IL2RA Genetic Variants Reduce IL-2–Dependent Responses and Aggravate Human Cutaneous Leishmaniasis

Abstract

The outcome of Leishmania infections varies substantially, depending on the host and the parasite strain; infection may be asymptomatic or cause mild or severe skin ulcers (cutaneous leishmaniasis [CL]), limited or disseminated lesions, or lethal visceral disease. We previously reported an association between IL-2R mutations and susceptibility to visceral leishmaniasis in children infected with Leishmania donovani. In the present study, we evaluated the possible role of IL-2 signaling in human CL. We first showed that the transcripts of several genes of the IL-2 pathway were abundant in skin lesions caused by Leishmania braziliensis. We then carried out a genetic analysis, focusing on major genes of the IL-2 pathway. We used a family-based approach and found that polymorphisms of several genes appeared to be associated with CL in a Brazilian population. Moreover, two polymorphisms of the IL2RA gene were significantly and independently associated with CL. We confirmed this result in a second Brazilian sample (also exposed to L. braziliensis) and in Iranians infected with Leishmania tropica: IL2RA rs10905669 T (Pcombined = 6 × 10−7) and IL2RA rs706778 T (Pcombined = 2 × 10−9) were associated with greater susceptibility to lesion development. These alleles were also correlated with a poor IFN-γ response and poor FOXP3+ regulatory T cell activation. Thus, IL-2 plays a crucial role in protection against the cutaneous ulcers caused by Leishmania, and the IL-2 pathway is a potential target for strategies aiming to control Leishmania-related diseases.

Gene Expression Profile of High IFN-γ Producers Stimulated with Leishmania braziliensis Identifies Genes Associated with Cutaneous Leishmaniasis

“…To address whether these genes are also expressed in CL lesions, we performed in silico analysis of microarray transcriptomic data generated from human CL lesions caused by L . braziliensis [12,13]. Expression of IRF1 , JAK2 , IL6 and IFI27 was significantly higher in CL lesions, corroborating our findings tiwht PBMCs (Fig 7A and 7B).…”

“…The number of transcripts for each gene was quantified in Data sets GSM1341365 [12] and GSM1560512 [13]. Data were normalized using RMA (Robust Multichip Average) for each dataset, log-transformed expression for each gene is shown as box and whiskers (displaying quartile range) and outliers (identified by Tukey’s test).…”

“…Several transcripts of the IL2 pathway are present in CL lesions caused by L . braziliensis and certain IL2RA gene polymorphisms were associated with a poor IFN-γ response and lower activation of regulatory Foxp3 + cells [13]; IL2RA was also upregulated in LPs though herein we did not probe for any of these polymorphisms. Among the top two pathways identified in the LP response were "Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses" and " Interferon Signaling", corroborating the upregulation in IFN-related genes such as IFI44 , IFIT1 and IFITM2 .…”

“…Hierarchical cluster analysis using the Ward’s method with bootstrap and principal component analysis (PCA) were performed using and JMP Statistical Discovery (V 12). The number of transcripts for ( IFI27 , IFIT1 , TLR2 , IRF1 , JAK2 and IL6) was quantified in data sets GSM1341365 [12] and GSM1560512 [13] containing transcriptomic data from CL lesions and from healthy (control skin). Data were normalized using RMA (Robust Multichip Average) for each dataset and the number of transcripts were compared by unpaired t-test using Prism (GraphPad Software, V 6.0).…”

Research Article Polymorphisms of the mannose binding lectin (<i>MBL2</i>) gene are related to protein plasma levels but not with visceral leishmaniasis in a northeastern brazilian population

“…The genetic background of the host has important impact in clinical manifestation of leishmaniasis. Variations in genes that are related to the immune system such as DLL1, TLR4, IL2RA and FCRN2 have been implicated in leishmaniasis development in human host (Mehrotra et al, 2012;Rasouli et al, 2012;Oliveira et al, 2015;Mishra et al, 2015b). The MBL protein is innate immune component that recognizes carbohydrate patterns, found on the surface of a large number of pathogenic microrganisms, leading to activation of the complement system by lectin pathway.…”