High SARS-CoV-2 tropism and activation of immune cells in the testes of non-vaccinated deceased COVID-19 patients.
High SARS-CoV-2 tropism and activation of immune cells in the testes of non-vaccinated deceased COVID-19 patients.
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DOI：
10.1186/s12915-022-01497-8
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发表时间：
2023-02-16
期刊：
影响因子：
5.4
通讯作者：
Furtado, Marcelo H.
中科院分区：
文献类型：
--
作者：
Costa, Guilherme M. J.;Lacerda, Samyra M. S. N.;Figueiredo, Andre F. A.;Wnuk, Natalia T.;Brener, Marcos R. G.;Andrade, Lidia M.;Campolina-Silva, Gabriel H.;Kauffmann-Zeh, Andrea;Pacifico, Lucila G. G.;Versiani, Alice F.;Antunes, Maisa M.;Souza, Fernanda R.;Cassali, Geovanni D.;Caldeira-Brant, Andre L.;Chiarini-Garcia, Helio;de Souza, Fernanda G.;Costa, Vivian V.;da Fonseca, Flavio G.;Nogueira, Mauricio L.;Campos, Guilherme R. F.;Kangussu, Lucas M.;Martins, Estefania M. N.;Antonio, Loudiana M.;Bittar, Cintia;Rahal, Paula;Aguiar, Renato S.;Mendes, Barbara P.;Procopio, Marcela S.;Furtado, Thiago P.;Guimaraes, Yuri L.;Menezes, Gustavo B.;Martinez-Marchal, Ana;Orwig, Kyle E.;Brieno-Enriquez, Miguel;Furtado, Marcelo H.
关键词：
SARS-CoV-2进入细胞依赖于血管紧张素转换酶2（ACE 2）受体，其在睾丸中的表达是体内最高的。此外，COVID-19男性患者的死亡风险似乎更高，尽管自COVID-19首例病例以来已经发表了很多文章，但关于SARS-CoV-2对睾丸的影响和对生殖健康的潜在后果仍然存在未解之谜。我们研究了未接种疫苗的死亡COVID-19患者的睾丸改变，病毒的精确位置，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睾丸嗜性比以前认为的要高，睾丸中可靠的病毒检测需要使用特定方法的敏感纳米传感器或RT-qPCR。通过将VERO细胞暴露于睾丸浸渍物的体外实验，我们观察到所有样品中的病毒含量，亚基因组RNA的存在增强了SARS-CoV-2在严重COVID-19患者睾丸中的复制活性。通过透射电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的主要寄宿场所，在内质网高尔基中间复合体内形成新的病毒粒子。此外，我们发现浸润性感染单核细胞迁移到睾丸实质。SARS-CoV-2在患者感染后很长时间内保持其复制和感染能力。此外，我们证明了高水平的血管紧张素II和激活的免疫细胞在死者的睾丸。感染的睾丸表现为固有图尼卡增厚、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，高血管紧张素II水平和肥大细胞和巨噬细胞的活化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，重症患者可能会出现严重的改变，并在睾丸中携带活性病毒。在线版本包含补充材料，可通过10.1186/s12915-022-01497-8获得。
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. The online version contains supplementary material available at 10.1186/s12915-022-01497-8.
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DOI：
10.1007/s10096-020-04138-6
发表时间：
2021-05
期刊：
European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology
影响因子：
--
作者：
Beyerstedt S;Casaro EB;Rangel ÉB
通讯作者：
Rangel ÉB
DOI：
10.1038/s41585-021-00542-5
发表时间：
2022-03
期刊：
Nature reviews. Urology
影响因子：
--
作者：
Edenfield RC;Easley CA 4th
通讯作者：
Easley CA 4th
影响因子：
6.7
作者：
Donders GGG;Bosmans E;Reumers J;Donders F;Jonckheere J;Salembier G;Stern N;Jacquemyn Y;Ombelet W;Depuydt CE
通讯作者：
Depuydt CE
影响因子：
5.4
作者：
Che, Zai-qian;Gao, Ping-jin;Zhu, Ding-liang
通讯作者：
Zhu, Ding-liang
影响因子：
4.5
作者：
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Hallak, Jorge