Human Placenta May Be Most Vulnerable To Zika In First Trimester

MedicalResearch.com Interview with:

R. Michael Roberts

Dr. R. Michael Roberts

R. Michael Roberts PhD
Curators’ Distinguished Professor
240b Bond Life Sciences Center
Columbia, Missouri 65211-7310

MedicalResearch.com: What is the background for this study?

Response: My background in placental biology and in communication between the embryo and the mother in early pregnancy made me curious about how the zika virus (ZIKV) crossed the placenta in early pregnancy to cause microcephaly. My group had been working on a laboratory model for placental trophoblast for over 10 years. We generate trophoblast from human pluripotent cells (embryonic stem cells and induced pluripotent stem cells) by exposing them to the growth factor BMP4 and two pharmaceuticals that inhibit the signaling pathways necessary to maintain pluripotency. I was curious to determine whether or not ZIKV could infect these cells, replicate, and release infectious virus, because work from my collaborator Yoel Sadovsky at the University of Pittsburgh indicated that the mature placenta was likely to be resistant to infection.

MedicalResearch.com: What are the main findings?

Response: There are, I believe two striking outcomes from this work.

One is that the results indicate that the human placenta is likely most vulnerable to infection by Zika during the first trimester. We also suggest that women whose fetus is affected from an infection occurring later in pregnancy likely had a past dengue infection. The second striking result is that the African strain of Zika may have greater virulence towards early placenta than the Asian strains, such as the ones that have spread in the New World.

The work with the virus only began when we realized that term trophoblasts lacked expression of the genes that encode the protein factors that promote flavivirus infection (ZIKV is a flavivirus, like dengue, West Nile virus), e.g. TYRO3, AXL, MERTK, and also had a poised innate immune system that would counteract virus replication. Conversely, the trophoblasts we create from embryonic stem cells had the factors that would promote virus uptake, but seemed ill-prepared to counteract virus replication once infection occurred. In other words, the early placental trophoblasts were potentially more susceptible to infection. We confirmed this hypothesis with two strains of ZIKV (an Asian strain related to the one encountered in Brazil, and an African strain often considered to be relatively benign). What was unexpected was the African strain appeared to be more virulent than the Asian strain.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: Whether the early placenta could be protected by some sort of immune therapy or by prior vaccination of the mother is clearly uncertain at present. Vaccination programs have not been altogether successful when used to protect against Dengue, which is a virus related to ZIKV.

There is evidence that the early placenta is also permissive to other viruses, such as Rubella. Also there is a very interesting paper in the Journal of the American medical Association by Honein et al. that was published on December 15, 2016. In this study, the overall risk for microcephaly and other brain abnormalities in infants born to a large cohort of U.S. women exposed to ZIKV while traveling (n = 442) was 5.9 % (18), and, of these, there were no cases noted among the women known to have been infected during their second or third trimesters. In Brazil, women appear to be at risk for fetal infections by ZIKV throughout their pregnancies but this may be because they had experienced an earlier infection by Dengue. I have discussed this puzzle in the paper.

I have no disclosures to make, nor conflicts of interest regarding the research or this response to your queries.

Citation:

PNAS Plus – Biological Sciences – Applied Biological Sciences:
Megan A. Sheridan, Dinar Yunusov, Velmurugan Balaraman, Andrei P. Alexenko, Shinichiro Yabe, Sergio Verjovski-Almeida, Danny J. Schust, Alexander W. Franz, Yoel Sadovsky, Toshihiko Ezashi, and R. Michael Roberts
Vulnerability of primitive human placental trophoblast to Zika virus PNAS 2017 114 (9) E1587-E1596; published ahead of print February 13, 2017, doi:10.1073/pnas.1616097114

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Human Genetics Contributes To Zika-Induced Brain Damage

MedicalResearch.com Interview with:

Ping Wu, MD, PhD John S. Dunn Distinguished Chair in Neurological Recovery Professor, Department of Neuroscience & Cell Biology University of Texas Medical Branch Galveston, TX 77555-0620

Dr. Ping Wu

Ping Wu, MD, PhD
John S. Dunn Distinguished Chair in Neurological Recovery
Professor, Department of Neuroscience & Cell Biology
University of Texas Medical Branch
Galveston, TX 77555-0620

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Zika viral infection poses a major global public health threat, evidenced by recent outbreaks in America with many cases of microcephaly in newborns and other neurological impairments. A critical knowledge gap in our understanding is the role of host determinants of Zika-mediated fetal malformation. For example, not all infants born to Zika-infected women develop microcephaly, and there is a wide range of Zika-induced brain damage. To begin to fill the gap, we infected brain stem cells that were derived from three human donors, and found that only two of them exhibited severer deficits in nerve cell production along with aberrant alterations in gene expression.

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Persistence of Zika Virus in Body Fluids — Preliminary Report

MedicalResearch.com Interview with:
Gabriela Paz-Bailey MD PhD

Senior Epidemiologist
Centers for Disease Control and Prevention 

MedicalResearch.com: What is the background for this study?

