Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients
Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients
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自身抗体介导的噬红细胞作用增加艾滋病毒患者的结核病易感性
DOI：
10.1128/mbio.03246-19
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发表时间：
2020-01-01
期刊：
影响因子：
6.4
通讯作者：
Tang, Xiaoping
中科院分区：
文献类型：
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作者：
Dai, Youchao;Cai, Yi;Tang, Xiaoping
由于CD4T细胞丢失和巨噬细胞功能障碍，艾滋病毒感染显著增加了结核病的易感性。虽然相对清楚的是，CD4T细胞的丢失代表了HIV感染的直接影响，但HIV感染如何抑制巨噬细胞功能的机制尚不清楚。在这里，我们表明，HIV感染增强了自身抗体介导的红细胞吞噬作用，这通过抑制HO-1相关的自噬来抑制巨噬细胞对结核病的杀菌活性。我们的发现揭示了一种新的机制，解释了艾滋病毒感染如何增加对结核病的易感性。我们建议，DAT可以作为一种潜在的措施来识别具有高结核病风险且适合进行抗结核化疗预防治疗的HIV患者。摘要巨噬细胞功能障碍与人类免疫缺陷病毒(HIV)感染患者结核病易感性增加有关。然而，HIV感染如何损害巨噬细胞功能的潜在机制尚不清楚。在这里，我们发现，通过直接抗球蛋白试验(DAT)确定的HIV患者中，针对红细胞(RBC)的自身抗体水平显著升高。在单因素和多因素分析中，DAT阳性与结核病发病率显著相关(优势比[OR] = 分别为11.96[可信区间{CI}，4.68~30.93]和12.65[3.33~52.75])。体外分析表明，抗红细胞自身抗体增强红细胞吞噬功能，从而显著削弱巨噬细胞对细胞内结核分枝杆菌的杀菌功能。在机制上，自身抗体介导的红细胞吞噬作用增加了血红素加氧酶-1(HO-1)的表达，从而抑制了结核分枝杆菌诱导的巨噬细胞的自噬。沉默ATG5是自噬的关键成分，完全消除了红细胞吞噬对巨噬细胞杀灭结核分枝杆菌活性的影响。总之，我们已经证明了HIV感染增加了自身抗体介导的红细胞吞噬功能。这一过程通过抑制HO-1相关的自噬来削弱巨噬细胞对结核分枝杆菌的杀菌活性。这些发现揭示了艾滋病毒感染如何增加结核病易感性的新机制。重要性艾滋病毒感染显著增加了由于CD4T细胞丢失和巨噬细胞功能障碍而导致的结核病易感性。虽然相对清楚的是，CD4T细胞的丢失代表了HIV感染的直接影响，但HIV感染如何抑制巨噬细胞功能的机制尚不清楚。在这里，我们表明，HIV感染增强了自身抗体介导的红细胞吞噬作用，这通过抑制HO-1相关的自噬来抑制巨噬细胞对结核病的杀菌活性。我们的发现揭示了一种新的机制，解释了艾滋病毒感染如何增加对结核病的易感性。我们建议，DAT可以作为一种潜在的措施来识别具有高结核病风险且适合进行抗结核化疗预防治疗的HIV患者。
HIV infection significantly increases TB susceptibility due to CD4 T-cell loss and macrophage dysfunction. Although it is relatively clear that CD4 T-cell loss represents a direct effect of HIV infection, the mechanism underlying how HIV infection dampens macrophage function is unknown. Here, we show that HIV infection enhances autoantibody-mediated erythrophagocytosis, which dampens macrophage bactericidal activity against TB by inhibiting HO-1-associated autophagy. Our findings reveal a novel mechanism explaining how HIV infection increases susceptibility to TB. We propose that DAT could be a potential measure to identify HIV patients who are at high TB risk and who would be suitable for anti-TB chemotherapy preventive treatment. ABSTRACT Macrophage dysfunction is associated with increased tuberculosis (TB) susceptibility in patients with human immunodeficiency virus (HIV) infection. However, the mechanisms underlying how HIV infection impairs macrophage function are unclear. Here, we found that levels of autoantibodies against red blood cells (RBCs) were significantly elevated in patients with HIV as determined by direct antiglobulin test (DAT). DAT positivity was significantly associated with TB incidence in both univariate and multivariate analyses (odds ratio [OR] = 11.96 [confidence interval {CI}, 4.68 to 30.93] and 12.65 [3.33 to 52.75], respectively). Ex vivo analysis showed that autoantibodies against RBCs enhanced erythrophagocytosis and thus significantly impaired macrophage bactericidal function against intracellular Mycobacterium tuberculosis. Mechanistically, autoantibody-mediated erythrophagocytosis increased heme oxygenase-1 (HO-1) expression, which inhibited M. tuberculosis-induced autophagy in macrophages. Silencing ATG5, a key component for autophagy, completely abrogated the effect of erythrophagocytosis on macrophage bactericidal activity against M. tuberculosis. In conclusion, we have demonstrated that HIV infection increases autoantibody-mediated erythrophagocytosis. This process impairs macrophage bactericidal activity against M. tuberculosis by inhibiting HO-1-associated autophagy. These findings reveal a novel mechanism as to how HIV infection increases TB susceptibility. IMPORTANCE HIV infection significantly increases TB susceptibility due to CD4 T-cell loss and macrophage dysfunction. Although it is relatively clear that CD4 T-cell loss represents a direct effect of HIV infection, the mechanism underlying how HIV infection dampens macrophage function is unknown. Here, we show that HIV infection enhances autoantibody-mediated erythrophagocytosis, which dampens macrophage bactericidal activity against TB by inhibiting HO-1-associated autophagy. Our findings reveal a novel mechanism explaining how HIV infection increases susceptibility to TB. We propose that DAT could be a potential measure to identify HIV patients who are at high TB risk and who would be suitable for anti-TB chemotherapy preventive treatment.