Publikationsdatenbank

Brugia malayi cystatin induced immunomodulation on human monocytes and macrophages and identification of immune gene polymorphisms associated with lymphatic filariasis (2019)

Art

Hochschulschrift

Autor

Venugopal, Gopinath (WE 6)

Quelle

Berlin, 2019 — VII, 75 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/25411

Kontakt

Institut für Immunologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51834
immunologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Title: Brugia malayi cystatin induced immunomodulation on human monocytes and macrophages and identification of immune gene polymorphisms associated with lymphatic filariasis. Lymphatic filariasis (LF) is an infection caused by Wuchereria bancrofti, Brugia malayi or Brugia timori, a debilitating disease with more than 120 million people infected worldwide. The lysate of the microfilarial larval stage (Mf) was formerly shown to induce human regulatory monocytes and macrophages. Brugia malayi microfilaria (mf) induce a regulatory monocyte phenotype with an upregulation of IL-10 and PD-L1 that correlates with asymptomatically infected individuals. Previous results have shown that filarial cystatin generally targets human PBMCs and murine macrophages to induce the production of IL-10 and thereby alter the host immune response. Brugia malayi cystatin (BmCPI-2) is known to be released in greater amounts by Brugia malayi microfilaria. Thus, here we aimed to determine how Brugia malayi cystatin contributes to immune hyporesponsiveness in human monocytes and macrophages elicited by microfilaria. For this purpose, filarial cystatin was depleted from microfilarial lysate and applied in functional cell assays. Detecting the immunomodulatory potential of cystatin-depleted Mf revealed that IL-10, but not IL-8 and IL-6 induction in monocytes and macrophages is dependent on the presence of cystatin. In addition, the Mf-induced expression of the regulatory surface markers PD-L1 and PD-L2 in human monocytes, but not in macrophages, is dependent on cystatin. While Mf-treated monocytes result in decreased CD4+ T-cell proliferation in a co-culture assay, stimulation of T-cells with human monocytes treated with cystatin-depleted Mf leads to a restoration of CD4+ T-cell proliferation. Moreover, we show that IL-10 expression in monocytes, but not in macrophages, is independent of ERK signaling, suggesting different pathways of IL-10 induction in these cell populations. Furthermore, it is assumed that genetic factors play a major role in the heterogeneity of clinical outcomes in filarial infections. Therefore, understanding the contribution of host genetics to the clinical outcome of infection lead in the direction of single nucleotide polymorphisms (SNPs) analysis in endemic populations. We examined the association of selected SNPs in PD‐L1, PD-L2, IL‐10, IL‐10RA, and IL-10RB with disease outcome in patients with lymphatic filariasis in a South Indian population. Association tests were performed by using logistic or linear regression when appropriate, including sex, age and pathological status with the help of SNPStats and SPSS. We have identified two polymorphisms, rs7854413 in PD-L2 and rs2834167 in IL-10RB, which are disproportionally distributed between the control and patient group, whereas no differences were found for the analysed SNPs in IL-10, IL-10RA and PD-L1. Most importantly, the SNP PD-L2 rs7854413 was strongly associated with an increased risk of developing chronic pathology (OR = 2.942, 95% CI = 0.957 – 9.046, p = 0.06). These data indicate that rs7854413 might play a role in the susceptibility to disease outcome in filarial infection and further functional studies are needed to understand the immune mechanism involved.