize the role of neutrophils in exacerbated mucosal immune activation, barrier integrity, and microbial translocation in SIV/malaria co-infected macaques. Finally, we will utilize in vitro co-culture systems to investigate the use of neutrophil targeting strategies to limit inflammatory responses and restore barrier integrity. In sum, these studies will generate critical knowledge of the impact of malaria co-infection on SIV-associated immune dysfunction. Moreover, these experiments will lay the groundwork for future pre-clinical and clinical studies targeting neutrophils to reduce intestinal inflammation and restore mucosal homeostasis. Ultimately, the successful completion of this project will propel the development of more effective therapies for use in resource-limited settings, where the burden of HIV and malaria are greatest.