Polymorphisms of toll-like receptor 2 and 4 genes in Chagas disease

Zafra, German; Flórez, Óscar; Morillo, Carlos A.; Echeverría, Luis Eduardo; Martı́n, Javier; González, Clara Isabel

doi:10.1590/s0074-02762008000100004

Cited by 28 publications

(19 citation statements)

References 31 publications

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“…In previous studies, this was not observed, 8 but our findings accord with the reported lack of effect on infection per se. 23 Our results also support the finding that common TLR1 and TLR2 SNPs do not seem to influence CD or CCC 8 and show the respective lack of impact for a frequent TLR6 variant. The reason for the lack of impact remains unclear but may involve redundancy of TLR signaling.…”

supporting

confidence: 88%

Mannose-Binding Lectin and Toll-Like Receptor Polymorphisms and Chagas Disease in Chile

Weitzel¹,

Zulantay²,

Hamann³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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Abstract. Mannose-binding lectin (MBL) and Toll-like receptor (TLR) polymorphisms may influence susceptibility and manifestation of Trypanosoma cruzi infection. In northern Chile, we examined 61 asymptomatic patients with chronic Chagas disease (CD), 64 patients with chronic Chagas cardiomyopathy (CCC), and 45 healthy individuals. Lowproducer MBL2*B genotypes were more common in CD patients (48%) than healthy individuals (31%; adjusted odds ratio ¼ 2.3, 95% confidence interval ¼ 1.01-5.4, P ¼ 0.047) but did not differ with manifestation. In contrast, the heterozygous Toll-like receptor 4 (TLR4)-deficiency genotype D299G/T399I occurred more frequently in asymptomatic (14.8%) than CCC patients (3.1%; P ¼ 0.02). TLR1-I602S, TLR2-R753Q, TLR6-S249P, and MAL/TIRAP-S180L did not associate with CD or CCC. These findings support the complement system to be involved in defense against Trypanosoma cruzi infection and indicate that curbed TLR4 activation might be beneficial in preventing CCC.Chagas disease (CD), caused by Trypanosoma cruzi, affects up to 8 million people in Latin America, with up to 13,000 annual deaths. Infection persists lifelong. Still, only one-third of patients develop manifestations, mainly chronic Chagas cardiomyopathy (CCC). The pathogenesis of progression to chronic symptomatic CD is poorly understood, but it involves immunological and autoimmunological factors and genetic disposition.1,2 Innate immune responses contribute to host control, and T. cruzi has been shown to bind to mannose-binding lectin (MBL), which activates the lectin pathway of early complement killing and reduces host cell invasion.3 Also, T. cruzi activates the Toll-like receptor (TLR) system, particularly TLRs 2 and 4, which ultimately leads to a proinflammatory response. 4 Genetic variation of innate immunity may influence infection and manifestation, which has been shown for MBL and TLR single-nucleotide polymorphisms (SNPs) and various infectious and inflammatory diseases. 5,6 Specifically, an increased risk of severe CCC has been attributed to high MBL serum levels, 7 but respective genotypic data are not available. In contrast, a mutation in the TLR adaptor protein MAL/TIRAP (S180L) has been associated with a reduced risk of CCC. 8In the provinces of Choapa and Limarí, northern Chile, CD is highly endemic, and although Chile was declared free of domestic T. cruzi transmission in 1999, vertical transmission and management of chronically infected patients continue.9 In this area, a cohort of patients has been regularly followed-up since the 1990s. 10 In these patients and healthy individuals, we typed common SNPs that reduce the function of TLRs involved in the recognition of T. cruzi as well as low-producer MBL2 alleles and analyzed associations with CD and CCC.Patients were recruited from the CD cohort in November of 2007 and May of 2008. In the patients' villages, healthy volunteers were asked to participate as controls. All study participants were thoroughly informed about study purpose and procedures, and they signed an ...

