Polymorphisms of innate immunity genes and susceptibility to lymphatic filariasis

Abstract

We examined 906 residents of an area of Papua New Guinea where bancroftian filariasis is endemic for genetic polymorphisms in three innate immunity genes suspected of contributing to susceptibility to infection and lymphatic pathology. Active infection was confirmed by the presence of blood-borne microfilariae and circulating filarial antigen in plasma. Disease was ascertained by physical examination for the presence of overt lymphedema (severe swelling of an arm or leg) or hydrocele. There was no association of infection status, lymphedema of an extremity, or hydrocele with chitotriosidase genotype (CHIT1). Polymorphisms of toll-like receptor-2 and toll-like receptor-4 genes (TLR4 A896G; TLR2 T2178A, G2258A) were not detected (N¼200-625 individuals genotyped) except for two individuals heterozygous for a TLR2 mutation (C2029 T). These results indicate that a CHIT1 genotype associated previously with susceptibility to filariasis in residents of southern India and TLR2 and TLR4 polymorphisms do not correlate with infection status or disease phenotype in this Melanesian population. Genes and Immunity (2003) 4, 524-527. doi:10.1038/sj.gene.6364015Keywords: filariasis; chitotriosidase; toll-like receptor; polymorphism; genetics Lymphatic filariasis is a mosquito-transmitted helminth infection endemic in sub-Saharan Africa, Asia, tropical islands of the Pacific Ocean, and focal areas of Latin America. Humans are infected when mosquitoes inoculate infective larvae into the skin that develop into lymphatic-dwelling adult worms and produce millions of microfilariae that circulate in the bloodstream. The life cycle is completed when microfilariae are taken up in the blood meal of the mosquito vector, where they develop into infective larvae over 10-14 days. The pathological consequences of Wuchereria bancrofti infection (there are also two less common filarial species that infect humans, Brugia malayi and B. timori) are mainly due to lymphatic dysfunction clinically manifested as lymphedema of the extremities or elephantiasis and disfigurement of the genitalia, especially hydroceles in men.Infection and disease due to W. bancrofti have a characteristic distribution in populations living in endemic areas. The frequency of infection is generally higher in adults than children, consistent with the notion that the parasite burden increases with cumulative exposure to mosquito-borne larvae. The prevalence of overt clinical manifestations among adult residents of endemic areas is usually less than 10% despite the fact that most individuals are presumably inoculated with infective larvae throughout life. In high transmission areas of Papua New Guinea, for example, communityspecific infection rates documented by the presence of blood-borne microfilariae and filarial antigenemia range from 50% to over 80% in persons older than 20 years of age, whereas fewer than 10% have lymphedema of the extremities.

Human chitotriosidase polymorphism is associated with human longevity in Mediterranean nonagenarians and centenarians

“…This supports the existence of a 'healthy aging' phenotype in which individuals somehow delay or avoid major clinical disease and disability until late in life. Although previous studies have suggested that CHIT-1-deficient individuals show a certain degree of disadvantage, such as increased susceptibility to parasitic disease infections, to microorganisms containing chitin and to Gram-negative infections, 17,[31][32][33][34][35] other studies indicate that CHIT-1 deficiency is not a disadvantage but rather a selective advantage. [36][37] Given the very high gene frequency of the main mutant allele, as shown in this study, it seems more likely that in humans, selection has occurred in the direction of decreasing or eliminating the activity of this enzyme.…”

Human CHIT1 gene distribution: new data from Mediterranean and European populations

“…DNA was extracted with the standard phenol-chloroform technique, and polymerase chain reaction (PCR) was performed using the primers described by Hise et al (2003) under the following conditions: 30 s at 94°C, 30 s at 55°C, and 30 s at 72°C, with a final extension of 5 min at 72°C. The two fragments of 99 bp and 75 bp were separated on 3% agarose gel stained with ethidium bromide.…”

“…The 24 bp duplication has been associated with susceptibility to infection by Wuchereria bancrofti in south India (Choi et al 2001) but not in Papua New Guinea (Hise et al 2003). The discovery of the existence of a second chitinase, named acidic mammalian chitinase (AMCase), in humans, has opened the possibility that a deficiency in chitotriosidase might be partly compensated for by the presence of the latter enzyme (Boot et al 2001).…”

Association between Mannose-Binding Lectin Polymorphisms and Wuchereria bancrofti Infection in Two Communities in North-Eastern Tanzania

“…11 It is also possible that innate characteristics of the individuals such as genetic factors could play a role, and various attempts have been made to analyze the human genetic composition in relation to both infection susceptibility and development of clinical manifestations. 2,[12][13][14][15][16] A study in India suggested that polymorphisms in the mbl-2 gene could affect susceptibility to W. bancrofti infection. 17 This gene is encoding for production of mannose-binding lectin (MBL), a collagen-like serum protein, which binds to a variety of sugars on the surface of pathogens and thereby facilitate innate host defense to invading pathogens.…”