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

Giannakopoulos, Stefanos; Strange, Daniel P.; Jiyarom, Boonyanudh; Abdelaal, Omar; Bradshaw, Aaron; Nerurkar, Vivek R.; Ward, Monika A.; Bakse, Jackson; Yap, Jonathan; Vanapruks, Selena; Boisvert, William A.; Tallquist, Michelle D.; Shikuma, Cecilia; Sadri‐Ardekani, Hooman; Clapp, Phillip; Murphy, Sean V.; Verma, Saguna

doi:10.1101/2022.09.21.508904

Cited by 2 publications

(5 citation statements)

References 85 publications

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“…As expected, the virus was cleared from the lungs by D8 (Fig. S1C and D) and there was no infectious virus detected in the testis as shown in our previous study (21) and Fig. S1D.…”

Section: Resultssupporting

confidence: 86%

“…However, a recent longitudinal cohort study indicated a significant increase in inflammatory and linked to multiple-organ damage and immune dysfunction during both acute stage of disease and in long COVID patients (23,24). Our data obtained with the K18-hACE2 transgenic mice demonstrated gross pathology in the testis during the acute stage of the disease (21) similar to testicular injury observed in post-mortem COVID patients, thus supporting the use of these mice to assess the long-term impact of SARS-CoV-2 infection on testes.…”

Section: Introductionmentioning

confidence: 44%

“…The copyright holder for this preprint this version posted November 1, 2023. ; https://doi.org/10.1101/2023.10.31.565042 doi: bioRxiv preprint Severe morphological alterations in the testis are observed during the acute stage of the disease and the recovery stage in SARS-CoV-2-infected hACE2 mice. We previously reported that SARS-CoV-2 infection in K18-hACE2 mice leads to gross histopathological changes in the testis during the acute stage of the disease in the absence of any active virus replication in the testis (21). To further understand the long-term implications of the infection on the injury and to quantify different types of defects at different stages of the disease, we monitored survivor mice for up to 30 days post-infection (D30).…”

Section: Resultsmentioning

confidence: 99%

“…# FNN0071). SARS-CoV-2 titers in the normalized tissue homogenates were measured by plaque assay using Vero E6 cells as described previously (21). Intracellular viral genome copies were measured in the RNA extracted from cell lysates and tissue homogenates at different time points post-infection by qRT-PCR as described by us previously (21).…”

Section: Infection Of K18-hace2 Mice and Virus Quantitationmentioning

confidence: 99%

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SARS-CoV-2 infection leads to sustained testicular injury and functional impairments in K18 hACE2 mice

Giannakopoulos,

Ward,

Bakse

et al. 2023

Preprint

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Compromised male reproductive health is one of the symptoms of long COVID with a decrease in male fertility markers including testosterone levels and sperm count for months in recovering patients. However, the long-term impact of SARS-CoV-2 infection on testicular injury and underlying mechanisms remains unknown. We previously demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis during the acute stage of the disease in K18-hACE2 mice. Here, we systematically delineate the consequences of SARS-CoV-2 infection on the testis injury and function both during the acute stage of the disease and up to 4 weeks after infection in survivor K18-hACE2 mice. The gross morphological defects included sloughing of healthy spermatids and spermatocytes into the lumen, lack of lumen, and increase in apoptotic cells that sustained for at least 2 weeks after infection. Testis injury correlated with systemic and testicular inflammation, and infiltration of immune cells in the interstitial space and seminiferous tubules. Transcriptomic analysis identified dysregulation of key pathways of testicular immune homeostasis, spermatogenesis, and cell death at the symptomatic and short-term recovery stages. Further, a significant reduction in testosterone levels was associated with transient reduction in sperm count and mouse fertility. Most of the testicular impairments except testosterone levels were resolved within 4 weeks, which is almost one spermatogenesis cycle in mice. These findings provide much-needed mechanistic insights beyond our current understanding of testicular pathogenesis, suggesting that recovering COVID-19 patients should be closely monitored to rescue the pathophysiological effects on male reproductive health.

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“…As expected, the virus was cleared from the lungs by D8 (Fig. S1C and D) and there was no infectious virus detected in the testis as shown in our previous study (21) and Fig. S1D.…”

Section: Resultssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 44%

Section: Resultsmentioning

confidence: 99%

Section: Infection Of K18-hace2 Mice and Virus Quantitationmentioning

confidence: 99%

See 2 more Smart Citations

SARS-CoV-2 infection leads to sustained testicular injury and functional impairments in K18 hACE2 mice

Giannakopoulos,

Ward,

Bakse

et al. 2023

Preprint

Self Cite

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show abstract

“…However, exposure of seminiferous tubule cells and human testicular organoids to inflammatory supernatant from infected airway epithelial cells and Covid‐19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Authors of this study also suggest that exposure of testicular cells to both cytokine storm and viral antigens may trigger pathological pathways and apoptotic death of germ cells that may be responsible for orchitis symptoms and lower sperm counts reported in Covid‐19 patients 69 …”

Section: Comorbidities Associated With Covid‐19 Morbidity and Mortali...mentioning

confidence: 67%

Men, testosterone and Covid‐19

Groti Antonic,

Antonic,

Caliber

et al. 2023

Clinical Endocrinology

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Men have more severe Coronavirus disease 2019 (Covid‐19) outcomes and higher mortality rates than women, and it was suggested that testosterone levels might promote severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and Covid‐19 severity. However, clinical studies have not supported this theory. Studies have consistently shown that serum testosterone concentrations during acute Covid‐19 in men are inversely proportional to the inflammatory cytokines and severity of illness. It is likely that lower testosterone concentrations in this setting are a result of acute Covid‐19 illness on the hypothalamic–pituitary–testicular axis. Clinical trials that attempted to lower testosterone concentrations further or block androgen signaling acutely during Covid‐19 in men did not result in improved Covid‐19 outcomes. Additionally, pre‐existing male hypogonadism, diagnosed before Covid‐19 pandemic, was found to be a risk factor for hospitalization from Covid‐19. In this review, we also discuss the preclinical and mechanistic studies that have evaluated the role of androgens in SARS‐CoV‐2 infection and illness. Finally, long‐term consequences of Covid‐19 on male reproductive health are reviewed. SARS‐CoV‐2 virus is known to infiltrate testis and induce orchitis in men, but it is unclear if Covid‐19 leads to an increase in incidence of male hypogonadism.

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

Cited by 2 publications

References 85 publications

SARS-CoV-2 infection leads to sustained testicular injury and functional impairments in K18 hACE2 mice

SARS-CoV-2 infection leads to sustained testicular injury and functional impairments in K18 hACE2 mice

Men, testosterone and Covid‐19

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