Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Clínica MF Fertilidade Masculina, Belo Horizonte, MG, Brazil.
BMC Biol. 2023 Feb 16;21(1):36. doi: 10.1186/s12915-022-01497-8.
Cellular entry of SARS-CoV-2 has been shown to rely on angiotensin-converting enzyme 2 (ACE2) receptors, whose expression in the testis is among the highest in the body. Additionally, the risk of mortality seems higher among male COVID-19 patients, and though much has been published since the first cases of COVID-19, there remain unanswered questions regarding SARS-CoV-2 impact on testes and potential consequences for reproductive health. We investigated testicular alterations in non-vaccinated deceased COVID-19-patients, the precise location of the virus, its replicative activity, and the immune, vascular, and molecular fluctuations involved in the pathogenesis.
We found that SARS-CoV-2 testicular tropism is higher than previously thought and that reliable viral detection in the testis requires sensitive nanosensors or RT-qPCR using a specific methodology. Through an in vitro experiment exposing VERO cells to testicular macerates, we observed viral content in all samples, and the subgenomic RNA's presence reinforced the replicative activity of SARS-CoV-2 in testes of the severe COVID-19 patients. The cellular structures and viral particles, observed by transmission electron microscopy, indicated that macrophages and spermatogonial cells are the main SARS-CoV-2 lodging sites, where new virions form inside the endoplasmic reticulum Golgi intermediate complex. Moreover, we showed infiltrative infected monocytes migrating into the testicular parenchyma. SARS-CoV-2 maintains its replicative and infective abilities long after the patient's infection. Further, we demonstrated high levels of angiotensin II and activated immune cells in the testes of deceased patients. The infected testes show thickening of the tunica propria, germ cell apoptosis, Sertoli cell barrier loss, evident hemorrhage, angiogenesis, Leydig cell inhibition, inflammation, and fibrosis.
Our findings indicate that high angiotensin II levels and activation of mast cells and macrophages may be critical for testicular pathogenesis. Importantly, our findings suggest that patients who become critically ill may exhibit severe alterations and harbor the active virus in the testes.
已证实 SARS-CoV-2 的细胞进入依赖血管紧张素转换酶 2（ACE2）受体，其在睾丸中的表达是体内最高的之一。此外，男性 COVID-19 患者的死亡率似乎更高，尽管自首例 COVID-19 病例以来已经发表了很多研究，但 SARS-CoV-2 对睾丸的影响及其对生殖健康的潜在后果仍有许多未解之谜。我们研究了未接种疫苗的 COVID-19 死亡患者的睾丸改变、病毒的确切位置、其复制活性以及发病机制中涉及的免疫、血管和分子波动。
我们发现 SARS-CoV-2 的睾丸趋向性高于先前的认识，并且需要使用敏感的纳米传感器或使用特定方法的 RT-qPCR 才能可靠地检测睾丸中的病毒。通过将 VERO 细胞暴露于睾丸匀浆的体外实验，我们观察到所有样本中的病毒含量，并且亚基因组 RNA 的存在增强了严重 COVID-19 患者睾丸中 SARS-CoV-2 的复制活性。通过透射电子显微镜观察到的细胞结构和病毒颗粒表明，巨噬细胞和精原细胞是 SARS-CoV-2 的主要寄居部位，新的病毒粒子在内质网高尔基中间复合物内形成。此外，我们还表明，浸润性感染的单核细胞迁移到睾丸实质中。SARS-CoV-2 在患者感染后很长时间内仍保持其复制和感染能力。此外，我们在已故患者的睾丸中证明了高水平的血管紧张素 II 和激活的免疫细胞。感染的睾丸显示固有层变厚、生殖细胞凋亡、支持细胞屏障丧失、明显出血、血管生成、间质细胞抑制、炎症和纤维化。
我们的研究结果表明，高水平的血管紧张素 II 和肥大细胞和巨噬细胞的激活可能是睾丸发病机制的关键。重要的是，我们的研究结果表明，病情严重的患者可能会出现严重的改变，并在睾丸中存在活跃的病毒。
