Co‐infection with Chikungunya virus alters trafficking of pathogenic CD 8 ⁺ T cells into the brain and prevents Plasmodium ‐induced neuropathology

Abstract

Arboviral diseases have risen significantly over the last 40 years, increasing the risk of co‐infection with other endemic disease such as malaria. However, nothing is known about the impact arboviruses have on the host response toward heterologous pathogens during co‐infection. Here, we investigate the effects of Chikungunya virus (CHIKV) co‐infection on the susceptibility and severity of malaria infection. Using the Plasmodium berghei ANKA (PbA) experimental cerebral malaria (ECM) model, we show that concurrent co‐infection induced the most prominent changes in ECM manifestation. Concurrent co‐infection protected mice from ECM mortality without affecting parasite development in the blood. This protection was mediated by the alteration of parasite‐specific CD8+ T‐cell trafficking through an IFNγ‐mediated mechanism. Co‐infection with CHIKV induced higher splenic IFNγ levels that lead to high local levels of CXCL9 and CXCL10. This induced retention of CXCR3‐expressing pathogenic CD8+ T cells in the spleen and prevented their migration to the brain. This then averts all downstream pathogenic events such as parasite sequestration in the brain and disruption of blood–brain barrier that prevents ECM‐induced mortality in co‐infected mice.

The Influence of Parasite Infections on Host Immunity to Co-infection With Other Pathogens

“…The sequestration of malaria parasites across the blood-brain barrier leads to the influx of immune lymphocytes and leukocytes into the brain, particularly parasite-specific CD8 + T cells, which ultimately leads to the development of neuropathology. Studies using a murine experimental cerebral malaria (ECM) model show that co-infection with Chikungunya virus can impede the sequestration of malaria parasites into the brain and provide some protection against ECM ( 19 ). In this model co-infection system, the malaria parasite-specific pathogenic CD8 + T cells appeared to be retained in the spleens of mice co-infected with Chikungunya virus due to their reduced expression of the CXCR3 chemokine receptor ( 19 ).…”

“…Studies using a murine experimental cerebral malaria (ECM) model show that co-infection with Chikungunya virus can impede the sequestration of malaria parasites into the brain and provide some protection against ECM ( 19 ). In this model co-infection system, the malaria parasite-specific pathogenic CD8 + T cells appeared to be retained in the spleens of mice co-infected with Chikungunya virus due to their reduced expression of the CXCR3 chemokine receptor ( 19 ). This implied that the reduced early migration of pathogenic CD8 + T cells into the brains of the virus co-infected mice may have impeded the development of ECM and brain pathology.…”

Role of T Cells in Chikungunya Virus Infection and Utilizing Their Potential in Anti-Viral Immunity

“…In mice, levels of IFN-γ-expressing NKT cell remain unchanged in CHIKV-infected mice, as compared to healthy controls (48). However, these cells accumulate in the spleens of mice that are co-infected with CHIKV and malaria parasites (48).…”

“…In mice, levels of IFN-γ-expressing NKT cell remain unchanged in CHIKV-infected mice, as compared to healthy controls (48). However, these cells accumulate in the spleens of mice that are co-infected with CHIKV and malaria parasites (48). This event is due to the increased expression of chemokines CXCL9 and CXCL10 in the spleens, which attract and retain lymphocytes that express cognate chemokine receptors.…”

“…CD4 + T CELLS Activated CD4 + T cells have been well-documented to play an essential role in the pathogenesis of CHIKV-induced joint swelling (31,34,48). Our laboratory has comprehensively proven this through multiple methods.…”