Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

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 agai...

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Autores principales:	Youchao Dai, Yi Cai, Xin Wang, Jialou Zhu, Xiaoqian Liu, Houming Liu, Linghua Li, Yinze Zhang, Shengze Liu, Zhihua Wen, Carl G. Feng, Xinchun Chen, Xiaoping Tang
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	HIV erythrophagocytosis heme oxygenase-1 autophagy tuberculosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9a7e959c21d5477f9a3f1ffe35a2382c
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spelling	oai:doaj.org-article:9a7e959c21d5477f9a3f1ffe35a2382c2021-11-15T15:56:57ZAutoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients10.1128/mBio.03246-192150-7511https://doaj.org/article/9a7e959c21d5477f9a3f1ffe35a2382c2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03246-19https://doaj.org/toc/2150-7511ABSTRACT 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.Youchao DaiYi CaiXin WangJialou ZhuXiaoqian LiuHouming LiuLinghua LiYinze ZhangShengze LiuZhihua WenCarl G. FengXinchun ChenXiaoping TangAmerican Society for MicrobiologyarticleHIVerythrophagocytosisheme oxygenase-1autophagytuberculosisMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV erythrophagocytosis heme oxygenase-1 autophagy tuberculosis Microbiology QR1-502
spellingShingle	HIV erythrophagocytosis heme oxygenase-1 autophagy tuberculosis Microbiology QR1-502 Youchao Dai Yi Cai Xin Wang Jialou Zhu Xiaoqian Liu Houming Liu Linghua Li Yinze Zhang Shengze Liu Zhihua Wen Carl G. Feng Xinchun Chen Xiaoping Tang Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients
description	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.
format	article
author	Youchao Dai Yi Cai Xin Wang Jialou Zhu Xiaoqian Liu Houming Liu Linghua Li Yinze Zhang Shengze Liu Zhihua Wen Carl G. Feng Xinchun Chen Xiaoping Tang
author_facet	Youchao Dai Yi Cai Xin Wang Jialou Zhu Xiaoqian Liu Houming Liu Linghua Li Yinze Zhang Shengze Liu Zhihua Wen Carl G. Feng Xinchun Chen Xiaoping Tang
author_sort	Youchao Dai
title	Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients
title_short	Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients
title_full	Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients
title_fullStr	Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients
title_full_unstemmed	Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients
title_sort	autoantibody-mediated erythrophagocytosis increases tuberculosis susceptibility in hiv patients
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/9a7e959c21d5477f9a3f1ffe35a2382c
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Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

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