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Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block.

海藻糖通过逆转 HIV 介导的自噬阻滞限制 HIV 合并感染期间机会性分枝杆菌存活。

  • 影响因子:7.01
  • DOI:10.1080/15548627.2020.1725374
  • 作者列表:"Sharma V","Makhdoomi M","Singh L","Kumar P","Khan N","Singh S","Verma HN","Luthra K","Sarkar S","Kumar D
  • 发表时间:2020-02-20
Abstract

:Opportunistic bacterial infections amongst HIV-infected individuals contribute significantly to HIV-associated mortality. The role of HIV-mediated modulation of innate mechanisms like autophagy in promoting opportunistic infections, however, remains obscure. Here we show, HIV reactivation in or infection of macrophages inhibits autophagy and helps the survival of pathogenic Mycobacterium tuberculosis (Mtb) and nonpathogenic non-tuberculous mycobacterial strains (NTMs). The HIV-mediated impairment of xenophagy flux facilitated bacterial survival. Activation of autophagy by trehalose could induce xenophagy flux and kill intracellular Mtb or NTMs either during single or co-infections. Trehalose, we delineate, activates PIKFYVE leading to TFEB nuclear translocation in MCOLN1-dependent manner to induce autophagy. Remarkably, trehalose significantly reduced HIV-p24 levels in ex-vivo-infected PBMCs or PBMCs from treatment-naive HIV patients and also controlled mycobacterial survival within Mtb-infected animals. To conclude, we report leveraging of HIV-mediated perturbed host innate-immunity by opportunistic bacterial pathogens and show an attractive therapeutic strategy for HIV and associated co-morbidities.Abbreviations: AIDS: acquired immune deficiency syndrome; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; BafA1: bafilomycin A1; CFU: colony forming unit; CTSD: cathepsin D; CD63: CD63 molecule; EGFP: enhanced green fluorescent protein; FRET: Förster resonance energy transfer; GABARAP: gamma-aminobutyric acid receptor-associated protein; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GLUT: glucose transporter; HIV: human immunodeficiency virus; hMDMs: human monocyte derived macrophages; IL2: interleukin 2; LAMP1: lysosomal-associated membrane protein 1; LC3B-II: lipidated microtubule-associated proteins 1A/1B light chain 3B; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin; mRFP: monomeric red fluorescent protein; M6PR: mannose-6-phosphate receptor; NAC: N- acetyl- L -cysteine; NTM's: non-tuberculous mycobacteria; PBMC: Peripheral Blood Mononuclear cells; PIKFYVE: phosphoinositide kinase; FYVE-Type Zinc Finger; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; PtdIns(3,5)P2: Phosphatidylinositol 3,5-bisphosphate; ptfLC3: pEGFP-mRFP-LC3; ROS: reactive oxygen species; SQSTM1: sequestosome1; TFEB: transcription factor EB; MCOLN1/TRPML1: mucolipin 1; PIP4P1/TMEM55B: Human trans-membrane Protein 55B; UVRAG: UV Radiation Resistance Associate; VPS35: vacuolar protein sorting associated protein 35; WDR45: WD repeat domain 45; YCAM: Yellow Chameleon.

