A study conducted at the University of São Paulo (USP) in Brazil suggests that people previously infected with Chikungunya virus may develop partial immunity to Mayaro virus. The result presented in the Journal of Virology is based on experiments with mice and blood serum from patients. According to the authors, this type of cross-protection could be one of the reasons why there has not been a major outbreak of Mayaro fever in Brazil. The study was supported by FAPESP.
In the experiments, mice were infected first with Chikungunya and one month later with Mayaro. The same procedure was performed in reverse on another group of mice. The inflammatory response to the second infection was milder in both groups.
“We observed a significant reduction in secondary disease. Our analyzes showed that cross-protection mitigated disease severity in several ways: reducing viral load, mitigating tissue damage, and partially inhibiting the inflammatory mediators that damage the cells, ”said Marcílio Fumagalli, PhD student on a FAPESP fellowship at the Center for Virology Research, part the Ribeirão Preto Medical School (FMRP-USP). “When we tested neutralizing antibodies to one virus against the other, we found weak protective responses to both.”
Although the mice initially infected with Chikungunya had low levels of neutralizing antibodies in their bloodstream, these levels rose rapidly after secondary infection with Mayaro, triggering cross-protection against the latter.
The researchers analyzed the neutralization by antibodies, but also identified other factors in the immune system of the mice that could influence this cross-protection. “An infected person becomes sensitized and begins to produce antibodies and other defense mechanisms,” said Fumagalli. “The organism develops an ‘immune memory’ and can react more quickly if it is infected again.”
The antibody levels produced after each infection were measured. “Manufacture of memory cells [B and T lymphocytes] takes time, but the mice first infected with chikungunya already had it, so during the secondary Mayaro infection the immune response was faster, including an increase in neutralizing antibodies, ”explained Fumagalli. “The immune response to pathogens is both innate [macrophages, neutrophils, natural killer cells] and adaptable [B and T lymphocytes], as well as soluble mediators such as antibodies and cytokines. “
In the study, we observed the important role of antibodies, one of the factors that mediate cross protection. We also concluded that other elements need to be included. “
Luiz Tadeu Figueiredo, Study Director, Center for Virology Research and Study Director
Upon analysis, the group removed B cells (which produce antibodies) from the infected mice and measured the level of cross-protection. “The analysis showed that other immune response factors are involved in this cross-protection, such as lymphocyte subpopulations or mechanisms of the innate immune response,” said Figueiredo. “Antibodies are important, but they’re not the only ones that create cross protection. There is something else that we have yet to identify.”
The researchers also analyzed blood serum from patients infected with chikungunya. The purpose of this experiment was to show that antibodies produced in response to infection with chikungunya also resulted in cross-protection against Mayaro.
Two viruses, different antibodies
Mayaro virus and Chikungunya virus both belong to the Togaviridae family. The symptoms of the diseases they cause in humans are similar, but their structures are slightly different. “Each disease requires the production of different antibodies, even though some recognize the same proteins. In other words, Mayaro and Chikungunya trigger the production of different antibodies, but some of those antibodies are effective against both diseases, ”said Fumagalli.
Chikungunya is transmitted by the bite of female mosquitos of the species Aedes aegypti and A. albopictus. In most cases, the main symptoms are high fever, headache, joint and muscle pain, nausea, tiredness and a rash. Joint pain can remain acute for several years.
Mayaro is transmitted by a forest vector, the mosquito Haemagogus spp. The main symptoms are sudden fever, rash, dizziness, chills, headache and muscle pain. In severe cases, joint pain also occurs, which may or may not be accompanied by edema. There are no vaccines for either disease.
Cross protection is uncommon, but is not unknown to immunologists. For example, dengue, a flavivirus, is more complex. “First of all, there are four serotypes of the same species. The immune response to each is different. Antibodies against one can protect against another, but some antibodies can make the disease worse,” Figueiredo said.
The affirmation of mutual protection between Mayaro and Chikungunya also explains why the former disease is not widespread in Brazilian cities, despite the outbreaks in recent years and warnings from health officials. “The finding hypothesizes that cross-immunity may be an evolutionary barrier to Mayaro virus adapting to the urban environment,” Figueiredo said. “Both pathogens are endemic to Brazil, but only Chikungunya has adapted sufficiently to circulate in cities. Mayaro is mostly forest dweller.”
Fumagalli stressed that in addition to the protection of the cross, other factors could also block the transmission of Mayaro. “To infect humans, the virus would have to adapt effectively to be transmitted to urban mosquitoes, but in fact, it is mainly transmitted between monkeys and other forest mosquitos,” he said.
Another key factor in the differences between the two diseases is viraemia. Mayaro creates a low viral load in humans for a short time after infection, which further reduces susceptibility to urban mosquitos. “Other animals like monkeys have significantly higher viral loads, which could also explain this evolutionary barrier that prevents Mayaro from circulating in urban environments,” said Fumagalli. “Our study suggests that prior immunity could be an obstacle to the spread of Mayaro among humans, as individuals infected with chikungunya are partially protected and this could help control new outbreaks.”
São Paulo Research Foundation (FAPESP)
Fumagalli, MJ, et al. (2021) Exposure to the Chikungunya virus partially protects against infection with the Mayaro virus in mice. Journal of Virology. doi.org/10.1128/JVI.01122-21.