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supporting

confidence: 88%

Mannose-Binding Lectin and Toll-Like Receptor Polymorphisms and Chagas Disease in Chile

Weitzel¹,

Zulantay²,

Hamann³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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“…In our study, the 2258A allele was present only in Europeans and not in other populations. These data are supported by data from previous studies showing that this SNP is not present in Asian populations, such as those from Taiwan (12), South Korea (45,62), and India (7); in a Chinese Han population (32); in one African cohort from Ethiopia (8); and in one American cohort from Colombia (63). In a southeastern Chinese population, the TLR2 2258A allele was found at a very low frequency and was not associated with susceptibility to tuberculosis (60).…”

Section: Discussionsupporting

confidence: 86%

Different Patterns of Toll-Like Receptor 2 Polymorphisms in Populations of Various Ethnic and Geographic Origins

et al. 2012

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ABSTRACTUpon the invasion of the host by microorganisms, innate immunity is triggered through pathogen recognition by pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are the best-studied class of PRRs, and they recognize specific pathogen-associated molecular patterns (PAMPs) from various microorganisms. A large number of studies have shown that genetic variation in TLRs may influence susceptibility to infections. We assessed the genetic variation ofTLR2, which encodes one of the most important TLRs, in various populations around the globe and correlated it with changes in the function of the molecule. The three best-known nonsynonymousTLR2polymorphisms (1892C>A, 2029C>T, and 2258G>A) were assessed in different populations from the main continental masses: Romanians, Vlax-Roma, Dutch (European populations), Han Chinese (East Asia), Dogon, Fulani (Africa), and Trio Indians (America). The 2029C>T polymorphism was absent in both European and non-European populations, with the exception of the Vlax-Roma, suggesting that this polymorphism most likely arose in Indo-Aryan people after migration into South Asia. The 1892C>A polymorphism that was found exclusively in European populations, but not in Asian, African, or American volunteers, probably occurred in proto-Indo-Europeans. Interestingly, 2258G>A was present only in Europeans, including Vlax-Roma, but at a very low frequency. The differential pattern of theTLR2polymorphisms in various populations may explain some of the differences in susceptibility to infections between these populations.

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“…This is in concordance with previous studies on other parasitic infections. In a previous study, frequencies of TLR4 Asp299Gly and Thr399Ile polymorphism did not show any significant differences in the distribution of alleles or genotypes between patients with chagasic cardiomyopathy and asymptomatic subjects [17]. In another study, TLR2 196-174 del heterozygosity was associated with protection from cerebral malaria (OR 0.34, 95% confidence intervals 0.16, 0.73) [18].…”

Section: Discussionmentioning

confidence: 92%

Association between Toll-Like Receptor 4 (Thr399Ile and Asp299Gly), Toll-Like Receptor 2 196-174 Deletion Polymorphisms with cryptosporidiosis

Dey¹,

Ghoshal²,

Agarwal³

et al. 2016

JBM

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Toll-like receptors (TLRs) 2 and 4 specifically recognize lipopolysaccharide motifs on surfaces of microorganisms. Polymorphims in the TLR genes result in structural variations in the proteins, abnormal host-pathogen interactions and hence, altered immune response. Opportunistic parasite Cryptosporidium spp. infects immunocompromised patients who present with heterogeneous clinical manifestations ranging from mild infection resolving in a few weeks, to severe form characterized by voluminous diarrhoea, prolonged symptoms and recurrences. The present study investigates the role of TLR2 196_174del, TLR4 Asp299Gly and Thr399Ile polymorphisms in pathogenesis of cryptosporidiosis. Stool samples were collected from 210 immuno-compromised (renal transplant recipients and patients with Human immunodeficiency virus infection) both with and without cryptosporidiosis, and 200 healthy subjects for detection of Cryptosporidium spp. Blood samples were also collected from the patients and healthy subjects for genotyping of Δ22 (TLR2 196_174del) polymorphism, A896G (TLR4 Asp299Gly) and C1196T (Thr399Ile) single nucleotide polymorphisms (SNPs) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Cryptosporidium spp. was detected in 70 immunocompromised patients, while it was absent in all the healthy controls. No significant difference was observed in Δ22, A896G and C1196T alleles and genotypes (P > 0.05), between cases and controls. Thus, TLR2 196_174del, TLR4 Asp299Gly and Thr399Ile polymorphisms are not significantly associated with the pathogenesis or progression of cryptosporidiosis, in the Indian population included in the study.

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Polymorphisms of toll-like receptor 2 and 4 genes in Chagas disease

Cited by 28 publications

References 31 publications

Mannose-Binding Lectin and Toll-Like Receptor Polymorphisms and Chagas Disease in Chile

Mannose-Binding Lectin and Toll-Like Receptor Polymorphisms and Chagas Disease in Chile

Different Patterns of Toll-Like Receptor 2 Polymorphisms in Populations of Various Ethnic and Geographic Origins

Association between Toll-Like Receptor 4 (Thr399Ile and Asp299Gly), Toll-Like Receptor 2 196-174 Deletion Polymorphisms with cryptosporidiosis

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