Genetic variation in Interleukin-32 influence the immune response against New World Leishmania species and susceptibility to American Tegumentary Leishmaniasis

PLoS Negl Trop Dis. 2020 Feb 5;14(2):e0008029. doi: 10.1371/journal.pntd.0008029. eCollection 2020 Feb.

Abstract

Interleukin-32 is a novel inflammatory mediator that has been described to be important in the immunopathogenesis and control of infections caused by Leishmania parasites. By performing experiments with primary human cells in vitro, we demonstrate that the expression of IL-32 isoforms is dependent on the time exposed to L. amazonensis and L. braziliensis antigens. Moreover, for the first time we show the functional consequences of three different genetic variations in the IL32 (rs4786370, rs4349147, rs1555001) modulating IL-32γ expression, influencing innate and adaptive cytokine production after Leishmania exposure. Using a Brazilian cohort of 107 American Tegumentary Leishmaniasis patients and a control cohort of 245 healthy individuals, the IL32 rs4786370 genetic variant was associated with protection against ATL, whereas the IL32 rs4349147 was associated with susceptibility to the development of localized cutaneous and mucosal leishmaniasis. These novel insights may help improve therapeutic strategies and lead to benefits for patients suffering from Leishmania infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Brazil / epidemiology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation / immunology
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Humans
  • Interleukins / genetics*
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism
  • Leishmania / classification*
  • Leishmaniasis, Cutaneous / epidemiology
  • Leishmaniasis, Cutaneous / genetics*
  • Leishmaniasis, Cutaneous / immunology
  • Leishmaniasis, Cutaneous / metabolism
  • Male
  • Middle Aged
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / metabolism
  • Protein Isoforms
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism

Substances

  • CLEC7A protein, human
  • Cytokines
  • IL32 protein, human
  • Interleukins
  • Lectins, C-Type
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Protein Isoforms
  • TLR4 protein, human
  • Toll-Like Receptor 4

Grants and funding

F.R-D receives PRONEM (CH 07-2016) grant from Fundação de Amparo à Pesquisa do Estado de Goiás/FAPEG, Brazil; F.R-D is fellow researcher of National Council for Scientific and Technological Development/CNPq/Brazil; This study was supported in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/Ministry of Education, Brazil - Finance Code 001". J.C.S is fellow of CAPES, Brazil; V.B.L.Q is fellow of FAPEG, Brazil; M.V.T.S is fellow of CAPES, Brazil; M.G.N was supported by a Spinoza grant of the Netherlands Organization for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.