Researchers strengthen the case for sexual transmission of Zika virus

December 20, 2016
Although Zika is primarily thought of as mosquito-borne illness, sexual transmission plays an important role in the spread of the virus. Weeks or even months after the virus has been cleared from the bloodstream, Zika can still be found in semen and transmitted through sexual contact. Women can pass the virus to their unborn babies during pregnancy. Credit: Dr. Kenneth Kim and Dr. Gina Kirchweger, La Jolla Institute for Allergy and Immunology

Aedes aegypti mosquitoes harboring parasitic Zika virus (ZIKV) are the primary transmitters of virus to humans, potentially causing catastrophic congenital microcephaly in babies born to women bitten by infected mosquitoes. But confirmation earlier this year by the Centers for Disease Control and Prevention (CDC) that ZIKV can also be sexually transmitted raised new alarm that virus could be passed between sexual partners in venues far from mosquito habitats.

Now La Jolla Institute for Allergy & Immunology (LJI) investigator Sujan Shresta, Ph.D., employs two different mouse models to confirm that live ZIKV placed directly in the vagina infects the mouse's reproductive tract, replicates, moves into the bloodstream, and causes clinical signs of disease. Intriguingly, that study published in the December 20, 2016 issue of Cell Reports, also reports that the stage of the reproductive cycle during which a female mouse is exposed to virus determines vulnerability to infection. If applicable to humans, this discovery has public health implications for to a population of great concern, women of child-bearing age.

"Currently, almost all of our efforts in terms of Zika prevention focus on mosquito control," says Shresta, an associate professor in LJI's Center for Infectious Disease. "Our new work begs clinicians to also address whether sexual transmission of the virus constitutes a small or large proportion of cases."

Investigators knew that virus hides in semen of men who contract ZIKV from mosquitoes and that virus is transmitted vaginally in rodent models. But the biological questions—what cells are infected, how stable the virus is in bodily fluids—were unanswered. Shresta's group began to explore them by placing live ZIKV in the vaginas of that had been genetically engineered to be immunocompromised.

But before the procedure, they treated mice with hormones to create two groups that differed with regard to where they were in their menstrual cycle. Dramatic differences emerged post-infection: mice infected in the diestrus or in between phase became progressively sick, lost weight, and died in 2-3 weeks, as one might predict in these mice. Remarkably, the same strain of immunocompromised AG129 mice infected in estrus phase showed no sign of disease.

William Weihao Tang, the study's first author, calls this one the paper's most intriguing findings. "The strain of mice we used, called AG129, were originally engineered to be extremely vulnerable to infection," he says. "But even these mice, when infected in estrus phase, appeared completely resistant to virus. That surprised us."

Shresta says that a caveat is that responses in mouse strains like AG129, which were purposely engineered to serve as a "lethal" model of infection, must be tested in mice with greater immune function. "For science to be relevant to humans, we always confirm results in the most 'immunocompetent' mouse that better reflects a normal human immune system."

To do that, her team repeated experiments in an entirely different type of engineered mouse, one only moderately susceptible to infection, which scientists call a "non-lethal" model. When infected in diestrus phase, those mice lost weight and exhibited clinical signs of disease but, unlike their AG129 counterparts, eventually recovered. However, just like the AG129 mice, when infected in estrus phase "non-lethal" mice showed no sign of Zika-like disease.

This trend was reflected in other experimental outcomes. For example, in both lethal and non-lethal strains, viral RNA, which serves as direct evidence of virus, persisted in the vaginal canal sometimes as long as 10 days post-infection in diestrus. By contrast, viral RNA disappeared three days after infection in estrus phase.

Virus persistence in vaginal fluids may account for why diestrus-infected mice become sick, regardless of mouse strain, yet the molecular or cellular basis for susceptibility remains unclear. Mice analyzed in the study were experimentally synchronized or "staged" at one of two reproductive phases by hormonal injection, which may provide a clue. "Hormones changed the mouse female reproductive tract in ways that either enhanced or protected against sexual transmission," says Tang, although he and Shresta caution it is much too early to generalize mouse findings to humans.

But if similar mechanisms prove relevant to human transmission, they are cause for concern, largely because most Zika-infected men or women show few or no symptoms. Thus they could unwittingly engage in sexual activity resulting in adult disease or even in utero transfer of virus to an unborn child.

