Virus World

Mosquito-borne viruses increasingly threaten human populations due to accelerating changes in climate, human and mosquito migration, and land use practices. Over the last three decades, the global distribution of dengue has rapidly expanded, causing detrimental health and economic problems in many areas of the world. To develop effective disease control measures and plan for future epidemics, there is an urgent need to map the current and future transmission potential of dengue across both endemic and emerging areas. Expanding and applying Index P, a previously developed mosquito-borne viral suitability measure, we map the global climate-driven transmission potential of dengue virus transmitted by Aedes aegypti mosquitoes from 1981 to 2019. This database of dengue transmission suitability maps and an R package for Index P estimations are offered to the public health community as resources towards the identification of past, current and future transmission hotspots. These resources and the studies they facilitate can contribute to the planning of disease control and prevention strategies, especially in areas where surveillance is unreliable or non-existent.

Preprint in medRxiv (Nov. 5, 2022):

https://doi.org/10.1101/2022.11.04.22281958 

NIH preclinical study suggests FDA-approved tetracycline-based antibiotics may slow infection and reduce neurological problems. In 2015, hundreds of children were born with brain deformities resulting from a global outbreak of Zika virus infections. Recently, National Institutes of Health researchers used a variety of advanced drug screening techniques to test out more than 10,000 compounds in search of a cure. To their surprise, they found that the widely used antibiotic methacycline was effective at preventing brain infections and reducing neurological problems associated with the virus in mice. In addition, they found that drugs originally designed to combat Alzheimer’s disease and inflammation may also help fight infections.  “Around the world, the Zika outbreak produced devastating, long-term neurological problems for many children and their families. Although the infections are down, the threat remains,” said Avindra Nath, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study published in PNAS(link is external). “We hope these promising results are a good first step to preparing the world for combating the next potential outbreak.” The study was a collaboration between scientists on Dr. Nath’s team and researchers in laboratories led by Anton Simeonov, Ph.D., scientific director at the NIH’s National Center for Advancing Translational Sciences (NCATS) and Radhakrishnan Padmanabhan, Ph.D., Professor of Microbiology & Immunology, Georgetown University Medical Center(link is external), Washington, D.C.

A new study led by scientists at the Walter Reed Army Institute of Research has shown for the first time that a single dose of an experimental Zika vaccine in a dengue-experienced individual can boost pre-existing flavivirus immunity and elicit protective cross-neutralizing antibody responses against both Zika and dengue viruses. Findings were published today in Nature Medicine. Researchers analyzed the antibody responses of a dengue-experienced volunteer who participated in a Phase 1 clinical trial of the WRAIR-developed Zika purified inactivated virus vaccine. They identified a potent cross-reactive antibody called MZ4 that demonstrated a potent ability to neutralize the Zika virus as well as the dengue virus serotype-2 strain. In addition, MZ4 protected against Zika and dengue in a mouse model of infection. 

"Rapid-onset countermeasures are needed to protect military personnel, travelers and residents in areas where emerging infections such as Zika and dengue viruses are already widespread and expanding," said Dr. Kayvon Modjarrad, who leads the U.S. Army Zika vaccine program, directs the Emerging Infectious Diseases Branch at WRAIR and is one of the lead authors on the paper. "These results demonstrate the potential for MZ4 to be part of the prevention toolbox for these diseases." The individual's immune profile was compared to trial volunteers who had no previous exposure to dengue virus. While the volunteer with prior dengue exposure experienced a sharp increase in antibodies that neutralize Zika and dengue viruses, following just one dose of the ZPIV vaccine, the dengue-naïve trial participants required two vaccinations to reach a similar magnitude of Zika antibody responses. Additionally, no cross-reactive antibody response to dengue virus. 

"These new findings indicate that an effective Zika vaccine could both boost dengue virus immune responses and generate potent Zika neutralizing antibodies that might have unique potential as a prevention tool in regions where both dengue and Zika are prevalent," said Dr. Shelly Krebs, a B cell researcher at WRAIR and senior author of the paper....

Published in Nat. Medicine (February 3, 2020):

https://doi.org/10.1038/s41591-019-0746-2

Researchers from The University of Texas Medical Branch at Galveston showed, for the first time, that a single, higher dose of vaccination to a pregnant mouse safely protects both her and her fetus from the Zika virus. The researchers found that a single, less potent dose was not enough to protect the fetus. The findings are currently available in Nature Communications.

