Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America.
PLoS Negl Trop Dis. 2023 Nov 20;17(11):e0011742. doi: 10.1371/journal.pntd.0011742. eCollection 2023 Nov.
Mayaro virus (MAYV) is a mosquito-transmitted alphavirus that causes debilitating and persistent arthritogenic disease. While MAYV was previously reported to infect non-human primates (NHP), characterization of MAYV pathogenesis is currently lacking. Therefore, in this study we characterized MAYV infection and immunity in rhesus macaques. To inform the selection of a viral strain for NHP experiments, we evaluated five MAYV strains in C57BL/6 mice and showed that MAYV strain BeAr505411 induced robust tissue dissemination and disease. Three male rhesus macaques were subcutaneously challenged with 105 plaque-forming units of this strain into the arms. Peak plasma viremia occurred at 2 days post-infection (dpi). NHPs were taken to necropsy at 10 dpi to assess viral dissemination, which included the muscles and joints, lymphoid tissues, major organs, male reproductive tissues, as well as peripheral and central nervous system tissues. Histological examination demonstrated that MAYV infection was associated with appendicular joint and muscle inflammation as well as presence of perivascular inflammation in a wide variety of tissues. One animal developed a maculopapular rash and two NHP had viral RNA detected in upper torso skin samples, which was associated with the presence of perivascular and perifollicular lymphocytic aggregation. Analysis of longitudinal peripheral blood samples indicated a robust innate and adaptive immune activation, including the presence of anti-MAYV neutralizing antibodies with activity against related Una virus and chikungunya virus. Inflammatory cytokines and monocyte activation also peaked coincident with viremia, which was well supported by our transcriptomic analysis highlighting enrichment of interferon signaling and other antiviral processes at 2 days post MAYV infection. The rhesus macaque model of MAYV infection recapitulates many of the aspects of human infection and is poised to facilitate the evaluation of novel therapies and vaccines targeting this re-emerging virus.
马亚罗病毒（MAYV）是一种通过蚊子传播的甲病毒，可引起使人虚弱且持续的关节炎疾病。虽然此前已有报道称 MAYV 可感染非人类灵长类动物（NHP），但目前对 MAYV 发病机制的特征描述仍存在不足。因此，在本研究中，我们对恒河猴中的 MAYV 感染和免疫进行了特征描述。为了明确用于 NHP 实验的病毒株，我们在 C57BL/6 小鼠中评估了 5 株 MAYV 毒株，并表明 MAYV 株 BeAr505411 可诱导大量组织扩散和疾病。将三只雄性恒河猴皮下接种该毒株的 105 噬菌斑形成单位至手臂。感染后 2 天达到血浆病毒血症峰值。在 10 dpi 对 NHP 进行尸检以评估病毒扩散情况，包括肌肉和关节、淋巴组织、主要器官、雄性生殖组织以及周围和中枢神经系统组织。组织学检查表明，MAYV 感染与附肢关节和肌肉炎症以及多种组织中存在血管周围炎症有关。一只动物出现斑丘疹皮疹，两只 NHP 的上半身皮肤样本中检测到病毒 RNA，与血管周围和滤泡周围淋巴细胞聚集有关。对纵向外周血样本的分析表明存在强烈的固有和适应性免疫激活，包括存在对相关 Una 病毒和基孔肯雅病毒具有中和活性的抗 MAYV 中和抗体。炎症细胞因子和单核细胞激活也与病毒血症同时达到峰值，我们的转录组分析突出强调了 MAYV 感染后 2 天干扰素信号和其他抗病毒过程的富集，很好地支持了这一结果。MAYV 感染恒河猴模型再现了许多人类感染的特征，有望促进针对这种重新出现的病毒的新型治疗方法和疫苗的评估。
