October 31, 2016

expert reaction to study looking at Zika infection and testes and sperm in mice

Researchers publishing in the journal Nature have looked at the effects of Zika virus infection in mice and report that infection with certain strains was associated with damage to the testes of male mice, cell death and lower testosterone levels.

All our previous output on this subject can be seen here. The SMC also produced a Factsheet on the Zika virus.

Prof. Allan Pacey, Professor of Andrology, University of Sheffield, said:

“The more we learn about the Zika virus, the more interesting and alarming it becomes.  However, I must urge caution over the interpretation of these results and the implications that they may or may not have for human health.

“Firstly, the experiments were performed in mice and there is no guarantee that the effects shown will necessarily be replicated in humans. Whilst we do have some effective animal models for some sexually transmitted infections (e.g. Chlamydia) it is not currently certain if the mouse is an effective model organism for the Zika virus.

“Secondly, whilst the damage that the Zika virus appears to be causing to the mouse testicles in these experiments, we don’t yet know if it has a permanent impact on fertility which is the critical factor. However, the types of effects being observed are similar to that seen following human infection with other sexually transmitted infections.

“Thirdly, the images which appear to show Zika infection of mature sperm are very plausible but are similar to other images published over the years apparently showing other bacteria and viruses attached to sperm obtained from infected individuals. But in interpreting such images it’s always been unclear whether the attachment was real or whether the sperm were dead or alive. If we are to conclude that Zika piggy-backs on the back of sperm as the mechanism by which it affects other individuals, then more proof is needed.

“Finally, in spite of my reservations about how to interpret this particular data, I absolutely agree that we do need innovative animal studies like this. They certainly help to explore the physiology of the virus and try and make sense of how it is incubated and transmitted. They will ultimately help guide future studies in human subjects which are really needed as our evidence base about Zika is really poor at present.”

Dr Peter Barlow, British Society for Immunology spokesperson and Reader in Immunology & Infection at Edinburgh Napier University said:

“In humans, Zika virus has been shown to be present in the semen of males for many months after symptoms appear, but the direct effects of the virus on the male reproductive tract are largely unknown. This study used mice to look at how Zika virus could infect, and survive, in the testes over time. This is particularly important as Zika virus can be sexually transmitted between humans, although such transmission is currently thought to be rare.

“The study showed that one strain of Zika virus, which could efficiently infect mice, caused a decrease in the size and weight of the testes in mice, and caused damage to parts of the testes that produce semen. Zika also altered the levels of hormones that influence the production of sperm. All of these effects translated to much lower rates of pregnancy when the male mice that had been infected with Zika were mated with females. However, it is worth noting that when another strain of Zika virus was compared, one that did not replicate well in mice, the damage to the testes was not as serious. It is not currently known if all strains of Zika virus would have the same effects.

“While it is currently unclear if Zika virus infection would cause reduced testes size and fertility in man, this study does raise concerns that Zika virus could potentially have direct effects on male fertility. Therefore, more work is needed to determine if these observations in mice would translate to men.”

Dr Derek Gatherer, Lecturer in the Division of Biomedical and Life Sciences, Lancaster University, said:

“It’s been known for a while that Zika virus in men can find its way into the reproductive organs and may then go on to be sexually transmitted, but this study in mice is the first suggestion that this passage through the reproductive tract may actually be damaging.

“Zika-infected mice were found to have signs of inflammation in their testes, lower sperm counts, and when mated with females had fewer live offspring.

“Whether the results are relevant to human Zika infection remains to be seen, since Zika does not normally cause disease in mice and an immune-suppressing antibody had to be administered for the Zika infection to progress.

“Nevertheless, some clinical reports of pain in the lower pelvis of Zika patients, and blood in their sperm would be consistent with a similar effect happening in humans.

“The question of whether or not male Zika patients develop subsequent fertility problems ought to be answerable by comparing the numbers of children born to that group, and their sperm counts, against a social and age matched Zika-negative group. At the moment we just don’t know the answer.”

Prof. Richard Sharpe, Honorary Professor, MRC Centre for Reproductive Health, and expert in male reproductive health, University of Edinburgh, said:

“This well-conducted study shows that male mice infected with one strain of Zika virus develop severe impairment of testis structure and function over several weeks following infection. This appears to involve direct infection of Sertoli cells and germ cells which then results in a series of changes, such as cell death and invasion by immune cells, and pronounced inflammatory-like changes within the testes. This results in progressive damage to testis architecture and impaired hormonal and spermatogenic function in the infected mice. From the data presented, I would predict that much of this damage would be irreversible in these mice even once the infection was controlled.

“The big question is whether the same course of events might happen in men infected with Zika, because if so, it could well result in permanent loss of or reduction in fertility. As the present study reports, there is already some evidence that Zika infects the human testis (including sperm) plus anecdotal reports of testicular and groin pain, but the reality is that we do not know yet if effects shown here in the mouse can or will occur in humans. For sure, any generalised infection of the testes bad enough to provoke an immune reaction within the testes is bad news for testis function and sperm generation, but we also know that viruses can show highly species-specific effects.  So the answer is that we just don’t know.

“However, these new findings strongly suggest that testes function in human men infected with Zika should be closely investigated so that we can try and establish whether or not Zika poses a new threat to male reproductive function.”

‘Zika virus infection damages the testes in mice’ by Jennifer Govero et al. published in Nature on Monday 31 October 2016. 

Declared interests

Prof. Allan Pacey: “Chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology, Editor in Chief of Human Fertility and Trustee of the Progress Educational Trust (all unpaid). Also, recent work for the World Health Organisation, British Broadcasting Corporation, Purple Orchid Pharma (paid consultancy with all monies going to University of Sheffield). Co-applicant on a research grant from the Medical Research Council (ref: MR/M010473/1).”

Dr Peter Barlow: “No interests to declare.”

Dr Derek Gatherer: “Derek Gatherer has no conflict of interest relevant to the subject of Zika virus.”

Prof. Richard Sharpe: “No conflicts.”