HIV/SIV infections lead to a breakdown of the integrity of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression can result in candidiasis, necrotizing gingivitis, periodontitis, hairy leukoplakia, increased oral tumors, and can also contribute to and predict distal disease complications elsewhere. ROR?t+ innate lymphoid cells type 3 (ILC3) produce IL-17 and IL-22 and are vital for maintaining the integrity of the GI epithelium, mediating mucosal antimicrobial defense and stability of commensal microflora, but others and we have recently shown massive, systemic alterations in ILC3 numbers and functions in the oral, reproductive and gastrointestinal mucosae (Li and Reeves, Front Immunol, 2013; Li et al., PLoS Path, 2014). Furthermore, in our unpublished preliminary data we show: 1. SIV infection induces a highly inflammatory and cytotoxic ILC3 phenotype in the oral cavity; 2. Efficient depletion in oral, colorectal, and vaginal mucosae using a novel ILC3-depleting antibody developed by our laboratory specifically for rhesus macaques. 3. Dysbiosis of specific microbial species is associated with chronic immune activation; and 4. Probiotic therapy reduces immune activation during SIV infection and induces expansion of functional ILC3 numbers in the mucosae. In this innovative and transformative proposal we will evaluate the core hypothesis that ILC3 act as a sensitive and targetable modulator for mucosal homeostasis, immune activation, and microflora in the oral cavity through three complementary specific aims: 1. Experimentally determine the role of ILCs in modulating the oral microbiome and oral mucosae homeostasis; 2. Define the kinetics, activation, and detailed immunologic effects of SIV infection on ILCs and microbiome in the oral cavity; and 3. Investigate the effects of probiotic therapy on oral ILCs and microbiome during chronic treated and untreated SIV infection.
The microbiota of the oral cavity and gastrointestinal tract are critical for shaping immunity and maintaining tissue homeostasis. A major function of recently described innate lymphoid cells (ILCs) is regulation of the microbiome. However, ILCs are depleted and have dysregulated function in HIV and SIV infections. The net result in HIV/SIV disease includes dysbiosis, increased inflammation, tissue-disruption and poor mucosal immune responses. In this proposal we will explore the mechanisms of SIV-induced dysregulation of ILCs and microbiome in the oral mucosae, and propose to restore ILC functions and microbial homeostasis through enhancing the microbiota via probiotic therapy.
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| Autissier, Estelle; Li, Haiying; Goepfert, Paul A et al. (2018) Short Communication: Apoptotic Membrane Microparticles Quantified by Fluorescent Bead-Based Assay Are Elevated in HIV and SIV Infections. AIDS Res Hum Retroviruses 34:446-448 |
| Manickam, Cordelia; Nwanze, Chiadika; Ram, Daniel R et al. (2018) Progressive lentivirus infection induces natural killer cell receptor-expressing B cells in the gastrointestinal tract. AIDS 32:1571-1578 |
| Mudd, Joseph C; Busman-Sahay, Kathleen; DiNapoli, Sarah R et al. (2018) Hallmarks of primate lentiviral immunodeficiency infection recapitulate loss of innate lymphoid cells. Nat Commun 9:3967 |
| Shah, Spandan V; Manickam, Cordelia; Ram, Daniel R et al. (2017) Innate Lymphoid Cells in HIV/SIV Infections. Front Immunol 8:1818 |
