Macrophages as target cells for Mayaro virus infection: involvement of reactive oxygen species in the inflammatory response during virus replication

Abstract

Alphaviruses among the viruses that cause arthritis, consisting in a public health problem worldwide by causing localized outbreaks, as well as large epidemics in humans. Interestingly, while the Old World alphaviruses are arthritogenic, the New World alphaviruses cause encephalitis. One exception is Mayaro virus (MAYV), which circulates exclusively in South America but causes arthralgia and is phylogenetically related to the Old World alphaviruses. Although MAYV-induced arthritis in humans is well documented, the molecular and cellular factors that contribute to its pathogenesis are completely unknown. In this study, we demonstrated for the first time that macrophages, key players in arthritis development, are target cells for MAYV infection, which leads to cell death through apoptosis. We showed that MAYV replication in macrophage induced the expression of TNF, a cytokine that would contribute to pathogenesis of MAYV fever, since TNF promotes an inflammatory profile characteristic of arthritis. We also found a significant increase in the production of reactive oxygen species (ROS) at early times of infection, which coincides with the peak of virus replication and precedes TNF secretion. Treatment of the cells with antioxidant agents just after infection completely abolished TNF secretion, indicating an involvement of ROS in inflammation induced during MAYV infection.

Mayaro: an emerging viral threat?

“…MAYV replication in macrophages induces tumor necrosis factor (TNF) synthesis in association with fever, since TNF promotes an inflammatory profile characteristic of arthritis. Additionally, they observed an increase of reactive oxygen species (ROS) at early points of infection, which coincided with the acute phase of viral replication followed by TNF secretion 16 . These findings were confirmed by Camini et al 17 , who found that MAYV induces significant oxidative stress in infected HepG2 cells.…”

“…The in vitro study by Cavalheiro et al 16 showed that MAYV infection of macrophages leads to apoptosis. MAYV replication in macrophages induces tumor necrosis factor (TNF) synthesis in association with fever, since TNF promotes an inflammatory profile characteristic of arthritis.…”

In-depth characterization of a novel live-attenuated Mayaro virus vaccine candidate using an immunocompetent mouse model of Mayaro disease

“…As these molecules are associated to monocytes response and to alphavirus normal response 37,38,[57][58][59] , our data indicate lower level of monocyte activation by the vaccinal strain as compared to the WT virus. This is important for a vaccine for MAYV since activation of monocytes may contribute to the pathogenesis of MAYV-induced arthritis 53,[59][60][61][62][63] . Finally, flow cytometric analyses of spleen leukocytes showed more robust immune response in MAYV/IRES immunized mice when compared to the WT strain.…”

Mayaro Virus Pathogenesis and Transmission Mechanisms

“…Many cell types have been shown to be implicated in the pathogenesis of MAYV. The role of macrophages, being targets for MAYV infection, in the development of arthritis has been demonstrated through the secretion of TNF-α and ROS [60]. In this respect, it is of interest to note that high serum levels of TNF-α have previously been reported in MAYV-infected patients and mice [50,61].…”