Alveolar macrophages from persons living with HIV show impaired epigenetic response to Mycobacterium tuberculosis
Alveolar macrophages from persons living with HIV show impaired epigenetic response to Mycobacterium tuberculosis
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DOI：
10.1172/jci148013
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发表时间：
2021-11-15
影响因子：
15.9
通讯作者：
Schurr, Erwin
中科院分区：
文献类型：
--
作者：
Correa-Macedo, Wilian;Fava, Vinicius M.;Schurr, Erwin
艾滋病毒感染者 (PLWH) 患结核病 (TB) 的风险较高。 HIV 相关结核病通常是最近感染结核分枝杆菌 (M. tuberculosis) 后迅速进展为疾病的结果。肺泡巨噬细胞 (AM) 是先天免疫系统中最先接触结核分枝杆菌的细胞，但 HIV 和抗逆转录病毒治疗 (ART) 如何影响 AM 的抗分枝杆菌反应尚不清楚。为了调查 HIV 和 ART 对 AM 对结核分枝杆菌的转录组和表观遗传反应的影响，我们通过支气管肺泡灌洗从 20 名接受 ART 的 PLWH、16 名未感染 HIV 的对照受试者 (HC) 和 14 名接受 ART 作为暴露前预防 (PrEP) 以预防 HIV 感染的受试者中获得了 AM。在体外用结核分枝杆菌攻击后，每组的 AM 都表现出重叠但不同的基因谱，以响应结核分枝杆菌而显着上调和下调基因。相比之下，从 PLWH 和 PrEP 受试者中分离出的 AM 表现出明显较弱的转录反应。此外，来自接受结核分枝杆菌攻击的 HC 受试者的 AM 会出现明显的染色质可及性变化，而从 PLWH 和 PrEP 受试者获得的 AM 的染色质状态没有显着变化。总的来说，这些结果揭示了 ART 对 AM 的表观遗传景观和转录反应性的不利影响比 HIV 更强。
Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (M. tuberculosis) followed by rapid progression to disease. Alveolar macrophages (AMs) are the first cells of the innate immune system that engage M. tuberculosis, but how HIV and antiretroviral therapy (ART) affect the anti-mycobacterial response of AMs is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AMs to M. tuberculosis, we obtained AMs by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as preexposure prophylaxis (PrEP) to prevent HIV infection. Following in vitro challenge with M. tuberculosis, AMs from each group displayed overlapping but distinct profiles of significantly up-and downregulated genes in response to M. tuberculosis. Comparatively, AMs isolated from both PLWH and PrEP subjects presented a substantially weaker transcriptional response. In addition, AMs from HC subjects challenged with M. tuberculosis responded with pronounced chromatin accessibility changes while AMs obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state. Collectively, these results revealed a stronger adverse effect of ART than HIV on the epigenetic landscape and transcriptional responsiveness of AMs.