Functional Analysis of Genetic Variations in Surfactant Protein D in Mycobacterial Infection and Their Association With Tuberculosis

Abstract

Surfactant proteins (SPs)-A and -D are C-type lectins of the collectin family and function in the clearance of infectious particles in the lungs. Some polymorphisms of SPs that give rise to amino acid changes have been found to affect their function. Several SP-A gene polymorphisms have been reported to be associated with respiratory infection diseases, such as tuberculosis (TB). However, the relationship between surfactant proteins D (SP-D) polymorphisms and TB is still unclear. To study the associations between SP-D polymorphisms and TB, the correlations of SP-D polymorphisms with TB were examined in a case–control study, which included 364 patients with TB and 177 control subjects. In addition, we cloned two major SP-D exonic polymorphism C92T (rs721917) and A538G (rs2243639) constructs and used these for in vitro assays. The effects of SP-D polymorphisms on agglutination and other interactions with Mycobacterium bovis bacillus Calmette–Guérin (M. bovis BCG) were evaluated. In comparison with SP-D 92C (amino acid residue 16, Threonine), our results showed that SP-D 92T (amino acid residue 16, Methionine) had a lower binding ability to M. bovis BCG, a lower capacity to inhibit phagocytosis, lesser aggregation, poorer survival of bacillus Calmette–Guérin (BCG)-infected MH-S cells, and less inhibition of intracellular growth of M. bovis BCG. The case–control association study showed that the 92T homozygous genotype was a risk factor for TB. However, a lesser effect was seen for polymorphism A538G. In conclusion, the results of functional and genetic analyses of SP-D variants consistently showed that the SP-D 92T variant increased susceptibility to TB, which further confirmed the role of SP-D in pulmonary innate immunity against mycobacterial infection.

Complement Dependent and Independent Interaction Between Bovine Conglutinin and Mycobacterium bovis BCG: Implications in Bovine Tuberculosis

“…This is the first definitive observation of conglutinin pattern recognition and binding to a Gram-positive bacterium (e.g., mycobacteria). SP-D has also recently been shown to bind to M. bovis BCG (36). The mycobacterial ligand for conglutinin is likely to be those reported for SP-D and M. tuberculosis , namely the terminal dimannosyl units of lipoarabinomannan (LAM) (37, 38), since SP-D is structurally similar to conglutinin (2) and M. bovis BCG shares an almost identical bacterial surface, including LAMs (39, 40).…”

Association of Surfactant-Associated Protein D Gene Polymorphisms with the Risk of COPD: a Meta-Analysis

“…Some researchers have studied the association between SPD polymorphisms and COPD susceptibility; this association was first reported in the Mexican population in 2001 26. Some studies have reported that the SPD gene plays an important role in the development of asthma 15, silicosis 27 and tuberculosis 28. However, there is still controversy concerning the genetic associations of SPD with COPD at present.…”

Infection resisters: targets of new research for uncovering natural protective immunity against Mycobacterium tuberculosis

“…SP-A and SP-D polymorphisms are known to be associated with susceptibility to TB disease 44 . In fact, in a case-controlled study of 364 patients with TB and 177 control subjects in Taiwan, the SP-D 92T homozygous genotype was found to be a risk factor for TB 45 . In vitro assays further supplemented this finding by demonstrating that this variant had a lower binding ability to Mycobacterium bovis as well as a lower capacity to inhibit phagocytosis, resulting in less inhibition of intracellular growth of M. bovis 45 .…”