"Preventing birth defects in developing fetuses is an important goal of the Zika virus vaccine but studies on vaccinations in pregnant females have been lacking, raising a number of important questions that are critical to the clinical development and regulatory approval of Zika vaccines," said UTMB's Pei-Yong Shi, senior author and the I.H. Kempner professor at the department of biochemistry and molecular biology. "Could vaccination during pregnancy protect against infection and transmission to the fetus? Does pregnancy affect immune responses to Zika vaccination? Does maternal immunity from vaccination during pregnancy protect newborns against infection?"

Shi and his laboratory previously developed a Zika vaccine and continue studies to improve its efficacy. In addition to protecting both mother and fetus, Shi said that the researchers also learned that their live-attenuated vaccine has an excellent safety profile in pregnant female mice and her fetus. For example, they saw no adverse effects on pregnancy, fetal development or infant behavior. They also found that pregnancy weakens the mother's immune response to the vaccination, suggesting that that a higher dose of the vaccine or a more immunogenic vaccine is needed during pregnancy. Taken together, their results suggest that their vaccine may be considered for both pregnant and non-pregnant people.

Published in Nature Communications (12 Dec. 2019):

https://doi.org/10.1038/s41467-019-13589-1

A new study led by researchers at Baylor College of Medicine revealed how in utero Zika virus infection can lead to microcephaly in newborns. The team discovered that the Zika virus protein NS4A disrupts brain growth by hijacking a pathway that regulates the generation of new neurons. The findings point at the possibility of developing therapeutic strategies to prevent microcephaly linked to Zika virus infection. The study appears today in the journal Developmental Cell.

Patients with rare genetic mutations shed light on how Zika virus causes microcephaly

"The current study was initiated when a patient presented with a small brain size at birth and severe abnormalities in brain structures at the Baylor Hopkins Center for Mendelian Genomics (CMG), a center directed by Dr. Jim Lupski, professor of pediatrics, molecular and human genetics at Baylor College of Medicine and attending physician at Texas Children's Hospital," said Dr. Hugo J. Bellen, professor at Baylor, investigator at the Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital. This patient and others in a cohort at CMG had not been infected by Zika virus in utero. They had a genetic defect that caused microcephaly. CMG scientists determined that the ANKLE2 gene was associated with the condition. Interestingly, a few years back the Bellen lab had discovered in the fruit fly model that ANKLE2 gene was associated with neurodevelopmental disorders. Knowing that Zika virus infection in utero can cause microcephaly in newborns, the team explored the possibility that Zika virus was mediating its effects in the brain via ANKLE2.

In a subsequent fruit fly study, the researchers demonstrated that overexpression of Zika protein NS4A causes microcephaly in the flies by inhibiting the function of ANKLE2, a cell cycle regulator that acts by suppressing the activity of VRK1 protein.

The fruit fly helps clarify the mystery

The team found that fruit fly larvae with mutations in ANKLE2 gene had small brains with dramatically fewer neuroblasts—brain cell precursors—and could not survive into adulthood. Experimental expression of the normal human version of ANKLE2 gene in mutant larvae restored all the defects, establishing the loss of Ankle2 function as the underlying cause. "To understand why ANKLE2 mutants have fewer neuroblasts and significantly smaller brains, we probed deeper into asymmetric cell divisions, a fundamental process that produces and maintains neuroblasts, also called neural stem cells, in the developing brains of flies and humans," said first author Dr. Nichole Link, postdoctoral associate in the Bellen lab. Asymmetric cell division is an exquisitely regulated process by which neuroblasts produce two different cell types. One is a copy of the neuroblast and the other is a cell programmed to become a different type of cell, such as a neuron or glia. Proper asymmetric distribution and division of these cells is crucial to normal brain development, as they need to generate a correct number of neurons, produce diverse neuronal lineages and replenish the pool of neuroblasts for further rounds of division.

"When flies had reduced levels of Ankle2, key proteins, such as Par complex proteins and Miranda, were misplaced in the neuroblasts of Ankle2 larvae. Moreover, live imaging analysis of these neuroblasts showed many obvious signs of defective or incomplete cell divisions. These observations indicated that Ankle2 is a critical regulator of asymmetric cell divisions," said Link....

Published on Developmental Cell (November 14, 2019):

https://doi.org/10.1016/j.devcel.2019.10.009

Zika virus attracted worldwide attention in recent years due to the devastating consequences of infection for pregnant women and their fetuses, many of which were born with microcephaly and other severe neurological malformations. Although ZIKV infection has historically been associated to relatively mild symptoms, a number of serious neurological complications were described in adult patients during the 2015 outbreak in America. Despite these clinical observations, how ZIKV is toxic to the adult brain and how neurological problems are caused in infected adults have remained unknown.

