Plasmodium co-infection protects against chikungunya virus-induced pathologies

Abstract

Co-infection with Plasmodium and chikungunya virus (CHIKV) has been reported in humans, but the impact of co-infection on pathogenesis remains unclear. Here, we show that prior exposure to Plasmodium suppresses CHIKV-associated pathologies in mice. Mechanistically, Plasmodium infection induces IFNγ, which reduces viraemia of a subsequent CHIKV infection and suppresses tissue viral load and joint inflammation. Conversely, concomitant infection with both pathogens limits the peak of joint inflammation with no effect on CHIKV viraemia. Reduced peak joint inflammation is regulated by elevated apoptosis of CD4+ T-cells in the lymph nodes and disrupted CXCR3-mediated CD4+ T-cell migration that abolishes their infiltration into the joints. Virus clearance from tissues is delayed in both infection scenarios, and is associated with a disruption of B cell affinity-maturation in the spleen that reduces CHIKV-neutralizing antibody production.

Pathogenic Th1 responses in CHIKV‐induced inflammation and their modulation upon Plasmodium parasites co‐infection

“…Supporting this hypothesis, a recent mouse study reported that blockade of type I interferon signaling resulted in a better parasite control due to the establishment of robust antimalarial humoral responses reflected in increased Tfh numbers, GC reactions, and Plasmodium ‐specific antibody titers . Finally, the re‐challenge of recovered animals previously infected with either malaria or CHIKV with their respective heterologous pathogen did not affect the normal development of any of their individual pathologies …”

“…The reduction of CHIKV‐induced footpad swelling in co‐infected animals was associated with lesser numbers of joint‐infiltrating innate pathogenic subsets such as neutrophils, NK cells, and inflammatory monocytes . Reduced edema, muscle necrosis, and vascular leakage were also observed suggesting generalized suppression of signature inflammatory responses induced by CHIKV (Figure ).…”

“…Immune profiling of the popliteal LN (pLN), the nearest draining LN to the site of infection, from the concurrent co‐infected animals revealed decreased numbers of total and CHIKV‐specific CD4 + T cells . Concordantly, increased apoptotic CD4 + T cells in the pLN at 5 and 6 dpi were detected.…”

“…Furthermore, collective evidence has suggested that Plasmodium ‐associated immunosuppression increases the host susceptibility to secondary infections potentially leading to more complicated pathologies . Pre‐infection with murine malaria strains for 4 days followed by subsequent inoculation with CHIKV (early sequential co‐infection) or concurrent CHIKV‐ Plasmodium co‐infection markedly reduced the development of virus‐induced joint swelling . Moreover, sequential co‐infection but not concurrent co‐infection abolished viremia in infected animals.…”

“…Impaired expansion and early apoptosis of CD4 + T cells in draining lymph nodes in co‐infected mice could only partially explain the suppression of joint swelling. Virus‐specific CD4 + T cells in the pLN was only suppressed by ~50%, but CD4 + T cells detection in the co‐infected animals' footpad was almost completely abolished . Using adoptive transfer of CSFE‐labeled CD4 + T cells isolated from CHIKV‐infected mice, it was shown that the migratory potential of CD4 + T cells into the infected footpad was also abolished by co‐infection.…”