The long term objective of this project is to determine the properties of saliva that endow the oral cavity with unique resistance and immunologic responsiveness to HIV. Previous studies have demonstrated that defensins, host defense peptides involved in innate immunity, are capable of directly inhibiting HIV infection of susceptible target cells. In addition, defensins are known to activate elements of innate and adaptive immunity (T-cells, monocytes, macrophages, dendritic cells), thus providing signals essential for the acquisition of humoral and/or cell-mediated immunity against a variety of microbial pathogens. Defensins are produced in saliva of humans and non-human primates. This project seeks to characterize the role of salivary defensins in regulating immune responses in the oral cavity of rhesus macaques, a primate with a clinical response to SIV infection that is quite similar to that observed in human HIV infection. Recent studies in the PI's laboratory have demonstrated that, in addition to direct anti-HIV activity of defensin subclasses, these peptides also have profound immunomodulatory activities. We hypothesize that immunoregulation by salivary defensins establishes a unique immunologic milieu in oral mucosa that determines the early response of the host to HIV exposure. An understanding of the interactions between defensins and cellular elements of the oral mucosa will provide insights into the network of interactions that determine the immune responses to SIV in the oral cavity. To achieve these objectives, we propose the following Specific Aims: 1) Quantify the a, ?, and ?-defensin content in whole saliva of healthy and chronically SIV-infected macaques;2) determine the anti-SIV activity of physiologic concentrations of individual and combined peptides in the presence or absence of defensindepleted whole saliva;3) determine the effect of individual and combined salivary defensins on the activation profile of PBMCs, monocytes, monocyte-derived macrophages, monocyte-derived dendritic cells, and CD4+ lymphocytes;and 4) Evaluate the effect of salivary defensins on the infectivity of HIV of oral epithelial cells, the response of oral epithelium to bacterial antigens, and the transport of HIV from the epithelial cells to permissive CD4+ target cells. Taken together, these studies will provide new insights into the unique features of immunity in the oral cavity of rhesus monkeys, thereby guiding preclinical approaches to SIV and HIV vaccine development.
Oral exposure to HIV rarely results in infection in adults. Moreover, antibodies present in the saliva of patients who have been exposed to HIV but who remain uninfected, appear to be protective. This project seeks to understand how small proteins (defensins) produced in saliva influence the resistance of the oral cavity to HIV infection, and how they may be useful in the design of anti-HIV vaccines.
|Schaal, Justin B; Maretzky, Thorsten; Tran, Dat Q et al. (2018) Macrocyclic ?-defensins suppress tumor necrosis factor-? (TNF-?) shedding by inhibition of TNF-?-converting enzyme. J Biol Chem 293:2725-2734|
|Jayne, Jordanna G; Bensman, Timothy J; Schaal, Justin B et al. (2018) Rhesus ?-Defensin-1 Attenuates Endotoxin-induced Acute Lung Injury by Inhibiting Proinflammatory Cytokines and Neutrophil Recruitment. Am J Respir Cell Mol Biol 58:310-319|
|Basso, Virginia; Garcia, Angie; Tran, Dat Q et al. (2018) Fungicidal Potency and Mechanisms of ?-Defensins against Multidrug-Resistant Candida Species. Antimicrob Agents Chemother 62:|
|Bensman, Timothy J; Jayne, Jordanna G; Sun, Meiling et al. (2017) Efficacy of Rhesus Theta-Defensin-1 in Experimental Models of Pseudomonas aeruginosa Lung Infection and Inflammation. Antimicrob Agents Chemother 61:|
|Beringer, Paul M; Bensman, Timothy J; Ho, Henry et al. (2016) Rhesus ?-defensin-1 (RTD-1) exhibits in vitro and in vivo activity against cystic fibrosis strains of Pseudomonas aeruginosa. J Antimicrob Chemother 71:181-8|
|Oh, Young Taek; Tran, Dat; Buchanan, Thomas A et al. (2015) ?-Defensin RTD-1 improves insulin action and normalizes plasma glucose and FFA levels in diet-induced obese rats. Am J Physiol Endocrinol Metab 309:E154-60|
|Tai, Kenneth P; Kamdar, Karishma; Yamaki, Jason et al. (2015) Microbicidal effects of ?- and ?-defensins against antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Innate Immun 21:17-29|
|Tongaonkar, Prasad; Trinh, Katie K; Schaal, Justin B et al. (2015) Rhesus macaque ?-defensin RTD-1 inhibits proinflammatory cytokine secretion and gene expression by inhibiting the activation of NF-?B and MAPK pathways. J Leukoc Biol 98:1061-70|
|Mastroianni, Jennifer R; Lu, Wuyuan; Selsted, Michael E et al. (2014) Differential Susceptibility of Bacteria to Mouse Paneth Cell ?-Defensins under Anaerobic Conditions. Antibiotics (Basel) 3:493-508|
|Tai, Kenneth P; Le, Valerie V; Selsted, Michael E et al. (2014) Hydrophobic determinants of ?-defensin bactericidal activity. Infect Immun 82:2195-202|
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