Persistence of CNS T. pallidum in HIV infection

描述：在美国，梅毒仍然是男男性行为者的主要问题，尤其是那些感染了艾滋病毒的人。前青霉素时代的研究表明，梅毒螺旋体，一种引起梅毒的细菌，可以在一些（但不是全部）患者的病程早期在脑脊液（CSF）中被发现，并不是每个梅毒患者都发展为神经梅毒（NS）。我们的工作表明，高血清快速血浆反应素滴度和HIV感染，特别是如果未经治疗或外周血CD4+ T细胞低，预测NS风险增加。我们假设外周苍白球清除过程中的宿主免疫缺陷是NS发展的基础，这可能会因hiv诱导的免疫抑制而加剧。在这个提议中，我们回到对梅毒的基本免疫反应来验证我们的假设：T. pallidum被激活的巨噬细胞清除，巨噬细胞吞噬并杀死被活化的生物体。我们将在hiv感染和未感染的梅毒患者外周血中研究这一机制的每一步，并确定其对NS的影响。具体目的是：1)确定影响HIV感染和未感染梅毒患者NS发展的遗传变异。我们发现，TLR1、2和6基因中存在常见单核苷酸多态性的患者更容易患NS。假设：一个或多个尚未确定的罕见变异比我们研究的TLR snp对NS易感性的影响更大；2)确定hiv感染和未感染梅毒患者单核细胞源性巨噬细胞（MDMs）摄取T. pallidum的能力（“巨噬细胞功能”）与NS发生的关系。我们表明，来自正常供体的MDMs在其摄取被麻醉的尼科尔斯（实验室）菌株苍白球绦虫的内在能力方面存在差异。假设：巨噬细胞摄取被麻痹的苍白球绦虫的能力是NS患者宿主固有的一种特性，这种特性受损；3)判断与NS相关的苍白球绦虫菌株类型是否具有抗吞噬作用。我们发现，与非NS患者相比，NS患者更容易感染T. pallidum tp0548 f型菌株。假设：与NS相关的T. pallidum菌株类型被吞噬的程度低于与NS无关的菌株类型；4)确定hiv感染和未感染梅毒患者血清抗梅毒t细胞能力（“抗梅毒能力”）与NS发生的关系。我们发现，在HIV感染的患者中，与没有CSF异常的患者相比，脑脊液异常与NS一致的患者血清声压能力显着降低。假设：与无并发症梅毒患者相比，实验室和临床NS患者的血清声压能力较低；5)测定抗血清对苍白球绦虫蛋白Tp0548的菌株特异性拮抗能力。假设：针对Tp0548的抗体具有抗音性，且抗音能力因菌株而异，抗f型血清的抗音性比抗f型血清的弱

DESCRIPTION: In the US, syphilis continues to be a major problem in men who have sex with men, especially those infected with HIV. Studies from the pre-penicillin era documented that Treponema pallidum, the bacterium that causes syphilis, could be identified in cerebrospinal fluid (CSF) early in the course of disease in some, but not all, patients, and not every patient with syphilis developed neurosyphilis (NS). Our work has shown that high serum rapid plasma reagin titers, and HIV infection, particularly if untreated or with low peripheral blood CD4+ T cells, predict increased NS risk. We hypothesize that host immune defects in peripheral T. pallidum clearance underlie development of NS, which may be exacerbated by HIV-induced immunosuppression. In this proposal we return to the basic immune response to syphilis to test our hypothesis: T. pallidum is cleared by activated macrophages that ingest and kill opsonized organisms. We will investigate each step in this mechanism in the peripheral blood in HIV-infected and -uninfected patients with syphilis and determine the effect on NS. The Specific Aims are: 1) Identify genetic variants that impact development of NS in HIV- infected and -uninfected patients with syphilis. We show that patients with common single nucleotide polymorphisms in TLR1, 2 and 6 genes are more likely to have NS. Hypothesis: one or more as yet unidentified rare variants have a greater effect on NS susceptibility than the TLR SNPs that we have studied; 2) Determine the relationship between the ability of monocyte-derived macrophages (MDMs) to ingest T. pallidum ("macrophage function") and development of NS in HIV-infected and -uninfected patients with syphilis. We show that MDMs from normal donors differ in their intrinsic ability to ingest opsonized Nichols (laboratory) strain T. pallidum. Hypothesis: the ability of macrophages to ingest opsonized T. pallidum is a property intrinsic to the host that is impaired in patients with NS; 3) Determine whether T. pallidum strain types associated with NS resist phagocytosis. We show that patients with NS are more likely to be infected with T. pallidum tp0548 strain type f than patients without NS. Hypothesis: T. pallidum strain types associated with NS are phagocytosed to a lesser extent than strain types not associated with NS; 4) Determine the relationship between the ability of serum to opsonize T. pallidum ("opsonic capacity") and development of NS in HIV-infected and -uninfected patients with syphilis. We show that, among HIV- infected patients, those with CSF abnormalities consistent with NS have significantly lower serum opsonic capacity compared to those without CSF abnormalities. Hypothesis: serum opsonic capacity is lower in patients with laboratory and clinical NS compared to those with uncomplicated syphilis; 5) Determine strain- specific opsonic capacity of antisera to T. pallidum protein Tp0548. Hypothesis: antibody to Tp0548 is opsonic and opsonic capacity differs by strain, with antisera to type f being less opsonic than antisera to other types. This work offers the potential to transform our understanding of the pathogenesis of NS.