Researchers led by neuroscientists Sergio T. Ferreira e Claudia Figueiredo and virologist Andrea Da Poian at the Federal University of Rio de Janeiro (Brazil) have now come up with answers to these questions. First, they exposed small fragments of adult human brain tissue to ZIKV isolated from the blood of an infected Brazilian patient. Contrary to the previous belief that ZIKV only infects neuronal progenitor cells or neurons that are still immature in the developing brain, they found that the virus infected and replicated in adult human tissue, producing new viral particles capable of infecting more cells.

But what are the consequences of this infection? To address this question, they injected Zika virus directly into the brains of mice. As lead author Claudia P. Figueiredo and Ferreira explains: "Infected mice exhibited marked memory impairment that persisted even after infection had been fought off by the organism. Moreover, this was consistent with the fact that brain regions responsible for learning and memory processing were the main sites of viral replication in their brains." 

The work further showed that infection by ZIKV causes a strong inflammatory response in the mouse brain, and this includes activation of brain resident immune cells called microglia. Fernanda Barros-Aragão, a PhD student and author of the study, explains that this exaggerated inflammatory response is ultimately responsible for memory loss: "Neurons communicate through highly specialized regions called synapses. Surprisingly, we found that microglia that become aberrantly activated upon infection by ZIKV attack and engulf synapses. This impairs communication between neurons and, therefore, the formation of new memories." Interestingly, when animals were treated for about one week with anti-inflammatory drugs capable of blocking microglial activation, they recovered memory. Results from this study indicate that the adult brain is damaged by infection by ZIKV, and point to the need to carefully evaluate learning and memory performance in follow-up assessments of infected adults. Although no specific treatments for ZIKV infection are yet available, these findings further reveal the possibility that neurological symptoms caused to infection by controlling brain inflammation.

Findings published September 5 in Nature Communications:

https://www.nature.com/articles/s41467-019-11866-7

Scientists have detected Zika virus RNA in free-ranging African bats. RNA, or ribonucleic acid, is a molecule that plays a central role in the function of genes. A team of Colorado State University scientists, led by veterinary postdoctoral fellow Dr. Anna Fagre, has detected Zika virus RNA in free-ranging African bats. RNA, or ribonucleic acid, is a molecule that plays a central role in the function of genes.  According to Fagre, the new research is a first-ever in science. It also marks the first time scientists have published a study on the detection of Zika virus RNA in any free-ranging bat. The findings have ecological implications and raise questions about how bats are exposed to Zika virus in nature. The study was recently published in Scientific Reports, a journal published by Nature Research. Fagre, a researcher at CSU's Center for Vector-Borne Infectious Diseases, said while other studies have shown that bats are susceptible to Zika virus in controlled experimental settings, detection of nucleic acid in bats in the wild indicates that they are naturally infected or exposed through the bite of infected mosquitoes. "This provides more information about the ecology of flaviviruses and suggests that there is still a lot left to learn surrounding the host range of flaviviruses, like Zika virus," she said. Flaviviruses include viruses such as West Nile and dengue and cause several diseases in humans. CSU Assistant Professor Rebekah Kading, senior author of the study, said she, Fagre and the research team aimed to learn more about potential reservoirs of Zika virus through the project.

The team used 198 samples from bats gathered in the Zika Forest and surrounding areas in Uganda and confirmed Zika virus in four bats representing three species. Samples used in the study date back to 2009 from different parts of Uganda, years prior to the large outbreaks of Zika virus in 2015 to 2017 in North and South Americas. "We knew that flaviviruses were circulating in bats, and we had serological evidence for that," said Kading. "We wondered: Were bats exposed to the virus or could they have some involvement in transmission of Zika virus?" The virus detected by the team in the bats was most closely related to the Asian lineage Zika virus, the strain that caused the epidemic in the Americas following outbreaks in Micronesia and French Polynesia. The first detection of the Asian lineage Zika virus in Africa was in late 2016 in Angola and Cape Verde. "Our positive samples, which are most closely related to the Asian lineage Zika virus, came from bats sampled from 2009 to 2013," said Fagre. "This could mean that the Asian lineage strain of the virus has been present on the African continent longer than we originally thought, or it could mean that there was a fair amount of viral evolution and genomic changes that occurred in African lineage Zika virus that we were not previously aware of."

