Genetically Determined MBL Deficiency Is Associated with Protection against Chronic Cardiomyopathy in Chagas Disease

Abstract

Chagas disease (CD) is caused by Trypanosoma cruzi, whose sugar moieties are recognized by mannan binding lectin (MBL), a soluble pattern-recognition molecule that activates the lectin pathway of complement. MBL levels and protein activity are affected by polymorphisms in the MBL2 gene. We sequenced the MBL2 promoter and exon 1 in 196 chronic CD patients and 202 controls. The MBL2*C allele, which causes MBL deficiency, was associated with protection against CD (P = 0.007, OR = 0.32). Compared with controls, genotypes with this allele were completely absent in patients with the cardiac form of the disease (P = 0.003). Furthermore, cardiac patients with genotypes causing MBL deficiency presented less heart damage (P = 0.003, OR = 0.23), compared with cardiac patients having the XA haplotype causing low MBL levels, but fully capable of activating complement (P = 0.005, OR = 7.07). Among the patients, those with alleles causing MBL deficiency presented lower levels of cytokines and chemokines possibly implicated in symptom development (IL9, p = 0.013; PDGFB, p = 0.036 and RANTES, p = 0.031). These findings suggest a protective effect of genetically determined MBL deficiency against the development and progression of chronic CD cardiomyopathy.

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

“…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). Thus, variation in MBL levels can impact both early and late events during both acute and chronic Chagas' disease.…”

Chagas Disease Diagnostic Applications

“…This may be attributed in part to the genetic aspects and immune competence of local human populations (Ayo et al, 2013; Deng et al, 2013; Frade et al, 2013; Luz et al, 2016; Nogueira et al, 2012) and/or to parasite genetic heterogeneities. The latter hypothesis finds support in animal studies (that do not strictly recapitulate Chagas disease-associated physiopathologies), which revealed inter-strain variations in complex phenotypes such as parasitemia, virulence, tissue tropism/distribution and pathogenicity (Figure 1) (Andrade et al, 1999; Andrade, 1990; Camandaroba, Pinheiro Lima and Andrade, 2002; de Souza et al, 1996; Laurent et al, 1997; Monteiro et al, 2013; Revollo et al, 1998; Roellig et al, 2010).…”

“…The current consensus states that a failure to down-regulate the inflammatory response, which is maintained by parasite persistence in tissues, appears to play a predominant role. Other contributory factors include sex, age and genotypic features of the patient, route of infection, sustained vector exposure, auto-immune responses and the existence of co-infections (Ayo et al, 2013; Bonney and Engman, 2015; Deng et al, 2013; Frade et al, 2013; Luz et al, 2016; Machado et al, 2012; Nogueira et al, 2012; Tarleton, 2015; Teixeira et al, 2011). As mentioned, a possible role of parasite genotype on Chagas disease progression/outcome has been proposed, though further research supported by novel and robust epidemiologic and diagnostic tools, and appropriate animal models are needed to address this issue.…”

Complement Factor H as a potential atherogenic marker in chronic Chagas’ disease

“…Different studies have demonstrated the crucial role of complement as a first line of defence against T. cruzi infection, as well as in the maintenance of chronic infection and severity of CCC . The complement system includes more than 35 plasma proteins/regulators and cell surface receptors which act together in the recognition and elimination of microbial and foreign cells.…”

“…in the maintenance of chronic infection 11 and severity of CCC. [12][13][14][15] The complement system includes more than 35 plasma proteins/regulators and cell surface receptors which act together in the recognition and elimination of microbial and foreign cells. In order to keep complement activation under homeostatic conditions, an effective and fine system of regulatory molecules, such as complement Factor H (FH), is required.…”