Virus World

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 

Moderna, Inc., a clinical stage biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for its investigational Zika vaccine (mRNA-1893) currently being evaluated in a Phase 1 study for the prevention of Zika virus infection in healthy adults.

Fast Track is designed to facilitate the development and expedite the review of therapies and vaccines for serious conditions and fill an unmet medical need. Programs with Fast Track designation may benefit from early and frequent communication with the FDA, in addition to a rolling submission of the marketing application. Moderna previously received Fast Track designation for its methylmalonic acidemia (MMA) program (mRNA-3704), which is now recruiting patients for a Phase 1/2 clinical study. “Protecting against Zika virus transmission, particularly in women during pregnancy, continues to be an area of high unmet need. Fast Track designation supports our belief in the clinical potential of mRNA-1893 and the importance of developing an effective vaccine that can be rapidly developed and deployed,” said Tal Zaks, M.D., Ph.D., chief medical officer at Moderna. “Our Zika program is part of Moderna’s broader commitment to improving global public health through developing mRNA vaccines to prevent the spread of infectious diseases.”

mRNA-1893 contains an mRNA sequence encoding for the structural proteins of Zika virus and is designed to cause cells to secrete virus-like particles, mimicking the response of the cell after natural infection. Preclinical data published in The Journal of Infectious Diseases have shown that vaccination with mRNA-1893 protected against transmission of Zika virus during pregnancy in mice.1 mRNA-1893 is currently in a Phase 1 study evaluating safety, pharmacokinetics and pharmacodynamics in healthy volunteers.

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

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.