Chikungunya infection induces partial immunity against mayaro virus

A study conducted at the University of São Paulo (USP) suggests that individuals infected with the chikungunya virus may develop partial immunity to the mayaro virus. The conclusion, presented in the Journal of Virology, is based on experiments carried out with mice and with the blood serum of patients. According to the authors, this type of cross-protection may be one of the reasons why a major mayaro fever epidemic has not yet occurred in Brazil.

In the work, supported by FAPESP, the mice were first infected by chikungunya and a month later by mayaro — and, in another group of animals, the opposite procedure was carried out. In both cases, analyzes showed that the inflammatory response to the second infection was milder.

“We observed a significant reduction in secondary disease. The analyzes showed that cross-protection partially mitigates the disease picture in several aspects: it reduces the viral load, tissue damage and also the inflammatory mediators that cause cell damage”, says Marcílio Fumagalli, PhD scholarship holder at FAPESP at the USP Virology Research Center, in Ribeirão Preto. “When we tested the neutralizing antibodies of one virus against the other, we observed a low protective response against both,” he adds.

Although animals initially infected with chikungunya have a small amount of neutralizing antibodies circulating in their blood, these levels rise rapidly after secondary mayaro infection, which induces cross-protection against the disease.

The group analyzed the neutralization by antibodies, but also identified other immune system factors in rodents that can influence this cross-response. “The infected individual is sensitized, starting to produce antibodies and other defense mechanisms. The organism then develops an ‘immunological memory’, which allows it to respond more quickly during reinfection”, he says.

The work quantified levels of protective antibodies produced after each infection. “The production of memory cells [linfócitos B ou T] it takes some time, but as the animal had previously been infected with chikungunya, it already had them. This meant that, during secondary mayaro infection, the immune response, including the increase in the levels of neutralizing antibodies, occurred quickly”, explains Fumagalli.

As the researcher emphasizes, it is known that the immune response against pathogens involves different action fronts, including mechanisms of innate immunity [macrófagos, neutrófilos, células NK ou natural killers], adaptive immunity [linfócitos B e T] and also soluble mediators—such as antibodies and cytokines.

“In the study, we observed the important role of antibodies, which is one of the factors that mediate cross-protection. But, in addition, we also observed that other elements must be involved”, says Luiz Tadeu Figueiredo, coordinator of the Center for Research in Virology and study leader.

In the analysis, the group was able to remove the B (antibody-producing) cells from the infected mice and observe the levels of cross-protection. “These analyzes indicated that other immune response factors are also involved in cross-protection, such as other lymphocyte subpopulations or innate immune response mechanisms. The antibody is important, but it is not the only one acting in cross-protection. that we still haven’t been able to identify”, says Figueiredo.

The researchers also analyzed blood serum from patients infected with chikungunya. This experiment served to demonstrate that antibodies produced after a chikungunya infection also cross-react, fighting the action of the mayaro virus.

two viruses, different antibodies

Mayaro and chikungunya are “related” viruses as they belong to the same family as Togaviruses. However, although they trigger similar symptoms when infecting humans, they have slightly different structures. “Each disease requires the production of different types of antibodies, some of which recognize the same proteins. In other words, mayaro and chikungunya generate different antibodies, but the fact is that some of them work for both diseases”, explains Fumagalli.

Chikungunya is transmitted through the bite of female Aedes aegypti and Aedes albopictus mosquitoes. Most cases of the disease are characterized by the acute form of the infection, with high fever, headaches, joint and muscle pain, in addition to nausea, fatigue and skin rashes, which can reach the chronic state characterized by severe pain in the joints during years old.

Mayaro fever is transmitted by wild mosquitoes of the genus Haemagogus. Symptoms are very similar to those in the acute phase of chikungunya, including fever, reddened patches of skin, headache and muscle pain. More severe cases also present with joint pain, which may or may not be accompanied by swelling. Vaccines for either disease have not yet been developed.

Cross-protection is not new in immunology, but it is not usually the norm. The case of the dengue virus, for example, which belongs to the Flavivirus family, is even more complex. “First, that the same species has four different serotypes: dengue 1, 2, 3 and 4. They show certain differences during the activation of the immune response, inducing antibodies capable of generating cross-protection for another serotype, however, some antibodies are capable of aggravating the disease”, says Figueiredo.

urban adaptation

The discovery of cross-protection also helps to understand why there is not a wide circulation of Mayaro in Brazilian cities, despite the outbreaks that have occurred in recent years and the warnings of risk.

“With the finding, we hypothesized that this cross-immunity could be another evolutionary barrier that prevents the widespread adaptation of the mayaro virus to the urban environment. The two pathogens are endemic in Brazil, however, only chikungunya is adapted for circulation in cities , while the Mayaro is better maintained in wild regions”, says Figueiredo.

Fumagalli emphasizes that, in addition to cross-protection, other factors can contribute to blocking the transmission of mayaro. “In addition to being able to infect humans, the virus also needs to adapt well to be transmitted to urban mosquitoes, which does not occur for the Mayaro, which is preferentially transmitted between monkeys and other wild mosquitoes”, he says.

Another important point for the difference in cases between the two diseases is viremia, that is, humans produce a reduced viral load for a short period of time after infection by mayaro, which further reduces the susceptibility of urban mosquitoes to infection.

“In other animals, such as monkeys, the viral load is significantly higher, which may also explain this evolutionary barrier that prevents the arrival of mayaro in urban areas. Our study suggests that this prior immunity may further hinder the circulation of the mayaro virus among humans, considering that infected with chikungunya are partially protected, which can help to control new outbreaks”, says Fumagalli.