A study by Agency for Science, Technology and Research (A*STAR) researchers in Singapore has discovered that the Plasmodium parasite responsible for malaria triggers immune pathways that reduce the severity of symptoms caused by infection with the Chikungunya virus (CHIKV) in mice.

This discovery could lead to the development of novel treatments for the painful symptoms of CHIKV and possibly other viruses transmitted by mosquito vectors, including dengue and Zika, the scientists reported in a study published in the Sept. 25, 2018, edition of Nature Communications.

Spread by Aedes albopictus and Aedes aegypti, the latest CHIKV epidemic began in 2004 on islands in the Indian Ocean and rapidly spread to tropical areas of India, Southeast Asia, Latin America and Africa, causing millions of cases globally.

Expansion into tropical areas with endemic malarial Plasmodium increases likelihood of co-infection with CHIKV and Plasmodium, with co-infections having been confirmed in affected patients in seroprevalence studies.

Most co-infections have been reported in Africa and, while the global frequency of infection with CHIKV and Plasmodium is low, it is also likely underestimated, as arbovirus screening is performed only when patients are negative for malaria infection.

"The frequency of such co-infections remains unknown, as people are now only discovering these by chance," said study co-leader Lisa Ng, a professor and senior principal investigator at A*STAR's Singapore Immunology Network (SIgN).

While rarely fatal, CHIKV infection can cause severe, chronic polyarthritis and/or polyarthralgia, which can cause permanent disfigurement.

However, according to the World Health Organization (WHO), there are currently no effective treatments or vaccines for CHIKV infection available for humans and the impact of co-infection on pathogenesis remains unclear.

In a previous study published last year in EMBO Molecular Medicine, SIgN researchers had discovered that co-infection with CHIKV altered the trafficking of pathogenic killer T cells into the brain and prevented Plasmodium-induced neuropathology.

In the present study, researchers led by Ng and Laurent Rénia, a professor and SIgN executive director, demonstrated that prior exposure to Plasmodium suppressed CHIKV-associated pathologies such as joint swelling in mice.

"We demonstrated that prior Plasmodium exposure significantly reduced joint swelling in C57BL/6 mice," Ng told BioWorld Asia.

In both studies, Plasmodium infection was shown to induce interferon-gamma (IFN-gamma), which reduced viremia of subsequent CHIKV infections and suppressed tissue viral load and joint inflammation.

Co-infection with Plasmodium and CHIKV was shown to limit peak joint inflammation and had no effect on CHIKV viremia.

This reduced peak joint inflammation was shown to be regulated by elevated apoptosis of helper T cells in the lymph nodes and disrupted chemokine receptor (CXCR3)-mediated helper T-cell migration that abolishes their infiltration into the joints.

CXCR3 is a G protein-coupled receptor that is highly expressed on effector T cells and known to play a key role in T-cell trafficking and function.

"We used various cell death assays and sensitive ELISpot immunoassays to assess the number of T cells," Ng explained. Helper T cells "are pathogenic when they migrate to the joints and cause inflammation and swelling. With increased apoptosis, fewer cells migrate, so there is less inflammation and joint swelling."

The researchers further demonstrated that viral clearance from tissues was delayed in both infection scenarios, and was associated with a disruption of B-cell affinity-maturation in the spleen that reduced CHIKV-neutralizing antibody production.

"These findings are particularly exciting, because they open up potential new avenues for us to treat and control these diseases," noted Ng.

"We have also found that certain FDA-approved drugs could possibly be repurposed to target these pathways, allowing greater flexibility when treating the symptoms of mosquito-borne diseases," she added.

"In particular, we showed in a study published last year in Science Translational Medicine that the immunomodulatory agent Gilenya [fingolimod, Novartis AG] could abrogate CHIKV-induced joint swelling," said Ng.

These are timely findings, as the WHO is now increasing its malaria intervention programs to aggressively reduce the incidence of malaria, so the severity and numbers of CHIKV cases, and vector competence, could indirectly increase. CHIKV management should therefore be integrated as part of ongoing malaria intervention programs.

Meanwhile, the A*STAR SIgN research team will "continue to decipher novel inflammatory pathways and factors that can be targeted to control the manifestations of diseases including malaria and CHIKV," said Ng.

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