MASP2 haplotypes are associated with high risk of cardiomyopathy in chronic Chagas disease

Boldt, Angelica Beate Winter; Luz, Paola Rosa; Messias-Reason, Iara

doi:10.1016/j.clim.2011.03.008

Cited by 50 publications

(51 citation statements)

References 36 publications

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“…This finding accords with a recent study showing genotypes of low MASP-2 production to be overrepresented in CD patients. 20 However, MBL2*B did not influence manifestation, which contrasts findings from Brazil. In one study, MBL serum concentrations reportedly increased with increasing cardiac insufficiency, 7 suggesting ongoing inflammation.…”

contrasting

confidence: 55%

“…In a related study, low MASP-2 producer genotypes increased the risk of CCC. 20 These discrepant observations were attributed to differential roles of MBL and MASP-2 in phagocytosis, inflammation, and tissue damage. 20 In our study, neither MBL levels nor MASP-2 alleles were assessed, but it should be noted that MBL concentrations and actual activity do not necessarily correspond.…”

mentioning

confidence: 99%

“…20 These discrepant observations were attributed to differential roles of MBL and MASP-2 in phagocytosis, inflammation, and tissue damage. 20 In our study, neither MBL levels nor MASP-2 alleles were assessed, but it should be noted that MBL concentrations and actual activity do not necessarily correspond. 21 Also, differences in study design and activity of infection may be involved in the opposing findings from Brazil and Chile.…”

mentioning

confidence: 99%

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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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confidence: 55%

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confidence: 99%

mentioning

confidence: 99%

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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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“…Data from humans are less clear, however. 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).…”

Section: Discussionmentioning

confidence: 89%

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

Tako

Singer

2016

Infect Immun

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Infection with Giardia duodenalis is one of the most common causes of diarrheal disease in the world. While numerous studies have identified important contributions of adaptive immune responses to parasite control, much less work has examined innate immunity and its connections to the adaptive response during this infection. We explored the role of complement in immunity to Giardia using mice deficient in mannose-binding lectin (Mbl2) or complement factor 3a receptor (C3aR). Both strains exhibited delayed clearance of parasites and a reduced ability to recruit mast cells in the intestinal submucosa. C3aR-deficient mice had normal production of antiparasite IgA, but ex vivo T cell recall responses were impaired. These data suggest that complement is a key factor in the innate recognition of Giardia and that recruitment of mast cells and activation of T cell immunity through C3a are important for parasite control. Giardia duodenalis is one of the most common protozoan infections of humans as well as other mammals throughout the world and is a leading cause of diarrheal disease in these species (1-3). Symptomatic infections occur in ϳ20 to 80% of humans with positive stool samples and are characterized by nausea, vomiting, epigastric pains, and diarrhea (1, 2, 4, 5). These symptoms are associated with nutrient malabsorption and can lead to weight loss and malnutrition in children, exposing this vulnerable group to failure to thrive and developmental problems (6, 7). Disease resolves spontaneously in Ͼ85% of cases. In certain cases, in spite of a healthy and fully developed immune system, the acute phase of the disease develops into chronic disease. In these cases, symptoms of the disease will reappear for short and recurrent periods (3,4,8). The mechanisms explaining interactions between the host and the parasite leading to parasite clearance and disease pathogenesis are poorly understood.Studies of immune responses against Giardia have demonstrated important roles for both innate and adaptive immunity (7, 9). Antibody production following infection is robust, and IgA is very effective at eliminating parasites (9). Antibody-independent roles of T cells can also eliminate infections (10). Early studies indicated that Giardia trophozoites are susceptible to killing by factors in nonimmune human serum, milk, and intestinal fluid (11-13). Recently, killing by normal serum was demonstrated to involve the lectin pathway (14), consistent with the expression of N-acetylglucosamine (GlcNAc) on the surface of trophozoites (15,16). Studies of cells of the innate immune system indicate that macrophages, dendritic cells, mast cells, and intestinal epithelial cells are all involved. In vitro macrophages have been shown to be capable of ingesting Giardia, and we recently showed that macrophages accumulate in the lamina propria following infection (17, 18). Bone marrow-derived dendritic cells mature in response to Giardia extracts, but cytokine production in response to Toll-like receptor (TLR) agonists is modulated toward interle...

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“…For instance, in a recent large cohort study with patients affected by Chagas' disease, an association between low MASP-2 serum levels and higher risk of chagasic cardiomyopathy was found, suggesting that deficiency in this serine protease could favor disease progression. 41 Whether this response can also be observed in the mouse model of complete lectin pathway deficiency remains to be established.…”

mentioning

confidence: 99%

Deficiency in Mannose-Binding Lectin-Associated Serine Protease-2 Does Not Increase Susceptibility to Trypanosoma cruzi Infection

Ribeiro¹,

Lynch²,

Stover³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Trypanosoma cruzi is the causative agent of Chagas' disease, a chronic illness affecting 10 million people around the world. The complement system plays an important role in fighting microbial infections. The recognition molecules of the lectin pathway of complement activation, mannose-binding lectin (MBL), ficolins, and CL-11, bind to specific carbohydrates on pathogens, triggering complement activation through MBL-associated serine protease-2 (MASP-2). Previous in vitro work showed that human MBL and ficolins contribute to T. cruzi lysis. However, MBL-deficient mice are only moderately compromised in their defense against the parasite, as they may still activate the lectin pathway through ficolins and CL-11. Here, we assessed MASP-2-deficient mice, the only presently available mouse line with total lectin pathway deficiency, for a phenotype in T. cruzi infection. Total absence of lectin pathway functional activity did not confer higher susceptibility to T. cruzi infection, suggesting that it plays a minor role in the immune response against this parasite.

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MASP2 haplotypes are associated with high risk of cardiomyopathy in chronic Chagas disease

Cited by 50 publications

References 36 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

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

Deficiency in Mannose-Binding Lectin-Associated Serine Protease-2 Does Not Increase Susceptibility to Trypanosoma cruzi Infection

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