Implications of testicular ACE2 and the renin–angiotensin system for SARS-CoV-2 on testis function

Edenfield, R. Clayton; Easley, Charles A.

doi:10.1038/s41585-021-00542-5

Cited by 34 publications

(39 citation statements)

References 230 publications

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“…Our results suggest that SARS-CoV-2 rapidly and efficiently infects multiple tissues of the male genital tract (MGT) early during infection in rhesus macaques. 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] .…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…Multiple groups have shown the presence of viral RNA in cardiac, renal, and brain tissues 7–10 . There is also some evidence of virus in the male genital tract (MGT) 11, 12 . Furthermore, symptoms associated with all these organ systems have been regularly reported 13 .…”

Section: Introductionmentioning

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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“…These studies have yielded mixed results, ranging from some that suggest major roles to some that suggest none. Among possible emerging risk factors, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) should be considered as a factor that might affect testis function, including spermatogenesis and maturation 193 .…”

Section: Considering the Data As A Wholementioning

confidence: 99%

Spatiotemporal trends in human semen quality

2022

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Over the past four decades, studies of various designs have reported spatial and temporal trends in human semen quality. Several standardized-methodology studies in homogeneous populations that compare specific cities within a country or a continent provide clear evidence of geographical differences in sperm production, even over short distances within the same country. Human sperm production is widely believed to be declining over time, but evidence from the scientific literature is less clear. Studies based on repeated cross-sectional data from a single centre have shown mixed results. Among the numerous retrospective studies conducted in a single centre, only some included homogeneous groups of men and appropriate methods, and most of them suggest a temporal decrease in human sperm production in the geographical areas considered. Conclusions reporting temporal trends in sperm production that came from existing retrospective multicentre studies based on individual semen data and those using means, medians or estimates of sperm production are questionable, owing to intrinsic limitations in the studies performed. Regardless of study design, studies on the percentage of motile or morphologically normal spermatozoa are still limited by the inherent variability in assessment. Overall, available data do not enable us to conclude that human semen quality is deteriorating worldwide or in the Western world, but that a trend is observed in some specific areas. To understand these trends and contrasts in sperm and semen quality, prospective studies should be encouraged and combined with assessment of the male exposome.

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“…Thus, studying the cellular, enzymatic, hormonal, and critical gene alterations in the testes of COVID-19 patients should contribute to a better understanding of SARS-CoV-2 biology and its possible impact on testes and male fertility. Recently, Edenfield and Easley(6) published a perspective article in Nature Reviews Urology urging the need to unveil the potential mechanisms involving SARS-CoV-2’s entry and pathophysiological effects on affected subjects.…”

Section: Initroductionmentioning

confidence: 99%

SARS-CoV-2 infects, replicates, elevates angiotensin II and activates immune cells in human testes

Costa

Lacerda

Figueiredo

et al. 2022

Preprint

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Although much has been published since the first cases of COVID-19, there remain unanswered questions regarding SARS-CoV-2 impact on testes and the potential consequences for reproductive health. We investigated testicular alterations in deceased COVID-19-patients, the precise location of the virus, its replicative activity, and the molecules 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 nanosensoring or RT-qPCR using a specific methodology. Macrophages and spermatogonial cells are the main SARS-CoV-2 lodging sites and 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 infection, suggesting that the testes may serve as a viral sanctuary. Further, infected testes show thickening of the tunica propria, germ cell apoptosis, Sertoli cell barrier loss, evident hemorrhage, angiogenesis, Leydig cell inhibition, inflammation, and fibrosis. Finally, our findings indicate that high angiotensin II levels and activation of mast cells and macrophages may be critical for testicular pathogenesis. Importantly, our data suggest that patients who become critically ill exhibit severe damages and may harbor the active virus in testes.

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Implications of testicular ACE2 and the renin–angiotensin system for SARS-CoV-2 on testis function

Cited by 34 publications

References 230 publications

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

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

Spatiotemporal trends in human semen quality

SARS-CoV-2 infects, replicates, elevates angiotensin II and activates immune cells in human testes

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