Fagre said the relatively low prevalence of Zika virus in the bat samples indicates that bats may be incidental hosts of Zika virus infection, rather than amplifying hosts or reservoir hosts. "Given that these results are from a single cross-sectional study, it would be risky and premature to draw any conclusions about the ecology and epidemiology of this pathogen, based on our study," she said. "Studies like this only tell one part of the story." The research team also created a unique assay for the study, focusing on a specific molecular component that flaviviruses possess called subgenomic flavivirus RNA, sfRNA. Most scientists that search for evidence of Zika virus infection in humans or animals use PCR, polymerase chain reaction, to identify bits of genomic RNA, the nucleic acid that results in the production of protein, said Fagre.

Kading said her team will continue their research to try and learn more about how long these RNA fragments persist in tissues, which will allow them to approximate when these bats were infected with Zika virus. "There is always a concern about zoonotic viruses," she said. "The potential for another outbreak is there and it could go quiet for a while. We know that in the Zika forest, where the virus was first found, the virus is in non-human primates. There are still some questions with that as well. I don't think Zika virus has gone away forever."

See Scientific Reports (April 26, 2021):

https://doi.org/10.1038/s41598-021-87816-5 

A study of Nicaraguan children links prior Zika virus infection with aggravated dengue fever symptoms. The 2015–16 Zika virus epidemic that spread through Central and South America was followed last year by a surge in dengue virus cases. While this unfortunate series of diseases battered the region’s populace, it gave scientists, who had been following a cohort of several thousand children in the area, the opportunity to study how these two flaviviruses might jointly affect the immune system. That research has revealed that kids infected with dengue virus are more likely to suffer worse symptoms if they had previously been infected with Zika than if they hadn’t. The findings, reported in Science today (August 27), indicate that antibody-dependent enhancement—a phenomenon known for making a second infection with a virus worse than the first—is not limited to influencing infections by the same pathogen. This raises concerns that such cross-species effects may occur for other types of viruses—including coronaviruses—and may impact vaccine safety, scientists say.

“It’s a pretty amazing story. [It] addresses what I think is the most important question in the field that has emerged following the Zika virus outbreak, and that is, how do Zika virus and dengue virus influence each other?” says virologist Jean Lim of the Icahn School of Medicine at Mount Sinai who was not part of the research team. Dengue and Zika viruses are closely related members of the flavivirus genus and are both transmitted to humans via the bites of infected mosquitoes. Dengue virus infection can be asymptomatic or can cause symptoms such as fever, headache, muscle aches, and rash. In some cases the disease can be severe, causing hemorrhagic fever and even shock (a dangerous drop in blood pressure). Zika virus causes a mostly mild disease—characterized by fever, rash, and joint pain—that resolves within a week, but in adults it can occasionally cause Guillain-Barré syndrome, an autoimmune condition affecting the peripheral nerves, and in pregnant women, the virus can lead to brain defects in the developing fetus including microcephaly. 

There are four strains, or serotypes, of dengue virus and infection by one type has a curious effect on infection by another, explains epidemiologist Isabel Rodriguez-Barraquer of the University of California (UC), San Francisco, who also did not work on the project. While an infection with the same serotype twice will not cause disease the second time around, if a different serotype causes the second infection, the existing antibodies fail to neutralize the virus and actually assist its entry into host cells. “The antibodies that your body builds after that first infection make the second infection worse and that’s often referred to as antibody-dependent enhancement,” Rodriquez-Barraquer says. This phenomenon is also thought to explain the worsening of disease severity seen after dengue vaccination.  Because Zika is closely related to dengue, “when Zika came along there was a question [of whether] there was going to be some sort of immunological interaction,” says UC Berkeley’s Eva Harris. And her group was in a perfect position to provide an answer, she adds, thanks to a long-standing collaboration with scientists in Nicaragua who have been monitoring infections, measuring antibody titers, and collecting other data from a rolling cohort of children since 2004.

