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

Abstract

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 ...

A vital role for complement in heart disease

“…The lectin pathway has also been shown to attack T cruzi early during infection, and MBL, ficolin-2 and ficolin-3 bind to T cruzi (Cestari et al, 2009). Polymorphisms in the MBL2 gene with subsequent low levels of MBL increase the risk for Chagas disease, hence confirming that the lectin pathway has a protective role (Weitzel et al, 2012). Lower levels of plasma ficolin-2 have been observed in patients with Chagas disease than in controls (Luz et al, 2013).…”

Complement Activation by Giardia duodenalis Parasites through the Lectin Pathway Contributes to Mast Cell Responses and Parasite Control

“…Single-nucleotide polymorphisms (SNPs) in the gene for MBL-associated serine protease 2 (MASP-2) that are associated with low MASP-2 expression levels were found more frequently in Chagas' disease patients with cardiomyopathy than in patients in the indeterminate phase (58). Similarly, MBL genotypes with low expression were also correlated with increased pathology (59). However, a recent study found that low-MBL genotypes were associated with reduced pathology in Chagas' disease patients (60).…”

The Role of TLR4 896 A>G and 1196 C>T in Susceptibility to Infections: A Review and Meta-Analysis of Genetic Association Studies

“…Combined effects were also calculated for all Gram negative infections [30,31,33,35,39,46,47,52,53,57-60], all Gram positive infections [43,45,46] and all parasitic infections [36,37,40,50,51,54-56] (table 3). A significant risk was found for all parasitic infections combined (OR G 1.59; 95% CI 1.05-2.42, effect derived from Asian, African and South American populations; Figure 1) and malaria (OR G 1.31; 95% CI 1.04-1.66, a combined effect for African and Asian studies; Figure 2) .…”