Like Zika, Oropouche virus can also affect the brains of unborn babies

Discovered in 1955, the Oropouche virus has circulated mainly in the Amazon, causing a febrile illness virtually indistinguishable from those caused by dengue, Zika and chikungunya, viruses also transmitted by biting mosquitoes.

This similarity likely contributed to its being underdiagnosed for decades. Although little known to the general public, Oropouche has never been a rare virus, and in some areas of the northern region, it has caused more cases than other arboviruses.

This distribution appeared to be explained by the presence of its main urban vector, the midge Culicoides paraensis, which is typical of Amazonian environments. Recent studies, however, have shown that its distribution is much broader and that the historical concentration of cases may reflect, at least in part, limitations in epidemiological and entomological surveillance.

A virus that emerged from the forest

This scenario changed rapidly. Beginning in 2024, Brazil recorded the largest expansion in the circulation of the Oropouche virus ever documented. According to Brazil’s Ministry of Health, nearly 14,000 cases were confirmed that year, a number that remained high in 2025. For the first time, the virus began to circulate sustainably across all five regions of the country.

But the rise in the number of cases was not the only cause for concern. Reports also began to emerge of deaths, vertical transmission, miscarriages, fetal deaths and newborns with microcephaly and other congenital malformations born to women infected during pregnancy.

These clinical studies suggest a significant association, but they leave one question unanswered: What happens inside fetal brain cells when they are infected by the virus?

What Zika taught us

It is not possible to directly study the effects of a viral infection on a developing human brain. To overcome this limitation, researchers use brain organoids, popularly known as “mini-brains.”

These three-dimensional structures are produced from human stem cells and replicate various aspects of the first weeks of brain development.

Although they lack consciousness and do not represent a complete brain, they organize their cells in a manner similar to the embryonic brain and allow us to monitor, in real time, how viruses alter the development of nervous tissue.

Our work with this model began during the Zika epidemic. In 2016, we demonstrated in the journal Science that the virus directly infected human brain organoids and impaired their growth. With this finding, we provided a biological explanation for the microcephaly observed in newborns during the epidemic.

The same platform has now been used to investigate the Oropouche virus.

What happens in the first 24 hours

Before analyzing the organoids, we studied the virus’s behavior in neural stem cells, which are responsible for giving rise to virtually all neurons and support cells of the nervous system. Alterations during this early phase can compromise the entire course of brain development.

The cells were infected with two different strains of the virus. The first was the historical BeAn19991 strain, isolated in the Amazon in 1960.

The second was a strain obtained during the recent outbreak in Rio de Janeiro (RJ/LVM-2024) that has a genetic rearrangement. One of the main questions was whether this new variant had acquired a greater ability to infect the nervous system.

The results showed that both strains easily infected human neural stem cells. The historical strain infected about 87% of the exposed cells, while the recent strain showed only slightly lower infection rates.

In both cases, the virus completed its entire replication cycle, producing new viral particles capable of perpetuating the infection.

We then investigated how these cells responded to the viral attack using transcriptomics, a technique that allows for the simultaneous identification of thousands of genes that are activated or silenced during infection. The technique produces a true molecular snapshot of the cellular response.

Regardless of the strain used, we identified a common signature consisting of 657 differentially expressed genes.

The activity of genes responsible for neural stem cell proliferation was reduced, while the expression of genes related to the inflammatory response, viral replication and programmed cell death increased. These changes indicated a profound impairment of brain-forming cells.

But one fundamental question remained: Would these molecular changes be sufficient to alter the development of an entire brain tissue?

The scaffold collapses

Brain organoids replicate important aspects of the first weeks of human brain development. When we infected them with the Oropouche virus at around day 30 of development, the changes appeared rapidly.

The infected mini-brains grew less than the controls, had irregular edges and lost part of their structural organization. These changes reflected profound alterations in the biology of the tissue.

The virus primarily affected the ventricular zones, regions where neural stem cells divide rapidly to form new neurons.

In these areas, we observed a significant reduction in Ki67-positive cells, a classic marker of cell proliferation. In other words, the “engine” responsible for brain growth began to operate at a slower pace.

There was also a reduction in the PAX6 protein, a marker for radial glial cells. These cells function as a veritable biological scaffold. They give rise to new neurons, support the architecture of the developing brain and guide their migration to the cerebral cortex.

When this scaffold loses its organization, the entire process of brain development can be compromised.

In the more mature organoids, approximately two months old, the virus also infected neurons and astrocytes. This shows that its ability to invade is not restricted to neural stem cells.

Is the new variant more dangerous?

One of the study’s main questions was whether the strain responsible for the recent spread of the disease in Brazil had a greater capacity to damage the developing brain.

The historical BeAn19991 strain and the recent RJ/LVM-2024 strain produced very similar changes.

This result suggests that the neurotoxic potential of the Oropouche virus likely did not emerge recently. On the contrary, it may represent an inherent characteristic of the virus itself, which remained largely unrecognized while its circulation was restricted to the Amazon region.

An unexpected link to the Zika virus

Among the most important molecular changes, we observed a significant reduction in different subtypes of type IV collagen, an essential component of the basement membrane that serves as the foundation of the developing brain. It supports neural stem cells, preserves tissue organization and contributes to the integrity of the small blood vessels that supply the nervous system.

Without this foundation, the brain loses stability, much like a building constructed on weakened foundations.

This finding caught our attention because, years earlier, we had identified similar changes in the brains of newborns with congenital syndrome caused by the Zika virus.

Our results suggest that both Oropouche and Zika may target the same vulnerable point in neurodevelopment: the structure that supports and organizes brain growth.

What do these results mean?

Our study does not prove that every pregnant woman infected with the Oropouche virus will have a baby with neurological abnormalities.

Brain organoids replicate important stages of fetal development, but they do not capture the full complexity of a human pregnancy. Therefore, they do not, on their own, establish a definitive cause-and-effect relationship.

However, the results offer a plausible biological explanation for recent cases of microcephaly and congenital malformations associated with Oropouche virus infection. Furthermore, they underscore the need for clinical studies to monitor pregnant women and children exposed to the virus.

There are still many unanswered questions, but understanding how the virus interferes with the early stages of brain development represents an important step. This can guide us in developing strategies for surveillance, diagnosis and monitoring of pregnant women in areas where the virus is transmitted.

Research that began before the epidemic

Long before the Oropouche virus made headlines, professor Amilcar Tanuri of the Federal University of Rio de Janeiro (UFRJ) was already arguing that emerging viruses needed to be studied before they turned into public health crises.

One of Brazil’s most prominent virologists, Tanuri was involved in every stage of this study’s development. Unfortunately, he did not live to see its publication in eBioMedicine. This article also serves as a tribute to his scientific vision. For Tanuri, understanding viruses before they spread was essential to protecting public health.

Who’s behind this story?

Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021.

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Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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This article is republished from The Conversation under a Creative Commons license. Read the original article.