In an earlier study, Harris’s group had shown that dengue infections preceding the Zika outbreak that started in 2015 offered a slightly protective effect against Zika severity, at least in children. Then, in 2019, when a major epidemic of dengue infections blew through the region—the worst in Nicaragua’s history—the group looked at the reverse scenario: whether prior Zika infection influenced dengue severity.  A total of 302 children of a cohort of 3,434 were diagnosed with symptomatic dengue fever between 2019 and 2020, confirmed via PCR amplification of the virus’s genetic material. By analyzing the infection history of the cohort, the team then calculated that children who had had a prior Zika infection had a roughly 12 percent chance of developing symptomatic dengue, compared with an only a 3.5 percent chance for children that had had no prior flavivirus exposure. Children who had had one prior dengue infection had a roughly 9 percent chance of later symptomatic disease. Prior Zika or dengue infection also increased the risk that a child would experience the most severe symptoms of dengue—hemorrhagic fever and shock—compared with children who had not previously had flavivirus disease, the team showed...

Published in Science (August 28, 2020):

https://doi.org/10.1126/science.abb6143

Clinical evidence is mounting that Zika virus can contribute to Guillain-Barré syndrome which causes temporary paralysis, yet the mechanism is unknown. We investigated the mechanism of temporary acute flaccid paralysis caused by Zika virus infection in aged interferon αβ-receptor knockout mice used for their susceptibility to infection. Twenty-five to thirty-five percent of mice infected subcutaneously with Zika virus developed motor deficits including acute flaccid paralysis that peaked 8-10 days after viral challenge. These mice recovered within a week. Despite Zika virus infection in the spinal cord, motor neurons were not destroyed.

We examined ultrastructures of motor neurons and synapses by transmission electron microscopy. The percent coverage of motor neurons by boutons was reduced by 20%; more specifically, flattened-vesicle boutons were reduced by 46%, and were normalized in recovering mice. Using electromyographic procedures employed in people to help diagnose Guillain-Barré syndrome, we determined that nerve conduction velocities between the sciatic notch and the gastrocnemius muscle were unchanged in paralyzed mice. However, F-wave latencies were increased in paralyzed mice, which suggests that neuropathy may exist between the sciatic notch to the nerve rootlets. Reversible synaptic retraction may be a previously unrecognized cofactor along with peripheral neuropathy for the development of Guillain-Barré syndrome during Zika virus outbreaks.

Published in Nature Scientific Reports (20 December 2019):

https://doi.org/10.1038/s41598-019-55717-3

Using a relevant animal model (pigs), University of Saskatchewan researchers have shown that mild Zika virus infection in fetuses can cause abnormal brain development in apparently healthy young animals. The study, published Nov. 14 in PLOS Pathogens, provides new insights into the potential outcomes of Zika virus infection and could point to new prevention and treatment strategies to alleviate the long-term effects of Zika virus infection.

Spread by the bite of an infected Aedes species mosquito, Zika infection of pregnant mothers can lead to death and decreased brain size (microcephaly) in fetuses, leading to life-long developmental and cognitive impairment. However, there is growing concern that sub-clinical infections (showing no symptoms) in pregnant mothers can result in brain disorders and delayed neurodevelopmental abnormalities in offspring after birth. Using the pig as a model, new research at USask's Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac) has provided direct evidence to support this concern.

"We have demonstrated in a relevant animal model that mild infection in fetuses results in abnormal brain development and impaired immunity in young pigs," said VIDO-InterVac Director Dr. Volker Gerdts who also participated in the study. Some of the affected offspring also showed altered behaviour during stress. In 2016, the World Health Organization declared Zika virus a public health emergency. While this emergency declaration has been lifted, Zika infection remains a public health concern. There is currently no approved vaccine or therapy available to combat the infection. Karniychuk said a next step is to develop an animal model for the study of how to treat and cure infections such as Zika virus in utero. There are currently no in utero therapies for congenital viral infections. Earlier this year, Karniychuk was awarded $250,000 over two years by the federal New Frontiers in Research Fund to undertake this work aimed at reducing the long-term consequences of abnormalities in developing fetuses and the treatment required after birth. For almost 45 years, VIDO-InterVac has used large animal models to help understand how pathogens cause disease.

Published in PLOS Pathigens (November 14, 2019):

https://doi.org/10.1371/journal.ppat.1008038

Like an adjustable wrench that becomes the "go-to" tool because it is effective and can be used for a variety of purposes, an existing drug that can be adapted to halt the replication of different viruses would greatly expedite the treatment of different infectious diseases. Such a strategy would prevent thousands of deaths each year from diseases like dengue and Ebola, but whether it can be done has been unclear. Now, in new work, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) show that repurposing an existing drug to treat viral diseases is in fact possible - potentially bypassing the decades needed to develop such a broad-spectrum drug from scratch.

