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.

中文翻译：

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自身抗体介导的红细胞吞噬作用增加了HIV患者的结核易感性。

巨噬细胞功能障碍与人类免疫缺陷病毒（HIV）感染患者的结核病（TB）易感性增加有关。但是，尚不清楚HIV感染如何削弱巨噬细胞功能的潜在机制。在这里，我们发现，通过直接抗球蛋白测试（DAT）确定，HIV患者中针对红细胞（RBC）的自身抗体水平显着升高。在单变量和多变量分析中，DAT阳性均与结核病发病率显着相关（赔率[OR] = 11.96 [置信区间{CI}，4.68至30.93]和12.65 [3.33至52.75]）。体外分析显示，针对RBC的自身抗体可增强红细胞吞噬作用，从而从机械上显着削弱巨噬细胞对细胞内结核分枝杆菌的杀菌功能，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自噬。沉默ATG5是自噬的关键组成部分，完全消除了红细胞吞噬作用对巨噬细胞对结核分枝杆菌的杀菌活性。总而言之，我们证明了HIV感染会增加自身抗体介导的红细胞吞噬作用。此过程通过抑制HO-1相关的自噬，削弱了巨噬细胞对结核分枝杆菌的杀菌活性。这些发现揭示了关于HIV感染如何增加TB易感性的新机制。重要信息由于CD4 T细胞丢失和巨噬细胞功能障碍，HIV感染显着增加了TB易感性。尽管相对清楚的是CD4 T细胞丢失代表了HIV感染的直接影响，HIV感染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，通过抑制HO-1相关的自噬，从而抑制了巨噬细胞对TB的杀菌活性。我们的发现揭示了一种新颖的机制，可以解释HIV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方法来识别高结核病风险且适合进行抗结核化疗预防性治疗的HIV患者。我们的发现揭示了一种新颖的机制，可以解释HIV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方法来识别高结核病风险且适合进行抗结核化疗预防性治疗的HIV患者。我们的发现揭示了一种新颖的机制，可以解释HIV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方法来识别高结核病风险且适合进行抗结核化疗预防性治疗的HIV患者。