Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Infect Immun. 2018 Nov 20;86(12). doi: 10.1128/IAI.00565-18. Print 2018 Dec.
Tuberculosis (TB), caused by , is the leading cause of death among human immunodeficiency virus (HIV)-positive patients. The precise mechanisms by which HIV impairs host resistance to a subsequent infection are unknown. We modeled this coinfection in Mauritian cynomolgus macaques (MCM) using simian immunodeficiency virus (SIV) as an HIV surrogate. We infected seven MCM with SIVmac239 intrarectally and 6 months later coinfected them via bronchoscope with ∼10 CFU of Another eight MCM were infected with alone. TB progression was monitored by clinical parameters, by culturing bacilli in gastric and bronchoalveolar lavages, and by serial [F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging. The eight MCM infected with alone displayed dichotomous susceptibility to TB, with four animals reaching humane endpoint within 13 weeks and four animals surviving >19 weeks after infection. In stark contrast, all seven SIV animals exhibited rapidly progressive TB following coinfection and all reached humane endpoint by 13 weeks. Serial PET/CT imaging confirmed dichotomous outcomes in MCM infected with alone and marked susceptibility to TB in all SIV MCM. Notably, imaging revealed a significant increase in TB granulomas between 4 and 8 weeks after infection in SIV but not in SIV-naive MCM and implies that SIV impairs the ability of animals to contain dissemination. At necropsy, animals with preexisting SIV infection had more overall pathology, increased bacterial loads, and a trend towards more extrapulmonary disease than animals infected with alone. We thus developed a tractable MCM model in which to study SIV- coinfection and demonstrate that preexisting SIV dramatically diminishes the ability to control coinfection.
结核病（TB）是人类免疫缺陷病毒（HIV）阳性患者死亡的主要原因。HIV 损害宿主对随后感染的抵抗力的确切机制尚不清楚。我们使用猴免疫缺陷病毒（SIV）作为 HIV 替代物，在毛里求斯食蟹猕猴（MCM）中模拟了这种合并感染。我们通过直肠内感染 7 只 MCM 的 SIVmac239，并在 6 个月后通过支气管镜用约 10 CFU 的感染另外 6 只 MCM。通过临床参数、胃和支气管肺泡灌洗中培养细菌以及连续[F]氟脱氧葡萄糖（FDG）正电子发射断层扫描/计算机断层扫描（PET/CT）成像来监测 TB 的进展。单独感染的 8 只 MCM 对 TB 表现出二态易感性，其中 4 只动物在 13 周内达到人道终点，4 只动物在感染后>19 周存活。相比之下，所有 7 只 SIV 动物在合并感染后均表现出迅速进展的 TB，并且所有动物在 13 周内均达到人道终点。连续的 PET/CT 成像证实了单独感染的 MCM 存在二态结局，并且所有 SIV MCM 对 TB 均具有易感性。值得注意的是，成像显示在感染后 4 至 8 周，SIV 而非 SIV 未感染的 MCM 中，TB 肉芽肿的数量显著增加，这意味着 SIV 损害了动物控制传播的能力。尸检时，与单独感染的动物相比，预先存在 SIV 感染的动物具有更多的总体病理学、更高的细菌负荷和更多的肺外疾病趋势。因此，我们开发了一种可行的 MCM 模型，用于研究 SIV-合并感染，并证明预先存在的 SIV 极大地降低了控制合并感染的能力。
