? DESCRIPTION (provided by applicant): HIV and morphine increase susceptibility to lung opportunistic infections by modulating TLR2/IL17A mediated lung inflammation. HIV-1 and chronic opioids independently correlate with high incidence of opportunistic respiratory infections. Chronic Morphine abuse, by itself, has been shown to increase the pathogenic load in lung infections. Together, both factors lead to an early immunosuppression, followed by a toll-like receptor (TLR) and interleukin-17 (IL17) induced persistent inflammation. Although current literature seems to implicate circulating immune cells for this inflammation, our preliminary studies show a robust TLR2 mediated IL17 response in murine lungs and we show the bronchial epithelium being the source of the cytokine. While initial inflammatory response is beneficial towards containment of an infection, a persistent hyper-inflammation is detrimental to the lung mucosa in the long run. Under normal circumstances, an opportunistic infection brings about a tightly regulated balance between TLR and IL17 receptor (IL17R) mediated signaling resulting in an initial cytokine (primarily IL17) burst, followed by dampening of the signal. This balance is lost in the context of chronic morphine and likely HIV-1 infection. We have also seen putative cross talk between the TLR2 and IL17R pathways, mediated by the first messenger/adaptor molecules (MyD88 and Act1/CIKS respectively), which could potentially explain the tight control of IL-17A mediated inflammation in the lungs, otherwise disrupted by chronic morphine and HIV-1. In this study, we will attempt to define the lung inflammation dynamics using A) Chronic morphine model, B) Pneumococcus lung infection model, both well-established in our laboratory and C) Humanized BLT mice (Jackson Laboratories), infected with CCR5-tropic HIV-1 using the established protocols. Finally, we use these models individually and in combination to dissect the interplay of HIV, TLR/IL-17 mediated inflammation, risk factors like clinical or recreational use of morphine in the progression of HIV-linked lung diseases. Collectively, this study will (A) help us define the exact dynamics of lung inflammation in the context of chronic morphine, HIV infection and opportunistic pathogenic attack and (B) will generate clinically relevant information, implicating a static target (bronchial epithelia) and defined pathways (TLR2 and IL17R) for therapeutic intervention, compared to a systemic intervention (circulating immune cells) in the context of HIV and respiratory inflammation.
|Effective start/end date||9/1/15 → 6/30/18|
- National Heart, Lung, and Blood Institute: $191,875.00
- National Heart, Lung, and Blood Institute: $228,000.00
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