Tweet
Article
Published: 17 October 2022
Retrospective detection of monkeypox virus in the testes of nonhuman primate survivors
Jun Liu, Eric M. Mucker, Jennifer L. Chapman, April M. Babka, Jamal M. Gordon, Ashley V. Bryan, Jo Lynne W. Raymond, Todd M. Bell, Paul R. Facemire, Arthur J. Goff, Aysegul Nalca & Xiankun Zeng
Nature Microbiology (2022)
Abstract
Close contact through sexual activity has been associated with the spread of monkeypox virus (MPXV) in the ongoing, global 2022 epidemic. However, it remains unclear whether MPXV replicates in the testes or is transmitted via semen to produce an active infection. We carried out a retrospective analysis of MPXV-infected crab-eating macaque archival tissue samples from acute and convalescent phases of infection of clade I or clade II MPXV using immunostaining and RNA in situ hybridization. We detected MPXV in interstitial cells and seminiferous tubules of testes as well as epididymal lumina, which are the sites of sperm production and maturation. We also detected inflammation and necrosis during the acute phase of the disease by histological analysis. Finally, we found that MPXV was cleared from most organs during convalescence, including healed skin lesions, but could be detected for up to 37 d post-exposure in the testes of convalescent macaques. Our findings highlight the potential for sexual transmission of MPXV in humans.
...
Discussion
The ongoing 2022 monkeypox outbreak has been linked to sexual contact in patients with laboratory confirmed infection22,23. As MPXV can be transmitted through direct contact with bodily fluid, understanding the biology of MPXV infection of the testes during acute and convalescent phases of the disease, and shedding in semen, has substantial public health implications. By retrospectively analysing infection of MPXV in tissues of crab-eating macaques, a widely used NHP model for studying the pathogenesis and evaluating the efficacy of countermeasures against monkeypox, we showed that MPXV is present in testes during the acute phase of infection. MPXV antigen and messenger RNA (mRNA) were detected both in seminiferous tubules, an immune privileged site of sperm production, and in the lumen of the epididymal ducts, the site of sperm maturation. Importantly, preliminary evidence of persistent infection of MPXV was detected in two convalescent crab-eating macaques that survived MPXV challenge.
The testes are targets of many viral infections, including Zika virus (ZIKV)44, EBOV40,45, MARV39 and CCHFV41 in animal models. Shedding in semen and/or related sexual transmission has also been reported for ZIKV, EBOV, MARV and CCHFV in human patients46,47,48. Although direct evidence of transmission of MPXV via semen has not been reported, it has been hypothesized that sexual contact, including skin-to-skin sexual contact, may underlie some of the transmission of monkeypox in the ongoing 2022 outbreak22,23,49.
Our data provide evidence that MPXV may be shed into semen during both acute and convalescent stages of the disease in crab-eating macaques. MPXV viral DNA has been detected in semen of human patients23,24,50. Isolation of live MPXV from semen is required to confirm that semen contains infectious virus. More recently, infectious MPXV was reported to be isolated from a semen sample collected in the early phase of infection in a patient51.
Our data found that persistent infection of MPXV occurred in the testes, but not in healed skin lesions of two convalescent NHP that survived MPXV challenge until the end of studies at day 37 and day 21 post-exposure, respectively. It seems plausible, therefore, that human transmission in convalescent male patients might occur via semen. However, we hypothesize that few to no crab-eating macaque survivors would have testicular MPXV if we had extended the in-life study phase because persistent virus may be gradually cleared as time progresses. For example, EBOV RNA was detected in 100% of semen samples taken 2–3 months after acute EBOV disease onset, 65% of samples taken 4–6 months after onset, and 26% of samples taken 7–9 months after onset in humans52.
...
Published: 17 October 2022
Retrospective detection of monkeypox virus in the testes of nonhuman primate survivors
Jun Liu, Eric M. Mucker, Jennifer L. Chapman, April M. Babka, Jamal M. Gordon, Ashley V. Bryan, Jo Lynne W. Raymond, Todd M. Bell, Paul R. Facemire, Arthur J. Goff, Aysegul Nalca & Xiankun Zeng
Nature Microbiology (2022)
Abstract
Close contact through sexual activity has been associated with the spread of monkeypox virus (MPXV) in the ongoing, global 2022 epidemic. However, it remains unclear whether MPXV replicates in the testes or is transmitted via semen to produce an active infection. We carried out a retrospective analysis of MPXV-infected crab-eating macaque archival tissue samples from acute and convalescent phases of infection of clade I or clade II MPXV using immunostaining and RNA in situ hybridization. We detected MPXV in interstitial cells and seminiferous tubules of testes as well as epididymal lumina, which are the sites of sperm production and maturation. We also detected inflammation and necrosis during the acute phase of the disease by histological analysis. Finally, we found that MPXV was cleared from most organs during convalescence, including healed skin lesions, but could be detected for up to 37 d post-exposure in the testes of convalescent macaques. Our findings highlight the potential for sexual transmission of MPXV in humans.
...
Discussion
The ongoing 2022 monkeypox outbreak has been linked to sexual contact in patients with laboratory confirmed infection22,23. As MPXV can be transmitted through direct contact with bodily fluid, understanding the biology of MPXV infection of the testes during acute and convalescent phases of the disease, and shedding in semen, has substantial public health implications. By retrospectively analysing infection of MPXV in tissues of crab-eating macaques, a widely used NHP model for studying the pathogenesis and evaluating the efficacy of countermeasures against monkeypox, we showed that MPXV is present in testes during the acute phase of infection. MPXV antigen and messenger RNA (mRNA) were detected both in seminiferous tubules, an immune privileged site of sperm production, and in the lumen of the epididymal ducts, the site of sperm maturation. Importantly, preliminary evidence of persistent infection of MPXV was detected in two convalescent crab-eating macaques that survived MPXV challenge.
The testes are targets of many viral infections, including Zika virus (ZIKV)44, EBOV40,45, MARV39 and CCHFV41 in animal models. Shedding in semen and/or related sexual transmission has also been reported for ZIKV, EBOV, MARV and CCHFV in human patients46,47,48. Although direct evidence of transmission of MPXV via semen has not been reported, it has been hypothesized that sexual contact, including skin-to-skin sexual contact, may underlie some of the transmission of monkeypox in the ongoing 2022 outbreak22,23,49.
Our data provide evidence that MPXV may be shed into semen during both acute and convalescent stages of the disease in crab-eating macaques. MPXV viral DNA has been detected in semen of human patients23,24,50. Isolation of live MPXV from semen is required to confirm that semen contains infectious virus. More recently, infectious MPXV was reported to be isolated from a semen sample collected in the early phase of infection in a patient51.
Our data found that persistent infection of MPXV occurred in the testes, but not in healed skin lesions of two convalescent NHP that survived MPXV challenge until the end of studies at day 37 and day 21 post-exposure, respectively. It seems plausible, therefore, that human transmission in convalescent male patients might occur via semen. However, we hypothesize that few to no crab-eating macaque survivors would have testicular MPXV if we had extended the in-life study phase because persistent virus may be gradually cleared as time progresses. For example, EBOV RNA was detected in 100% of semen samples taken 2–3 months after acute EBOV disease onset, 65% of samples taken 4–6 months after onset, and 26% of samples taken 7–9 months after onset in humans52.
...
