STAT6 (Phospho-Thr645) ELISA Kit

Schistosomiasis is endemic in many parts of rural Africa, with previous reports showing interleukin-13 polymorphisms as drivers of infectivity and disease severity in West Africa while IL-13/IL-4 polymorphisms contributes to patterns of reinfection in East Africa. We have shown that there is a genetic delineation in susceptibility to and severity of infectious diseases in Africa, in addition to sub-continental differences in disease pattern. Therefore, which immunoregulatory biomarkers are essential in driving S. haematobium infection or regulate disease burden among Nigerian school children? One hundred and thirty one age and sex-matched schistosome-infected children and 275 uninfected controls, of same ethnicity, recruited from southwestern Nigeria, were screened for variability of cytokine genes, IL-10 (rs1800872), IL-13 (rs7719175), IL-4 (rs2243250) and STAT6 (rs3024974), utilizing a polymerase chain reaction-restriction fragment length polymorphism assay. We found no difference in genotypic or allelic frequencies of IL-10 and IL-13 promoter polymorphisms alone or in association with disease. Contrariwise, we report significant differences in the frequencies of IL-4 and STAT6 variants between groups. For IL-4, the rs2243250 T/T variant was significantly different for genotypes (71.6% versus 51.2%; p < .0004) and alleles (82.6% versus 71.1%; p < .001) between disease and control groups respectively. For STAT6 (rs3024974), the frequencies of genotypes C/C and C/T are 75.4% and 24.6%, both showing an association with disease; none of the infected subjects had the T/T variant. Despite minor differences in disease covariates, we found no association between IL-4 and STAT6 variants with age, gender or anemia. However, mean egg count (indicative of disease burden), was regulated based on IL-4 variants, with highest burden in infected subjects with rs2243250 T/T variant (mean egg count 207.5 eggs/10 ml of urine) versus rs2243250 C/T heterozygotes (mean egg count 84.3 eggs/10 ml of urine) versus rs2243250 C/C (mean egg count 127.9 eggs/10 ml of urine). Comparing rs2243250 C/T versus rs2243250 T/T (p < .008) or rs2243250 C/C + C/T versus rs2243250 T/T (p < .016) reveals an association with disease burden. We conclude that the IL-4 promoter gene is a susceptibility factor for schistosomiasis, and essential to regulate disease burden, with worse disease among carriers of the rs2243250 T/T variant. The absence of the STAT6, rs3024974T/T variant among infected subjects reveal the necessity of the STAT6 promoter gene in driving susceptibility to schistosomiasis in Nigeria.

Intestinal epithelial cells (IECs) constitute an important barrier between host and pathogen. Immune mechanisms that provide protection against gastrointestinal helminths often require IL-4R alpha-induced activation of STAT6-regulated genes in IECs. However, it is not known whether STAT6 activation in IECs enhances protective immunity against helminths. Furthermore, the regulation of proliferation and differentiation processes of the intestinal epithelium by IEC-intrinsic STAT6 signaling remains unclear. To address these questions, we generated mice with specific expression of a constitutively active version of STAT6 in IECs. These VillinCre_STAT6vt mice show accumulation of secretory IECs, increased proliferation of IECs and lengthening of the small intestine. They rapidly expelled Nippostrongylus brasiliensis worms even in the absence of T cells. Furthermore, primary infection with Heligmosomoides polygyrus resulted in larval trapping in the submucosa and the fecundity of adult worms was severely impaired. Our results reveal an important IEC-intrinsic role of STAT6-regulated genes for intestinal homeostasis and protective immunity against helminths.