Persistence of CNS T. pallidum in HIV infection

在美国，梅毒仍然是男男性行为者的主要问题，特别是那些感染艾滋病毒的人。前青霉素时代的研究证明，梅毒螺旋体（导致梅毒的细菌）可以在一些但不是所有患者的疾病过程中早期在脑脊液（CSF）中被鉴定出来，并且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CD 4 + T细胞低，预测NS风险增加。我们假设宿主外周T细胞的免疫缺陷。苍白球清除是NS发展的基础，而NS可能因HIV诱导的免疫抑制而加重。在这个建议中，我们回到梅毒的基本免疫反应来检验我们的假设：T。苍白球被活化的巨噬细胞清除，巨噬细胞摄取并杀死调理的生物体。我们将研究HIV感染和未感染梅毒患者外周血中这一机制的每一步，并确定对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，在TLR 1，2和6基因中具有常见单核苷酸多态性的患者更容易患有NS。假设：一种或多种尚未鉴定的罕见变体对NS易感性的影响比我们研究的TLR SNP更大; 2）确定单核细胞衍生的巨噬细胞（MDM）摄入T.梅毒（“巨噬细胞功能”）和NS在HIV感染和未感染梅毒患者的发展。我们发现，来自正常供体的MDM在摄取调理的Nichols（实验室）菌株T的内在能力方面存在差异。苍白球假设：巨噬细胞摄取调理T。苍白球是宿主固有的属性，在NS患者中受损;与NS相关的苍白球菌株类型抵抗吞噬作用。我们发现NS患者更容易感染T。梅毒tp 0548菌株F型患者的临床症状明显高于无NS的患者。假设：T.与NS相关的苍白球菌株类型比与NS无关的菌株类型被吞噬的程度更小; 4）确定血清调理T.梅毒（“调理能力”）和NS在HIV感染和未感染梅毒患者的发展。我们发现，在HIV感染患者中，与没有CSF异常的患者相比，CSF异常与NS一致的患者血清调理素能力显著降低。假设：与单纯梅毒患者相比，实验室和临床NS患者的血清调理素能力较低; 5）测定T.苍白球蛋白TP 0548。假设：Tp 0548抗体是调理的，调理能力因菌株而异，f型抗血清的调理能力低于 其他类型。这项工作提供了可能改变我们对NS发病机制的理解。

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.