Response: Zika virus is recognized as a cause of microcephaly and other severe birth defects when a woman is infected during pregnancy. Additionally, it has been associated with potentially fatal complications, such as Guillain-Barré syndrome. It is not well understood how often Zika virus particles can be detected in semen and other body fluids and for how long they remain detectable. Existing evidence is based on case reports and cross-sectional observations, primarily from returning travelers. A more comprehensive description of the dynamics of the early stages of Zika virus infection, observed within infected people over time, is needed to inform diagnostic testing as well as prevention recommendations and interventions.
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Zika Virus Infection in Pregnant Women in Rio de Janeiro

MedicalResearch.com Interview with:

Karin Nielsen, MD, MPH Professor of Clinical Pediatrics Division of Pediatric Infectious Diseases David Geffen School of Medicine at UCLA Director, Center for Brazilian Studies

Karin Nielsen

Karin Nielsen, MD, MPH
Professor of Clinical Pediatrics
Division of Pediatric Infectious Diseases
David Geffen School of Medicine at UCLA
Director, Center for Brazilian Studies

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Our research was a prospective study in which pregnant women in Rio de Janeiro who developed a rash in the last 5 days between the end of 2015 to mid 2016 were screened for possible infection with Zika virus by a special molecular test (PCR) which looked for the virus in blood or urine. Women who were found to have Zika virus in either blood, urine or both were followed throughout time to look for pregnancy and infant outcomes. We also followed women who had a negative PCR test for Zika as a comparison group. By July 2016, we had outcomes known for 125 Zika affected pregnancies, of these 58 had abnormal outcomes, with 9 fetal losses and 49 babies who had abnormal findings on physical exam or brain imaging, all consistent with neurologic abnormalities. This meant 46% of the pregnant women in our study had an abnormal pregnancy outcome, and 42% of live birth infants were found to have an abnormality in the first few months of life.

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OCT of Retinal Lesions in Infants with Congenital Zika Syndrome

MedicalResearch.com Interview with:
Camila Ventura MD
Pediatric Retina Research Fellow at Bascom Palmer Eye Institute (BPEI), USA
PhD student at Federal University of São Paulo (Unifesp)
Medical Retina, Ocular Oncology, and Uveitis Department at Altino Ventura Foundation Brazil

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The Brazilian outbreak of Zika virus (ZIKV) began in April 2015 and since then, we have not been able to stop its rapid spread throughout the Americas. Not only has ZIKV been disseminating very rapidly, patients affected by the ZIKV have also been presenting with some findings never before reported in the literature. Until recently, ZIKV infection was only associated with mild symptoms such as headache, rash, arthralgia, and conjunctivitis. However, in October 2015, a twenty-fold increase in the prevalence of newborns with microcephaly was reported that was later confirmed to be associated to ZIKV infection during pregnancy.

Although microcephaly and other central nervous system findings were the first abnormalities reported, recent publications have described other malformations associated with ZIKV congenital infection including hearing loss, limb anomalies and ocular findings. Due to all of these systemic findings, this new clinical condition has been named Congenital Zika Syndrome (CZS).

In January 2016, our group published the first report on the ocular findings of infants with microcephaly and presumed congenital ZIKV infection, followed by another manuscript describing 10 additional cases. We have also contributed with an article published in JAMA Ophthalmology reporting the risk factors associated to the ocular findings in babies with CZS. Other authors such as De Paula Freitas et al and Miranda 2nd et al, have also contributed to the literature by describing similar ocular findings in these infants with CZS.

In the present case series, we describe the Ocular Coherence Tomography (OCT) findings in ten eyes of eight infants with CZS.

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Zika Can Cause Multiple Other Brain Abnormalities Other Than Microcephaly

MedicalResearch.com Interview with:

Fernanda Tovar Moll, MD, PhD Vice president of the D'Or Institute for Research and Education Professor,Federal University of Rio de Janeiro Rio de Janeiro, Brazil

Dr. Fernanda Tovar-Moll

Fernanda Tovar Moll, MD, PhD
Vice president of the D’Or Institute for Research and Education
Professor,Federal University of Rio de Janeiro
Rio de Janeiro, Brazil

MedicalResearch.com: What is the background for this study?

Response: The consequences of congenital zika virus infection are still under investigation. Recent studies suggest microcephaly as one of the consequences, but we wanted to go deeper in investigating what other kinds of neurological changes could happen in the developing central nervous system.

Based on that, we performed a cohort study with multimodal images exams and longitudinal follow up (pre and post natal analyses) of some cases.

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CDC Reports Zika Has Spread to the Bahamas

Local mosquito transmission of Zika virus infection (Zika) has been reported on the island of New Providence in The Bahamas (which includes the city of Nassau). Local mosquito transmission means that mosquitoes in the area are infected with Zika virus and are spreading it to people……

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CDC Urges Wider Availability of Contraceptives In Regions Affected by Zika

MedicalResearch.com Interview with:

Charlan D. Kroelinger, PhD Division of Reproductive Health National Center for Chronic Disease Prevention and Health Promotion CDC

Dr. Charlan Kroelinger

Charlan D. Kroelinger, PhD
Division of Reproductive Health
National Center for Chronic Disease Prevention and Health Promotion
CDC

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Zika virus infection during pregnancy can cause microcephaly and other severe fetal brain defects. Doctors have also found other problems in pregnancies and among infants infected with Zika virus before birth, such as absent or poorly developed brain structures, defects of the eye, hearing deficits, and impaired growth. Nearly half of all pregnancies in the United States are unintended. Increased access to birth control may lead to reductions in unintended pregnancies, which may result in fewer adverse pregnancy and birth outcomes in the context of a Zika virus outbreak.

