Costa Allyson Guimarães, Ramasawmy Rajendranath, Ibiapina Hiochelson Najibe Santos, Sampaio Vanderson Souza, Xábregas Lilyane Amorim, Brasil Larissa Wanderley, Tarragô Andréa Monteiro, Almeida Anne Cristine Gomes, Kuehn Andrea, Vitor-Silva Sheila, Melo Gisely Cardoso, Siqueira André Machado, Monteiro Wuelton Marcelo, Lacerda Marcus Vinicius Guimarães, Malheiro Adriana
Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, AM, Brazil.
Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil.
PLoS One. 2017 Aug 29;12(8):e0183840. doi: 10.1371/journal.pone.0183840. eCollection 2017.
Plasmodium vivax malaria (Pv-malaria) is still considered a neglected disease despite an alarming number of individuals being infected annually. Malaria pathogenesis occurs with the onset of the vector-parasite-host interaction through the binding of pathogen-associated molecular patterns (PAMPs) and receptors of innate immunity, such as toll-like receptors (TLRs). The triggering of the signaling cascade produces an elevated inflammatory response. Genetic polymorphisms in TLRs are involved in susceptibility or resistance to infection, and the identification of genes involved with Pv-malaria response is important to elucidate the pathogenesis of the disease and may contribute to the formulation of control and elimination tools.
METHODOLOGY/PRINCIPAL FINDINGS: A retrospective case-control study was conducted in an intense transmission area of Pv-malaria in the state of Amazonas, Brazil. Genetic polymorphisms (SNPs) in different TLRs, TIRAP, and CD14 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 325 patients infected with P. vivax and 274 healthy individuals without malaria history in the prior 12 months from the same endemic area. Parasite load was determined by qPCR. Simple and multiple logistic/linear regressions were performed to investigate association between the polymorphisms and the occurrence of Pv-malaria and parasitemia. The C/T (TLR5 R392StopCodon) and T/T (TLR9 -1486C/T) genotypes appear to be risk factors for infection by P. vivax (TLR5: C/C vs. C/T [OR: 2.116, 95% CI: 1.054-4.452, p = 0.031]; TLR9: C/C vs. T/T [OR: 1.919, 95% CI: 1.159-3.177, p = 0.010]; respectively). Fever (COEF = 7599.46, 95% CI = 3063.80-12135.12, p = 0.001) and the C/C genotype of TLR9 -1237C/T (COEF = 17006.63, 95% CI = 3472.83-30540.44, p = 0.014) were independently associated with increased parasitemia in patients with Pv-malaria.
Variants of TLRs may predispose individuals to infection by P. vivax. The TLR5 R392StopCodon and TLR9 -1486C/T variants are associated with susceptibility to Pv-malaria. Furthermore, the TLR9 variant -1237C/C correlates with high parasitemia.
尽管间日疟原虫疟疾（Pv疟疾）每年感染人数惊人，但仍被视为一种被忽视的疾病。疟疾发病机制始于媒介-寄生虫-宿主相互作用，通过病原体相关分子模式（PAMP）与固有免疫受体（如Toll样受体（TLR））的结合而发生。信号级联反应的触发会产生增强的炎症反应。TLR基因多态性与感染的易感性或抗性有关，鉴定与Pv疟疾反应相关的基因对于阐明该疾病的发病机制很重要，并且可能有助于制定控制和消除工具。
方法/主要发现：在巴西亚马逊州一个Pv疟疾高强度传播地区进行了一项回顾性病例对照研究。通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析，对来自同一流行地区的325例间日疟原虫感染患者和274例在过去12个月内无疟疾病史的健康个体的不同TLR、TIRAP和CD14基因多态性（SNP）进行基因分型。通过qPCR确定寄生虫载量。进行单因素和多因素逻辑/线性回归分析，以研究多态性与Pv疟疾发生和寄生虫血症之间的关联。C/T（TLR5 R392StopCodon）和T/T（TLR9 -1486C/T）基因型似乎是间日疟原虫感染的危险因素（TLR5：C/C与C/T相比[比值比：2.116，95%可信区间：1.054-4.452，p = 0.031]；TLR9：C/C与T/T相比[比值比：1.919，95%可信区间：1.159-3.177，p = 0.010]）。发热（系数 = 7599.46，95%可信区间 = 3063.8-12135.12，p = 0.001）和TLR9 -1237C/T的C/C基因型（系数 = 17006.6, 95%可信区间 = 3472.83-30540.44，p = 0.014）与Pv疟疾患者寄生虫血症增加独立相关。
TLR变体可能使个体易受间日疟原虫感染。TLR5 R392StopCodon和TLR9 -1486C/T变体与Pv疟疾易感性相关。此外，TLR9变体-1237C/C与高寄生虫血症相关。
