Genetic variants of tumor necrosis factor-α -308G/A (rs1800629) but not Toll-interacting proteins or vitamin D receptor genes enhances susceptibility and severity of malaria infection.

Susceptibility to malaria infection has been associated with host genetic polymorphisms that differs between groups. We hypothesize that Toll-interacting proteins (TOLLIP), vitamin D receptor (VDR) and tumor necrosis factor-α (TNF) genes are significant contributors to susceptibility and disease severity in Plasmodium falciparum (Pf) infection. Our aim is to explore the genomic diversity and haplotype frequency of these genes, as well as extrapolate possible association with markers of severity, between malaria-infected and healthy controls. Genomic DNA samples extracted from the blood of 107 malaria-infected patients and 190 uninfected controls were analyzed, with no difference in genotypic or allelic frequencies of TOLLIP and VDR polymorphisms. However, a significant difference in the genotypic (p = 2.20E-16) and allelic frequencies (p = 2.20E-16) of the TNF-α (snp rs1800629) polymorphism was found. The preponderance of the mutant variant among the malaria-infected show a possible impaired capacity to mount an effective immune response, potentially confirmed by our association results. This result calls for analysis of clearly delineated uncomplicated versus severe disease groups, including serum assays, providing a basis to conclude that susceptibility to malaria infection and potential contribution to disease severity is significantly associated with polymorphisms of the tumor necrosis factor-α but not TOLLIP or VDR genes.

Induction of alpha and beta chemokines by intestinal epithelial cells stimulated with Campylobacter jejuni.

OBJECTIVES: To investigate the production of dynamic alpha and beta chemokines represented by interleukin-8 (IL-8) as alpha chemokine and CCL2 (monocyte-chemoattractant protein-1, CCR2 ligand), CCL4 (macrophage-inflammatory protein-1beta, CCR5 ligand), CCL3 (macrophage-inflammatory protein-1alpha, CCR1/5 ligand), (CCL5, regulated upon activation, normal T-cell expressed and secreted (RANTES, CCR5 ligand) as beta chemokines by the human intestinal cell line INT407 stimulated with factors produced by living Campylobacter jejuni (C. jejuni) and those present within sonicated and filtrated bacteria. METHODS: We used immunohistochemical technique modified to detect intracellular production of cytokines protein and RT-PCR to read RNA messages for evaluation of de novo cytokine synthesis. RESULTS: Living bacteria induced increased numbers of IL-8, CCL4 and CCL2 but not CCL3 or CCL5 producing cells. Low numbers of IL-8, CCL4 and CCL2 producing cells were detected with filtrated supernatant compared to living and sonicated bacteria. A non-significant low number of chemokine producing cells was noted when comparing numbers of chemokine producing cells stimulated with living C. jejuni to those stimulated with sonicated bacteria, indicating that the triggering factors involved in stimulation with living bacteria were still active after sonication, but they were largely lost upon filtration. The mRNA signals for IL-8 were noted in conformity with its protein levels as increased IL-8 mRNA signals were registered after stimulation with living and sonicated bacteria but not with filtrated supernatant. CONCLUSIONS: Preferential production of chemokines probably induced by membrane associate factors of C. jejuni acting on intestinal epithelial cells is presented. These chemokines are suggested to be part of an inflammatory network affecting cell types that contribute to initiation and/or resolution of the infection.