A new report from CDC estimates that use of highly effective, reversible forms of birth control, called long-acting reversible contraception (LARC), which includes intrauterine devices (IUDs) and implants, remains lower than use of moderate or less effective methods such as oral contraceptive pills and condoms, although contraception use varied across states and by age group and race/ethnicity.

CDC scientists used data from four state-based surveillance systems to estimate contraception use for non-pregnant and postpartum women at risk for unintended pregnancy and sexually active female high school students who live in states with the potential for local Zika virus transmission. Less than one in four sexually active women of reproductive age and fewer than one in 10 sexually active female high school students reported using LARC. A higher percentage of postpartum women reported LARC use. Moderately effective and less effective contraceptive methods, including pills, patches, rings, injections, condoms and other barrier methods, were used more frequently than highly effective methods. These estimates are of concern because the most commonly used methods of contraception are not as effective at preventing unintended pregnancy.

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CDC Gives Recommendations For Limiting Zika Spread After RIO Olympics

MedicalResearch.com Interview with:

Dr. Martin Cetron, MD Director of the CDC’s Division of Global Migration and Quarantine

Dr. Martin Cetron

Dr. Martin Cetron, MD
Director of the CDC’s Division of Global Migration and Quarantine

MedicalResearch.com: What is the background for this study?

Response: According to the Brazilian Tourism Board, approximately 350,000 – 500,000 international visitors and athletes from 207 countries are expected to travel to Rio de Janeiro, Brazil for the 2016 Olympic and Paralympic Games. This travel volume represents a very small fraction – less than 0.25% – of the total estimated 2015 travel volume to Zika-affected countries.

CDC conducted a risk analysis to predict those countries at risk for Zika virus importation exclusively attributable to the Games.

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Two New Vaccines Provide Protection Against Zika in Mice

MedicalResearch.com Interview with:

Dan Barouch, M.D., Ph.D. Professor of Medicine Harvard Medical School Ragon Institute of MGH, MIT, and Harvard Director, Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center

Dr. Dan Barouch

Dan Barouch, M.D., Ph.D.
Professor of Medicine
Harvard Medical School
Ragon Institute of MGH, MIT, and Harvard
Director, Center for Virology and Vaccine Research
Beth Israel Deaconess Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We showed that two vaccines, a DNA vaccine and a purified inactivated virus vaccine, both provided complete protection against Zika virus challenge in mice. To the best of our knowledge, this is the first demonstration of Zika vaccine protection in any animal model.

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Requests for Abortions in South American Rise Dramatically Since Zika, Especially in Brazil

MedicalResearch.com Interview with:

Abigail R.A. Aiken, MD, MPH, PhD Assistant Professor LBJ School of Public Affairs University of Texas at Austin Austin, TX, 78713

Dr. Abigail Aiken

Abigail R.A. Aiken, MD, MPH, PhD
Assistant Professor
LBJ School of Public Affairs
University of Texas at Austin
Austin, TX, 78713

MedicalResearch.com: What is the background for this study?

Response: As Zika began to emerge as an epidemic in Latin America and its links with microcephaly began to be realized, we were aware that women in the region who were already pregnant or who would become pregnant would have a very limited set of reproductive options. Research and media attention about the possible biological effects of Zika in pregnancy began to appear rapidly. But much less attention was been paid to the impacts of Zika on women. We followed the responses of governments and health organizations and when they began to issue advisories warning women to avoid pregnancy, we knew it would be important to investigate the impacts of those advisories. A country-wide policy that is impossible to follow if you are pregnant or cannot avoid pregnancy is an unusual and important public issue. Accurate data on abortion are very difficult to obtain in Latin America because in most countries, abortion is highly restricted. We wanted to provide a window on the issue of how women were responding to the risks of Zika and its associated advisories, so we worked with Women on Web (WoW), an online non-profit telemedicine initiative that provides safe medical abortion to women in countries where safe, legal abortion is not universally available.

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Inflammation Caused By Mosquito Bites Helps Viral Infections Spread

MedicalResearch.com Interview with:
Clive McKimmie PhD
Research Fellow,
Virus Host Interaction Team (VHIT),
University of Leeds
St James’ University Hospital
Leeds UK

MedicalResearch.com: What is the background for this study?

Response: With the rapid spread of Zika in the Americas, attention has been drawn to this group of neglected mosquito-borne viral infections. The Zika virus is not alone in causing problems, others such as dengue and chikungunya viruses are infecting millions of people each year. Yet there’s little doctors can do to help people who get sick.
When mosquitoes bite you they can transmit these disease causing viruses. We don’t understand what happens during the early stages of infection very well. However, it is known that the mosquito bite itself somehow helps the virus to infect your body.

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