Recent CDC "case counts" suggest that thus far that few Zika cases in the US were likely transmitted sexually. But these numbers are estimates, and sexual transmission of ZIKV is taken extremely seriously in other regions, such as South America. In fact, one mathematical modeling study of Baranquilla, Colombia, estimated that as many as 47% of Zika cases reported there emerged from sexual contact.

"In humans may be a bigger deal than has been thought," says Shresta, emphasizing that currently we know very little about this mode of Zika transmission. "We know that in males virus can remain in semen for possibly months, while a man shows no symptoms. During that time he could unknowingly pass it to a sexual partner."

The next step for the Shresta lab is to take advantage of these two mouse models to define immune signals that make mice susceptible to or protected from ZIKV infection. "We are ultimately interested in drugs or vaccines to prevent the disease," says Shresta, who has also used immunodeficient as models to study dengue infection. "Being able to test interventions in two animal models, one that succumbs to infection and another that recovers, is a plus. Developing vaccines requires access to models representing all scenarios."

Explore further: Scientists develop new mouse model to aid Zika virus research

More information: "A Mouse Model of Zika Virus Sexual Transmission and Vaginal Viral Replication" Cell Reports, DOI: 10.1016/j.celrep.2016.11.070 , http://www.cell.com/cell-reports/fulltext/S2211-1247(16)31644-8

Related Stories

Scientists develop new mouse model to aid Zika virus research

November 17, 2016
Researchers have developed a new mouse model that could be used in Zika research to better understand the virus and find new treatments, according to a study published in PLOS Pathogens.

Zika virus may persist in the vagina days after infection

August 25, 2016
The Zika virus reproduces in the vaginal tissue of pregnant mice several days after infection, according to a study by Yale researchers. From the genitals, the virus spreads and infects the fetal brain, impairing fetal development. ...

Mouse study hints at damage Zika may cause to adult brain

October 25, 2016
(HealthDay)—Certain brain cells in adults may be vulnerable to damage from Zika infection, research with mice suggests.

Women at greater risk for Zika infection due to suppressed vaginal immune response

November 16, 2016
Scientists at the Gladstone Institutes discovered that the vaginal immune system is suppressed in response to RNA viruses, such as Zika. The delayed antiviral immune response allows the virus to remain undetected in the vagina, ...

Mouse model reveals extensive postnatal brain damage caused by Zika infection

November 22, 2016
A team of scientists led by researchers at the University of Georgia has developed a new mouse model that closely mimics fetal brain abnormalities caused by the Zika virus in humans.

New Zika mouse model accumulates virus in the brain and other tissues

May 5, 2016
The ongoing Zika virus (ZIKV) epidemic with its link to birth defects and serious immune disease has created an urgent need for a small animal model that can improve our understanding of how the virus causes disease symptoms ...

Recommended for you

Four simple tests could help GPs spot pneumonia and reduce unnecessary antibiotics

November 23, 2017
Testing for fever, high pulse rate, crackly breath sounds, and low oxygen levels could be key to helping GPs distinguish pneumonia from less serious infections, according to a large study published in the European Respiratory ...

New approach to tracking how deadly 'superbugs' travel could slow their spread

November 22, 2017
Killer bacteria - ones that have out-evolved our best antibiotics—may not go away anytime soon. But a new approach to tracking their spread could eventually give us a fighting chance to keep their death toll down.

Research points to diagnostic test for top cause of liver transplant in kids

November 22, 2017
Biliary atresia is the most common cause of liver transplants for children in the United States. Now researchers report in Science Translational Medicine finding a strong biomarker candidate that could be used for earlier ...

Metabolites altered in chronic kidney disease

November 22, 2017
Chronic kidney disease (CKD) affects 1 in 7 people in the United States, according to the U.S. National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK). These individuals have a very high risk of cardiovascular ...

Alcohol consumption and metabolic factors act together to increase the risk of severe liver disease

November 22, 2017
A new study provides insights into the interaction between alcohol consumption and metabolic factors in predicting severe liver disease in the general population. The findings, which are published in Hepatology, indicate ...

Rainfall can indicate that mosquito-borne epidemics will occur weeks later

November 22, 2017
A new study demonstrates that outbreaks of mosquito-borne viruses Zika and Chikungunya generally occur about three weeks after heavy rainfall.Researchers also found that Chikungunya will predominate over Zika when both circulate ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

OverTheMoon
not rated yet Dec 20, 2016
Wow. Sex is getting scarier and scarier. Good thing I'm not having any.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.