Reduced CD3/TCR complex expression leads to immunosuppression during Plasmodium falciparum malaria

Abstract

Inhibition of T cell function is an important pathological feature in malaria. We investigated which T cell population is reduced contributing to immunosuppression. We examined protein and RNA level of various cell receptors, specific for T cells in children having Plasmodium falciparum infection and compared those to healthy children of the same age. We observe reduced levels of cluster of differentiation (CD)3 and T cell receptor (TCR)alphabeta in both RNA and protein expression level. This reduced expression was associated with a collapsed membrane asymmetry as determined by enhanced annexinV binding. Also human leukocyte antigen (HLA)-A,B,C- and HLA-DR-positive cells increasingly bound annexinV. The enhanced binding of annexinV was paralleled by a reduced expression of transcription factors such as T cell transcription factor 7 and GATA binding protein 3, which are involved in the expression of T cell specific genes. Also the expression of the transcription factors major histocompatibility complex class II transactivator and regulatory factor X 5, which are part of the HLA transcription machinery, is reduced during infection. We show that two mechanisms may lead to a suppression of the immune system during malaria: cell damage and reduction of gene expression of the CD3/TCR complex.

The blood transcriptome of childhood malaria

“…Based on microarray technology, several studies have tried to more precisely describe particular features of the host's immune response against the Plasmodium parasite in both naturally and experimentally infected humans [5,6]. Here, we extend previous studies on the expression of candidate genes in whole blood of Gabonese children with malaria [7,8] and describe the whole blood signature of gene expression in relevant clinical presentations of childhood malaria. The various presentations of P. falciparum infection were discriminated, and discrete signatures for transcription factor binding sites in promoters of genes were identified, either up-regulated across all disease manifestations, specifically up-regulated in uncomplicated malaria or specifically down-regulated in cerebral malaria.…”

Ficolin-2 levels and genetic polymorphisms of FCN2 in malaria

“…These apoptotic cells are found in higher numbers in severe malaria than in the milder forms [30,31,32]. Rather than having a direct influence on malarial infections by interacting with the parasite, ficolin-2 might play an important role to clear dying cells and DNA from the bloodstream.…”

Acquired Antibody Responses against Plasmodium vivax Infection Vary with Host Genotype for Duffy Antigen Receptor for Chemokines (DARC)

“…It is known that the elevated DARC expression in double-positive individuals confers a higher risk of P. vivax infection in comparison to those with one negative gene (FY*A/FY*Bnull, FY*B/FY*Bnull) [43], [44], [60], [61]. Furthermore, active erythrocytic malaria infections have been reported to induce immune suppression that prevents the host from mounting an effective immune response against the blood stage parasites and other co-infecting agents [38], [68], [69], [70], [71], [72], [73]. This immune suppression ranges from inhibition of dendritic cell maturation [38], to inhibition of the generation of specific CD4 T cells [69] and apoptosis of specific CD4 T cells [73].…”

“…Furthermore, active erythrocytic malaria infections have been reported to induce immune suppression that prevents the host from mounting an effective immune response against the blood stage parasites and other co-infecting agents [38], [68], [69], [70], [71], [72], [73]. This immune suppression ranges from inhibition of dendritic cell maturation [38], to inhibition of the generation of specific CD4 T cells [69] and apoptosis of specific CD4 T cells [73]. Thus, it is likely that the high susceptibility to P. vivax blood stage infection and concomitant high P. vivax erythrocytic parasite load in FY*A/FY*B and FY*B/FY*B double-positive individuals may contribute to the suppression of antibody responses against erythrocytic antigens when compared with FY*A/FY*Bnull and FY*B/FY*Bnull individuals.…”