The effect of Strongyloides stercoralis on HTLV-1 disease progression

项目总结/摘要 HTLV-1是一种逆转录病毒，在全世界感染了1000 - 2000万人，在秘鲁的血清阳性率为2-3%。 HTLV-1感染CD 4 + T淋巴细胞，导致细胞永生化。临床表现包括 自身免疫性疾病（尤其是HTLV-1相关的脊髓病伴热带痉挛性下肢轻瘫）， 调节性T细胞数量增加，导致特定感染（包括 类圆线虫过度感染和皮肤感染）和恶性转化（T细胞淋巴增生性 包括成人T细胞白血病/淋巴瘤（ATL）的疾病。一旦确诊，ATL往往是迅速致命的，但 它只有在长时间的潜伏期后才会发生，通常是>30年的感染。 HTLV-1易感染粪类圆线虫（SS）。SS是一种土壤传播的 据估计，这种线虫感染了全球1亿多人。大多数SS感染导致很少 症状SS与HTLV-1感染的成人T细胞白血病/淋巴瘤的早发相关 患者SS加速HTLV-1受试者ATL发展的确切机制尚不清楚。 明白合并感染与前病毒载量增加有关。我们展示了一个 共感染患者中调节性T细胞的增加。最近的研究表明， 慢性类圆线虫病的细菌移位我们假设SS感染导致 HTLV-1前病毒负荷、细胞增殖和免疫调节，这反过来又使患者容易出现以下情况 恶性转化这可能是由于细菌移位，非特异性或抗原特异性 淋巴细胞增殖或调节性T细胞增加。为此，我们将利用3个独特的 特征：a）在我们秘鲁利马的研究所跟踪的一个大的HTLV-1患者队列，B）最近的 观察到CADM 1在HTLV-1感染细胞的表面上唯一表达，和c）CADM 1在HTLV-1感染细胞的表面上唯一表达，和 作为T细胞的细胞转化的早期标志物的CD 7表达降低的相关性。 本项目的具体目标是检验两个假设：1）粪类圆线虫感染导致 增加的HTLV-1前病毒载量，增加的感染细胞数量，和早期转化的 感染的CD 4 + T细胞。我们将比较前病毒载量和受感染的CD 4 + T细胞的数量， 使用CADM 1染色的外周血和CD 7（转化的早期标志物）的损失。在HTLV-1/SS中 类圆线虫病治疗前和治疗后6个月内的合并感染患者;合并感染病例 随访>5年或对照组; HTLV-1/SS共感染患者前瞻性随访。2)早期细胞 转化（CADM 1阳性，CD 7低）由以下机制驱动： 淋巴细胞增殖（前病毒负荷、自发性和抗原驱动的淋巴细胞增殖）;细菌性 易位和相关炎症，和/或调节性T细胞的扩增。 SS感染作为淋巴组织增生性疾病辅助因子的重要性，并探索更多 在HTLV-1患者以及一般人群中，

PROJECT SUMMARY / ABSTRACT HTLV-1 is a retrovirus that infects 10-20 million people worldwide with a seroprevalence of 2-3% in Peru. HTLV-1 infects CD4+ T lymphocytes, causing cells to be immortalized. Clinical manifestations include autoimmune diseases (especially HTLV-1 associated myelopathy with tropical spastic paraparesis), increased numbers of regulatory T-cells and susceptibility leading to specific infections (including Strongyloides hyperinfection and skin infections), and malignant transformation (T-cell lymphoproliferative disorders including Adult T-cell Leukemia/Lymphoma (ATL). Once diagnosed, ATL is often rapidly fatal, but it only develops after a prolonged latent period, typically >30 years of infection. HTLV-1 predisposes to infection with Strongyloides stercoralis (SS). SS is a soil-transmitted nematode that infects an estimated over 100 million people worldwide. Most SS infections cause few symptoms. SS is associated with early onset of Adult T-cell Leukemia/Lymphoma in HTLV-1 infected patients. The exact mechanism by which SS accelerates ATL development in HTLV-1 subjects is not understood. Co-infection has been associated with an increase in proviral load. We have demonstrated an increase in regulatory T-cells in co-infected patients. Recent studies have demonstrated evidence of bacterial translocation in chronic strongyloidiasis. We hypothesize that SS infection leads to increased HTLV-1 proviral load, cellular proliferation, and immunomodulation, which in turn predisposes patients to malignant transformation. This might be due to bacterial translocation, non-specific or antigen-specific lympho-proliferation, or increased regulatory T-cells. To this purpose, we will take advantage of 3 unique features: a) a large cohort of HTLV-1 patients being followed at our institute in Lima Peru, b) the recent observation that CADM1 is uniquely expressed on the surface of HTLV-1 infected cells, and c) the association of decreased expression of CD7 as an early marker of cellular transformation for T-cells. The specific aims of this project will test two hypotheses: 1) Strongyloides stercoralis infection leads to increased HTLV-1 proviral load, increased numbers of infected cells, and early transformation of infected CD4+ T-cells. We will compare proviral load and number of infected CD4+ T-cells in the peripheral blood using CADM1 staining and loss of CD7 (an early marker for transformation). In HTLV-1/SS co-infected patients before and up to six months after treatment of strongyloidiasis; cases of co-infection with >5 years’ follow-up or controls; HTLV-1/SS coinfected patient following prospectively. 2) Early cell transformation (CADM1 positive, CD7 low) is driven by the following mechanisms: a) Viral driven lymphoproliferation (proviral load, spontaneous and antigen-driven lymphoproliferation); bacterial translocation and associated inflammation, and/or expansion of regulatory T-cells These studies will test the importance of SS infection as a co-factor in lymphoproliferative disorders and explore a rationale for more aggressive approaches to SS in HTLV-1 patients as well as in general populations.