In a new study published in the journal Molecular Therapy, the Temple researchers report that a drug used in the treatment of HIV also suppresses Zika virus infection. In cell and animal models, they show that the drug, called rilpivirine, stops Zika virus by targeting enzymes that both HIV and Zika virus depend on for their replication. These enzymes occur in other viruses closely related to Zika, including the viruses that cause dengue, yellow fever, West Nile fever, and hepatitis C. Dr. Khalili, a senior investigator on the new study, attributed the breakthrough work to a productive collaboration with Temple University colleagues, including Dr. Michael L. Klein, FRS, Laura H. Carnell Professor of Science and Dean of the College of Science and Technology at Temple; and Ilker K. Sariyer, DVM, PhD, and Jennifer Gordon, PhD, Associate Professors of Neuroscience at Temple's Center for Neurovirology.

Historically rare and isolated to parts of Africa and Asia, Zika virus is now present throughout the Americas and occurs in multiple other regions of the world. It has attracted increasing attention in recent years, owing to its damaging effects to the brain and nervous system. The virus is transmitted to humans by mosquitoes. Once in the body, it infects cells and replicates, typically taking up residence in cells in neural tissues. In severe cases, Zika virus infection can cause an autoimmune condition known as Guillain-Barré syndrome, which culminates in muscle paralysis. Infants born to mothers infected during pregnancy may experience delays in neurological development and may be affected by microcephaly (abnormal smallness of the head).

To replicate inside cells, Zika virus requires an enzyme called non-structural protein 5 RNA-dependent RNA polymerase (NS5 RdRp). In the new study, Dr. Sariyer showed that rilpivirine suppresses Zika virus infection in cells by blocking viral replication. Using structural biology and computational studies, Eleonora Gianti, PhD, a research assistant professor in Dr. Klein's laboratory, was able to show that rilpivirine prevents viral replication by binding specifically to the NS5 domain. Dr. Gordon's team carried out experiments in mice, in which animals were infected with Zika virus through their footpads, similar to the way a person becomes infected through a mosquito bite. Mice that become infected with Zika virus normally become very sick within about a week and eventually die. "We found, however, that when treated with rilpivirine, the animals survived," Dr. Gordon said. "Our conclusion is that rilpivirine disrupted the virus's usual course of infection."

Rilpivirine is one of several non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs that have been developed for the treatment of HIV infection. Experiments in which the Temple researchers tested two other NNRTIs in Zika-infected cells revealed similar effects on viral replication, with the drugs specifically inhibiting NS5 activity.

Published on Molecular Therapy (October 11, 2019):

https://doi.org/10.1016/j.ymthe.2019.10.006

Seventy-one of 110 Brazilian infants at the highest risk for experiencing problems due to exposure to the Zika virus in the womb experienced a wide spectrum of brain abnormalities, including calcifications and malformations in cortical development.  The infants were born at the height of Brazil's Zika epidemic, a few months after the nation declared a national public health emergency. Already, many of the infants had been classified as having the severe form of congenital Zika syndrome, and many had microcephaly, fetal brain disruption sequence, arthrogryposis and abnormal neurologic exams at birth. These 110 infants "represented a group of ZIKV-exposed infants who would be expected to have a high burden of neuroimaging abnormalities, which is a difference from other reported cohorts," Sarah B. Mulkey, M.D., Ph.D., writes in an invited commentary published in JAMA Network Open that accompanies the Rio de Janeiro study.

Indeed, a retrospective cohort of 82 women exposed to Zika during their pregnancies led by a research team at Children's National found only three pregnancies were complicated by severe fetal brain abnormalities. Compared with the 65% abnormal computed tomography (CT) or magnetic resonance imaging (MRI) findings in the new Brazilian study, about 1 in 10 (10%) of babies born to women living in the continental U.S. with confirmed Zika infections during pregnancy had Zika-associated birth defects, according to the Centers for Disease Control and Prevention.

"Centered on the findings of Pool, et al, and others, early neuroimaging remains one of the most valuable investigations of the Zika-exposed infant," Dr. Mulkey writes, including infants who are not diagnosed with congenital Zika syndrome. She recommends:

• Cranial ultrasound as the first-line imaging option for infants, if available, combined with neurologic and ophthalmologic exams, and brainstem auditory evoked potentials
• Zika-exposed infants with normal cranial ultrasounds do not need additional imaging unless they experience a developmental disturbance
• Zika-exposed infants with abnormal cranial ultrasounds should undergo further neuroimaging with low-dose cranial CT or brain MRI.