Polymorphisms in TLRs influence circulating cytokines production in Plasmodium vivax malaria

Abstract

The efficiency of the immune system has been shaped throughout the evolutionary process allowing adaptations. In a Plasmodium vivax infection, the host attempts to develop an innate immune response to keep in check the parasite that is associated with inflammatory and regulatory processes. Production of pro-inflammatory and regulatory cytokines simultaneously appears to be a balancing mechanism for the host to prevent the onset of severe disease. Changes in the dynamics of circulating cytokines production can influence the pathogenesis, severity of the disease and episodes of recurrent Plasmodium vivax malaria (Pv-malaria). A cross-sectional study was conducted in endemic areas for Pv-malaria in the Amazonas State, Brazil. Several SNPs in TLR genes were genotyped by PCR-RFLP in 137 patients infected with P. vivax. Circulating cytokines IL-6, TNF, IL-2, IL-10, IFN-γ and IL-4 were measured by CBA. Influence of the studied SNPs on circulating cytokines was investigated by applying the Kruskal-Wallis test followed by Dunns' multiple comparison post-test. A Spearman correlation test also was performed to elaborate circulating cytokine networks and to demonstrate the level of interaction between each molecule. Individuals with genotypes A/G (TLR4 A299G), C/C (TLR6 S249P) and T/T (TLR9 -1486C/T) appear to produce less/gain IL-6, IFN-γ, IL-10, IL-2 and IL-4 compared to patients with wild-type and heterozygous genotypes. In addition, these genotypes seem to influence the interaction network between the molecules studied, causing a lower interaction, absence or even negative interaction between the cytokines. Data presented in this study suggests the influence of polymorphisms TLR4 (A299G), TLR6 (S249P) and TLR9 (-1486C/T) on the production of circulating cytokines during Pv-malaria.

Impact of Plasmodium vivax malaria and antimalarial treatment on cytochrome P450 activity in Brazilian patients

“…Cytokine‐induced inhibition of the expression and activity of CYP enzymes in hepatocytes is one likely mechanism. The host immune response against P. vivax triggers production and increased circulating levels of several proinflammatory and regulatory cytokines, which influence the pathogenesis and severity of the disease, and recurrence of acute episodes 11–15 Our results verified the increase in circulating IL‐6, IL‐8 and IL‐10 in acute vivax malaria (phase 1), and reversal to baseline (IL‐6 and IL‐10) or considerable reduction (IL‐8) at the end of the 7‐day combined chloroquine‐primaquine treatment (phase 2), in agreement with previous results 11 . The time course of changes in circulating IL‐6 and IL‐10, and to a lesser degree IL‐8, parallels the transient inhibition of CYP2C19 activity observed in phase 1 of this study.…”

“…[5][6][7][8] Increased levels of circulating proinflammatory cytokines are hallmarks of human parasitic diseases such as leishmaniasis 9,10 and malaria. [11][12][13][14][15] We have previously shown that the phenotypic activities of CYP3A4 and CYP2C19 were significantly reduced during acute visceral leishmaniasis and restored after curative chemotherapy; suppression of CYP activity was attributed to increased plasma concentrations of proinflammatory cytokines during active disease. 16 Regarding human malaria, there is only limited information for Plasmodium falciparum, suggestive of reduced activity of CYP1A2 and CYP3A enzymes.…”

An Immunological Stairway to Severe Tissue Complication Assembly in Bothrops atrox Snakebites

“…The positive and negative correlations are considered significant when p < 0.05. The correlation index (r) was used to categorize the correlation strength as being weak ( r ≤ 0.35), moderate ( r ≥ 0.36 to r ≤ 0.67), or strong ( r ≥ 0.68), as previously described (30, 31). The levels of statistical significance defined in both cases were p < 0.05.…”

TLR-Mediated Host Immune Response to Parasitic Infectious Diseases

“…The AA genotype proved to be protective against the development of this parasite in a local population of Pakistan [77]. Additionally, TLR4 A299G, TLR6 S249, and TLR 9-1486C/T influence the levels of circulating cytokines IL-6, IFN-γ, IL-12, IL-10, and IL-4 during a P. vivax infection [78].…”