Abstract
Tuberculosis (TB) is a multifactorial disease governed by bacterial, host and environmental factors. On the host side, growing evidence shows the crucial role that genetic variants play in the susceptibility to Mycobacterium tuberculosis (Mtb) infection. Such polymorphisms have been described in genes encoding for different cytokines and pattern recognition receptors (PRR), including numerous Toll-like receptors (TLRs). In recent years, several members of the C-type lectin receptors (CTLRs) have been identified as key PRRs in TB pathogenesis. Nevertheless, studies to date have only addressed particular genetic polymorphisms in these receptors or their related pathways in relation with TB. In the present study, we screened the main CTLR gene clusters as well as CTLR pathway-related genes for genetic variation associated with pulmonary tuberculosis (PTB). This case-control study comprised 144 newly diagnosed pulmonary TB patients and 181 healthy controls recruited at the Bhagwan Mahavir Medical Research Center (BMMRC), Hyderabad, India. A two-stage study was employed in which an explorative AmpliSeq-based screening was followed by a validation phase using iPLEX MassARRAY. Our results revealed one SNP (rs3774275) in MASP1 significantly associated with PTB in our population (joint analysis p = 0.0028). Furthermore, serum levels of MASP1 were significantly elevated in TB patients when compared to healthy controls. Moreover, in the present study we could observe an impact of increased MASP1 levels on the lectin pathway complement activity in vitro. In conclusion, our results demonstrate a significant association of MASP1 polymorphism rs3774275 and MASP1 serum levels with the development of pulmonary TB. The present work contributes to our understanding of host-Mtb interaction and reinforces the critical significance of mannose-binding lectin and the lectin-complement pathway in Mtb pathogenesis. Moreover, it proposes a MASP1 polymorphism as a potential genetic marker for TB resistance.
Highlights
Tuberculosis (TB) remains a major global health problem affecting millions of people each year and ranking as the first leading cause of death from an infectious disease worldwide [1]
In the discovery phase of this study, we screened the Dectin-1 and Dectin-2 gene clusters, as well as other C-type lectin receptors (CTLRs)-relevant genomic regions for potential variants that might be associated with pulmonary tuberculosis in an Indian population
Our AmpliSeq design covered 83% of the targeted regions, and yielded over six hundred known SNPs that passed the filters for sequencing depth, MAF and Hardy-Weinberg Equilibrium (HWE) (Table S2 in Supplementary Material)
Summary
Tuberculosis (TB) remains a major global health problem affecting millions of people each year and ranking as the first leading cause of death from an infectious disease worldwide [1]. In TB pathogenesis, the host cellular immune response determines whether an infection is arrested as latent or persistent infection or progresses to the stages, i.e., the active TB infection [3]. Efficient cell-mediated immunity hinders tuberculosis infection by permanently arresting the infection at latent or persistent stage, but if the initial infection in the lung is not controlled or if the immune system becomes weakened, Mtb can cause active pulmonary and to a lesser extend extrapulmonary tuberculosis [4]. Several pattern recognition receptors (PRRs) expressed on various immune cells play a major role in the recognition of Mtb and transduce signals either directly via receptor ligation or through various adaptor molecules to initiate an appropriate immune response [5]. CTLRs binding to Mtb are associated with the induction or the modulation of several important signaling pathways such as the Syk-CARD9-Bcl10MALT1 pathway, phagosome maturation, and complement activation [18,19,20,21,22]
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