Zika is capable of modulating brain inflammation, study shows

Preliminary findings from research conducted under the aegis of the Zika Network were presented at the annual meeting of Brazil's Federation of Experimental Biology Societies.

By Karina Toledo, in Foz do Iguaçu (Paraná)  |  Agência FAPESP – When researchers at the University of São Paulo (USP) in Brazil analyzed the brains of mouse pups exposed to Zika during gestation, they found that the virus is capable of modulating the host organism’s central nervous system to prevent an acute inflammatory immune response because this would be harmful to the virus.

The preliminary findings from the research project, which is supported by FAPESP, were presented on September 1 by Jean Pierre Peron, a professor at USP’s Biomedical Science Institute (ICB), during the 31st Annual Meeting of the Federation of Experimental Biology Societies (FeSBE), held in Foz do Iguaçu, Paraná State, Brazil.

“There’s no encephalitis and no local defense cell infiltration – we found neither macrophages nor lymphocytes there,” Peron said. “Apparently, the virus is capable of modulating inflammation at the site. The brain lesions are associated mainly with direct damage to cells caused by the virus.”

Peron is a member of the Zika Network and co-author of a paper published in the May issue of Nature that reports definitive evidence that infection by Zika during pregnancy can cause fetal brain malformation (read more at: agencia.fapesp.br/23286).

These previous experiments, in which female mice were infected between the tenth and twelfth day of pregnancy, showed that Zika virus is capable of crossing the placental barrier to infect and kill what would become future brain cells in murine fetuses. As well as having malformed brains, the pups were small in size when born.

“After this publication, we continued our research,” Peron said. “We analyzed the expression of all genes in the brains of these mouse pups to identify which genes were more expressed and which ones were less expressed than in the control group. Overall, the results showed decreased expression of inflammatory cytokines.”

Curiously, there was no reduction in the expression of interferon-beta (IFNß), a cytokine that binds to infected cells and activates a signaling pathway that leads to cell death.

“Production of alpha and beta interferon is known to play a key role in eliminating the virus from the organism effectively. We believe C57BL/6 mice proved resistant to Zika and their offspring didn’t develop congenital brain malformations in the previous research precisely because the lineage produces large amounts of these cytokines,” Peron said.

He raised the hypothesis that the virus produces a molecule that prevents beta interferon from signaling to the cell nucleus.

“As a result, the cell doesn’t die, and that’s good for the virus. It doesn’t want to kill its host, of course, because then it too would die. But more research is needed to understand all this better,” Peron said.

In his presentation, he also commented on recent research findings published by other groups. In one instance, Zika virus was shown to be capable of surviving for up to six months in human semen. Moreover, he said, according to a paper published in August in the journal Cell, when the virus was inoculated into the vaginas of pregnant mice, it replicated, crossed the placenta and caused damage to the developing fetus.

“The earlier the infection, the more likely miscarriage or fetal reabsorption will occur. This shows that transmission by Aedes mosquitoes shouldn’t be the only concern. Sexual transmission during pregnancy is a risk,” Peron said.

Another participant in the FeSBE symposium on Zika, Patricia Beltrão-Braga, a researcher at the University of São Paulo’s School of Veterinary Medicine & Animal Science (FMVZ-USP) and also co-author of the paper published in Nature, reported that she has been testing several commercially available drugs in cultured human neural progenitor cells in search of one that can block replication of the virus or prevent it from entering cells.

“When we find a drug that gives good results, we’ll test it in an animal model,” she said.

Maurício Maia, a researcher at the Federal University of São Paulo (UNIFESP), presented studies of ocular lesions in fetuses caused by Zika infection during gestation. “Unfortunately, as we’ve shown, even newborns without microcephaly can have brain and ocular damage due to infection by Zika during pregnancy,” he said (read more at: agencia.fapesp.br/23462).

Another participant in the symposium was virologist Gubio Soares Campos, the first scientist to describe a case of Zika infection in Brazil. Campos, who is a researcher at the Federal University of Bahia (UFBA), presented data suggesting that a specific strain of Zika found in Salvador, the state capital, displays minor genetic differences compared with viruses isolated in other states.

The differences observed do not change the characteristics of the disease, Campos explained, but should be considered in the development of vaccines.

“This virus is adapting and may also cause problems in adults one day, like meningitis,” he said.