Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection by Intranasal or Intratesticular Route Induces Testicular Damage

Li, Can; Ye, Zhanhong; Zhang, Anna Jinxia; Chan, Jasper Fuk‐Woo; Song, Wenchen; Liu, Feifei; Chen, Yanxia; Kwan, Mike Yat Wah; Lee, Andrew Chak-Yiu; Yan, Zhao; Wong, Bosco Ho-Yin; Yip, Cyril Chik-Yan; Cai, Jian‐Piao; Sridhar, Siddharth; Jin, Dong-Yan; Chu, Hin; To, Kelvin Kai‐Wang; Yuen, Kwok‐Yung

doi:10.1093/cid/ciac142

Cited by 31 publications

(29 citation statements)

References 35 publications

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“…Prolonged testicular damage after acute COVID-19 was shown in an animal study [ 32 ], and other endocrine organs including the hypothalamus, pituitary gland, adrenal gland, and thyroid gland are also likely to be affected by COVID-19 from the acute phase through to the chronic phase [ 33 , 34 ]. In addition to pulmonary and neurological damage, direct infiltration of SARS-CoV-2 into the hypothalamus or pituitary gland may activate related autoimmunity and then induce an ME/CSF-like condition through central hypogonadism [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Detection of Male Hypogonadism in Patients with Post COVID-19 Condition

Yamamoto

Otsuka

Sunada

et al. 2022

JCM

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The pathogenesis and prognosis of post COVID-19 condition have remained unclear. We set up an outpatient clinic specializing in long COVID in February 2021 and we have been investigating post COVID-19 condition. Based on the results of our earlier study showing that “general fatigue” mimicking myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the most common symptom in long COVID patients, a retrospective analysis was performed for 39 male patients in whom serum free testosterone (FT) levels were measured out of 61 male patients who visited our clinic. We analyzed the medical records of the patients’ backgrounds, symptoms and laboratory results. Among the 39 patients, 19 patients (48.7%) met the criteria for late-onset hypogonadism (LOH; FT < 8.5 pg/mL: LOH group) and 14 patients were under 50 years of age. A weak negative correlation was found between age and serum FT level (r = −0.301, p = 0.0624). Symptoms including general fatigue, anxiety, cough and hair loss were more frequent in the LOH group than in the non-LOH group (FT ≥ 8.5 pg/mL). Among various laboratory parameters, blood hemoglobin level was slightly, but significantly, lower in the LOH group. Serum level of FT was positively correlated with the levels of blood hemoglobin and serum total protein and albumin in the total population, whereas these interrelationships were blurred in the LOH group. Collectively, the results indicate that the incidence of LOH is relatively high in male patients, even young male patients, with post COVID-19 and that serum FT measurement is useful for revealing occult LOH status in patients with long COVID

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Section: Discussionmentioning

confidence: 99%

Detection of Male Hypogonadism in Patients with Post COVID-19 Condition

Yamamoto

Otsuka

Sunada

et al. 2022

JCM

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“…The complex vasculature and known ACE2 expression of the tissues of the MGT make it a potential target of the virus 11,[41][42][43] . The SARS-CoV-2 infection of the testicles has been reported in mouse and hamster respiratory challenge models [44][45][46] . Likewise, the testicles are also a target of Ebola and Zika virus during systemic infection 47 .…”

Section: Discussionmentioning

confidence: 99%

An immunoPET probe to SARS-CoV-2 reveals early infection of the male genital tract in rhesus macaques

Madden

Thomas

Blair

et al. 2022

Preprint

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Because of the recognized systemic nature of SARS-CoV-2 infection, a non-invasive and unbiased method is needed to clarify its spatiotemporal dynamics in vivo after transmission. We recently developed a probe based on the anti-SARS-CoV-2 spike antibody CR3022 to study SARS-CoV-2 pathogenesis in vivo. Herein, we describe its use in immunoPET to investigate SARS-CoV-2 infection of rhesus macaques. Using PET/CT imaging of macaques at different times post-SARS-CoV-2 inoculation, we demonstrate that the 64Cu-labelled CR3022-F(ab′)2 probe targeting the spike protein of SARS-CoV-2 can be used to study the dynamics of infection within the respiratory tract and uncover novel sites of infection. Differences in lung pathology between infection with the WA1 isolate and the delta variant were readily observed using immunoPET and corroborated CT lung pathology. The ability of the probe to illuminate lung-associated pathology demonstrates its specificity and function to detect infection in PET scan. The 64Cu-CR3022-probe also demonstrated dynamic changes occurring between 1- and 2-weeks post-infection. Remarkably, a robust signal was seen in the male genital tract (MGT) of all three animals studied. Infection of the MGT was validated by immunofluorescence imaging of infected cells in the testicular and penile tissue and severe pathology was observed in the testes of one animal at 2-weeks post-infection. The results presented here underscore the utility of using immunoPET to study the dynamics of SARS-CoV-2 infection to understand its pathogenicity and discover new anatomical sites of viral replication. We provide direct evidence for SARS-CoV-2 infection of the MGT in rhesus macaques revealing the possible pathologic outcomes of viral replication at these sites.

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“…The presence of SARS-CoV-2 RNA in the human postmortem testes tissue is not a common observation and is limited to RT-PCR detection of very low levels of viral genome copies (7). Even in the animal models, subgenomic SARS-CoV-2 RNA was detected only in the intratesticular inoculated hamsters (65). Further, the suggestion that SARS-CoV-2 can infect testes of the rhesus macaques by Madden and colleagues was based on the staining of Spike protein (66) and does not confirm if testis can support active replication of the virus.…”

Section: Discussionmentioning

confidence: 99%

In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury

Giannakopoulos

Strange

Jiyarom

et al. 2022

Preprint

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The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ failure including testicular injury and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury can likely result either from direct virus infection of resident cells or by exposure to systemic inflammatory mediators or virus antigens. We here characterized SARS-CoV-2 infection in different human testicular 2D and 3D models including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not establish a productive infection in any testicular cell types. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma depicted a significant decrease in cell viability and death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 envelope protein, but not Spike or nucleocapsid proteins led to cytopathic effects on testicular cells that was dependent on the TLR2 receptor. A similar trend was observed in the K18h-ACE2 mouse model which revealed gross pathology in the absence of virus replication in the testis. Collectively, data strongly indicates that the testicular injury is not due to direct infection of SARS-CoV-2 but more likely an indirect effect of exposure to systemic inflammation or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection by Intranasal or Intratesticular Route Induces Testicular Damage

Cited by 31 publications

References 35 publications

Detection of Male Hypogonadism in Patients with Post COVID-19 Condition

Detection of Male Hypogonadism in Patients with Post COVID-19 Condition

An immunoPET probe to SARS-CoV-2 reveals early infection of the male genital tract in rhesus macaques

In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury

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