HIV and morphine increase susceptibility to lung opportunistic infections by modulating TLR2/IL17A mediated lung inflammation

 描述(由申请人提供)：艾滋病毒和吗啡通过调节TLR2/IL17A介导的肺部炎症增加肺部机会性感染的易感性。艾滋病毒-1和慢性阿片类药物与机会性呼吸道感染的高发病率独立相关。慢性吗啡滥用本身已被证明增加了肺部感染的致病负荷。这两个因素共同导致早期免疫抑制，随后是Toll样受体(TLR)和白介素17(IL17)诱导的持续性炎症。尽管目前的文献似乎表明循环免疫细胞与这种炎症有关，但我们的初步研究表明，TLR2介导的IL17在小鼠肺中有强大的反应，我们发现支气管上皮是细胞因子的来源。虽然最初的炎症反应有利于控制感染，但从长远来看，持续的过度炎症对肺粘膜是有害的。在正常情况下，机会性感染会导致TLR和IL17受体(IL17R)介导的信号之间的严格调控平衡，导致最初的细胞因子(主要是IL17)爆发，随后信号受到抑制。这种平衡在慢性吗啡和可能感染艾滋病毒-1的情况下失去了。我们还看到了TLR2和IL17R通路之间可能的串扰，由第一信使/适配器分子(分别为MyD88和Act1/CIKS)介导，这可能解释了IL-17A介导的肺部炎症的严格控制，否则被慢性吗啡和HIV-1干扰。在这项研究中，我们将尝试使用A)慢性吗啡模型，B)肺炎球菌肺部感染模型，以及C)人源化BLT小鼠(Jackson实验室)，使用所建立的方案感染CCR5嗜性HIV-1。最后，我们单独和结合使用这些模型来剖析HIV、TLR/IL-17介导的炎症、临床或娱乐使用吗啡等危险因素在HIV相关肺部疾病进展中的相互作用。总而言之，这项研究将(A)帮助我们确定慢性吗啡、艾滋病毒感染和机会性致病攻击背景下肺部炎症的确切动力学，(B)将产生临床相关信息，涉及用于治疗干预的静态靶点(支气管上皮)和明确的途径(TLR2和IL17R)，而不是艾滋病毒和呼吸道炎症背景下的全身干预(循环免疫细胞)。

 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.