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Co-infection with Chikungunya virus alters trafficking of pathogenic CD8⁺ 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.

SUBMITTER: Teo TH

PROVIDER: S-EPMC5760855 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Co-infection with Chikungunya virus alters trafficking of pathogenic CD8+ T cells into the brain and prevents Plasmodium-induced neuropathology.

Teo Teck-Hui TH Howland Shanshan W SW Claser Carla C Gun Sin Yee SY Poh Chek Meng CM Lee Wendy Wl WW Lum Fok-Moon FM Ng Lisa Fp LF Rénia Laurent L

EMBO molecular medicine 20180101 1

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 ...[more]

PMID: 29113976

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Project description:The N-linked biantennary glycans on the heavy chain of immunoglobulin G (IgG) antibodies (mAbs) are instrumental in the recognition of the Fc region by Fc-gamma receptors (FcγR). In the case of full-length mAb-based imaging tracers targeting immune cell populations, these Fc:FcγR interactions can potentially deplete effector cells responsible for tumor clearance. To bypass this problem, we hypothesize that the enzymatic removal of the Fc glycans will disrupt Fc:FcγR interactions and spare tracer-targeted immune cells from depletion during immunopositron emission tomography (immunoPET) imaging. Herein, we compared the in vitro and in vivo properties of 89Zr-radiolabeled CD8-specific murine mAb (anti-CD8wt, clone 2.43), a well-known depleting mAb, and its deglycosylated counterpart (anti-CD8degly). Deglycosylation was achieved via enzymatic treatment with the peptide: N-glycosidase F (PNGaseF). Both anti-CD8wt and anti-CD8degly mAbs were conjugated to p-SCN-Bn-desferrioxamine (DFO) and labeled with 89Zr. Bindings of both DFO-conjugated mAbs to FcγR and CD8+ splenocytes were compared. In vivo imaging and distribution studies were conducted to examine the specificity and pharmacokinetics of the radioimmunoconjugates in tumor-naive and CT26 colorectal tumor-bearing mice. Ex vivo analysis of CD8+ T cell population in spleens and tumors obtained postimaging were measured via flow cytometry and qRT-PCR. The removal of the Fc glycans from anti-CD8wt was confirmed via SDS-PAGE. A reduction in FcγR interaction was exhibited by DFO-anti-CD8degly, while its binding to CD8 remained unchanged. Tissue distribution showed similar pharmacokinetics of [89Zr]Zr-DFO-anti-CD8degly and the wt radioimmunoconjugate. In vivo blocking studies further demonstrated retained specificity of the deglycosylated radiotracer for CD8. From the imaging studies, no difference in accumulation in both spleens and tumors was observed between both radiotracers. Results from the flow cytometry analysis confirmed depletion of CD8+ T cells in spleens of mice administered with DFO-anti-CD8wt, whereas an increase in CD8+ T cells was shown with DFO-anti-CD8degly. No statistically significant difference in tumor infiltrating CD8+ T cells was observed in cohorts administered with the probes when compared to control unmodulated mice. CD8 mRNA levels from excised tumors showed increased transcripts of the antigen in mice administered with [89Zr]Zr-DFO-anti-CD8degly compared to mice imaged with [89Zr]Zr-DFO-anti-CD8wt. In conclusion, the removal of Fc glycans offers a straightforward approach to develop full length antibody-based imaging probes specifically for detecting CD8+ immune molecules with no consequential depletion of their target cell population in peripheral tissues.

Dataset Information

Co-infection with Chikungunya virus alters trafficking of pathogenic CD8⁺ T cells into the brain and prevents Plasmodium-induced neuropathology.

Publications

Co-infection with Chikungunya virus alters trafficking of pathogenic CD8<sup>+</sup> T cells into the brain and prevents <i>Plasmodium</i>-induced neuropathology.

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