摘要

: HIV 感染者中机会性细菌感染显著增加 HIV 相关死亡率。然而,HIV 介导的自噬等固有机制的调节在促进机会性感染中的作用仍不清楚。这里我们展示了,HIV 在巨噬细胞中的再激活或感染抑制了自噬,有助于致病性结核分枝杆菌 (Mtb) 和非致病性非结核分枝杆菌菌株 (NTMs) 的存活。HIV 介导的异种通量受损促进了细菌存活。海藻糖激活自噬可诱导异噬流,在单次或共感染过程中杀死细胞内 Mtb 或 NTMs。我们描绘的海藻糖以 MCOLN1-dependent 的方式激活 PIKFYVE 导致 TFEB 核转位以诱导自噬。值得注意的是,海藻糖显著降低了体外感染 pbmc 或未经治疗的 HIV 患者 pbmc 的 HIV-p24 水平,也控制了 Mtb 感染动物体内的分枝杆菌存活率。总之,我们报告了利用 HIV 介导的受干扰的宿主天然免疫的机会致病菌,并显示了 HIV 和相关 co-morbidities.Abbreviations 的一个有吸引力的治疗策略: AIDS: 获得性免疫缺陷综合征; AMPK: AMP 活化蛋白激酶; ATG5: 自噬相关 5; BafA1: bafilomycin A1; CFU: 集落形成单位; CTSD:组织蛋白酶 D; CD63: CD63 分子; EGFP: 增强型绿色荧光蛋白; FRET: f ö rster 共振能量转移; GABARAP: γ-氨基丁酸受体相关蛋白; GAPDH: 3-磷酸甘油醛脱氢酶; GLUT: 葡萄糖转运蛋白; HIV: 人类免疫缺陷病毒 hMDMs: 人单核细胞源性巨噬细胞; IL2: 白细胞介素 2; LAMP1:溶酶体相关膜蛋白 1; LC3B-II: 脂化微管相关蛋白 1A/1B 轻链 3B; Mtb: 结核分枝杆菌; MTOR: 雷帕霉素的机制靶点; mRFP: 单体红色荧光蛋白; m6PR: mannose-6-phosphate 受体; NAC: N-乙酰-L-半胱氨酸; NTM 's: 非结核分枝杆菌; PBMC: 外周血单核细胞; PIKFYVE:磷酸肌醇激酶; FYVE 型锌指; PHA: 植物血凝素; PMA: 佛波酯 12-肉豆蔻酸 13-乙酸酯; PtdIns (3,5) P2: 磷脂酰肌醇 3,5-二磷酸; ptfLC3: pEGFP-mRFP-LC3; ROS: 活性氧; SQSTM1: sequestosome1; TFEB: 转录因子 EB; MCOLN1/TRPML1: 粘液脂素 1; PIP4P1/TMEM55B: 人跨膜蛋白 55B; UVRAG:UV 抗辐射相关蛋白; VPS35: 液泡蛋白分选相关蛋白 35; WDR45: WD 重复结构域 45; YCAM: 黄色变色龙。

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METHODS:BACKGROUND:Ultrasound has been demonstrated to accurately diagnose rectal deep endometriosis (DE) and pouch of Douglas (POD) obliteration. The role of ultrasound in the assessment of patients who have undergone surgery for rectal DE and POD obliteration has not been evaluated. AIM:To describe the transvaginal ultrasound (TVS) findings of patients who have undergone rectal surgery for DE. MATERIALS AND METHODS:An observational cross-sectional study at a tertiary care centre in Sydney, Australia between January and April 2017. Patients previously treated for rectal DE (low anterior resection vs rectal shaving/disc excision) were recruited and asked to complete a questionnaire on their current symptoms. On TVS, POD state and rectal DE were assessed. Correlating recurrence of POD obliteration and/or rectal DE to surgery type and symptoms was done. RESULTS:Fifty-six patients were contacted; 22/56 (39.3%) attended for the study visit. Average interval of surgery to study visit was 52.8 ± 24.6 months. Surgery type breakdown was as follows: low anterior resection (56%) and rectal shaving/disc excision (44%). The prevalence of POD obliteration was 16/22 (72.7%) intraoperatively and 8/22 (36.4%) at study visit, as per the sliding sign. Nine patients (39.1%) had evidence on TVS of recurrent rectal DE. Recurrence of POD obliteration and rectal DE was not associated with surgery type or symptomatology. CONCLUSION:Despite surgery for rectal DE, many patients have a negative sliding sign on TVS, representing POD obliteration, and rectal DE. Our numbers are too small to correlate with the surgery type or their current symptoms.

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METHODS::Minimally invasive surgery for complex endometriosis requires preoperative planning that intimately connects the gynecologic surgeon to the radiologist. Understanding the surgeon's perspective to endometriosis treatment facilitates a productive relationship that ultimately benefits the patient. We examine minimally invasive surgery for endometriosis and the key radiologic information which enable the surgeon to successfully negotiate patient counseling, preoperative planning, and an interdisciplinary approach to surgery.

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