MAJOR ARTICLE IL23R Variant in Cutaneous Leishmaniasis • JID 2022:225 (1 January) • 163 The Journal of Infectious Diseases Received 18 March 2021; editorial decision 13 June 2021; accepted 15 June 2021; published online June 17, 2021. Correspondence: Rajendranath Ramasawmy, PhD, Faculdade de Medicina, Universidade Nilton Lins, Av Prof Nilton Lins, Parque Larangeiras, Manaus, Amazonas, CEP 69058030, Brazil (ramasawm@gmail.com). The Journal of Infectious Diseases ® 2022;225:163–71 © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. https://doi.org/10.1093/infdis/jiab320 IL-23R Variant rs11805303 Is Associated With Susceptibility to the Development of Cutaneous Leishmaniasis in Leishmania guyanensis –Infected Individuals Lener Santos da Silva, 1,2 José do Espírito Santo Júnior, 1,3 Tirza Gabrielle Ramos de Mesquita, 1,2 Veronica Alice Marinho Santos, 1 Josué Lacerda de Souza, 1,3 Felipe Jules de Araújo, 1,2 Cláudio Marcello da Silveira Júnior, 1 Cilana Chagas da Silva, 1 Krys Layane Guimarães Duarte Queiroz, 1 Héctor David Graterol Sequera 1,2 , Marcus Vinitius de Farias Guerra, 1 Mara Lúcia Gomes de Souza, 1 and Rajendranath Ramasawmy 1,2,3,4, 1 Fundação de Medicina Tropical Dr Heitor Viera Dourado, Manaus, Amazona, Brazil, 2 Programa de Pós Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Amazonas, Brazil, 3 Programa de Pós Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil, and 4 Faculdade de Medicina, Universidade Nilton Lins, Manaus, Amazonas, Brazil Background. Emerging evidence suggests that the interleukin (IL) 17/ IL-23 axis may play a role in the pathogenesis of leish- maniasis. Our aim was to investigate whether the IL-23R variant rs11805303 is a risk factor for the development of cutaneous leish- maniasis (CL) in Leishmania guyanensis–infected individuals. Methods. We genotyped by polymerase chain reaction–restriction fragment length polymorphism the rs11805303 C/T in 828 patients with CL and 806 healthy individuals. Plasma tumor necrosis factor–α, IL-6, interferon-γ, IL-1β, and IL-17 were measured with the Bioplex assay. Results. Te distribution of the genotypes difered between patients with CL and healthy controls with a common odds ratio of 1.78 (P = 2.2 × 10 –11 ) for the disease-associated T allele. Leishmania guyanensis–infected individuals homozygous for the T al- lele show a 200% increased risk of progressing to disease development, with a 95% confdence interval ranging from 81% to 400% (P = 9.9 × 10 –6 ) in comparison to individuals homozygous for the C allele. Males homozygous for the T allele have higher plasma levels of IL-17 compared with heterozygous or homozygous CC individuals. Conclusions. Te present association of the IL-23R variant rs11805303 with the development of CL suggests that the IL-17/ IL-23 axis may play an important role in the pathogenesis of CL. Keywords. cutaneous leishmaniasis; Leishmania guyanensis; IL23R variant; susceptibility. Leishmaniasis is caused by infection with the intracellular protozoan parasite Leishmania. The clinical manifestations of Leishmania infection depend on the genetic background of the host, the vector, the site of infection, the skin microbiota, and the Leishmania species [1–4]. The clinical outcome may range from asymptomatic, self-healing to nonhealing cutaneous le- sions known as cutaneous leishmaniasis (CL), to a severe disfiguring condition classified as mucosal leishmaniasis (ML), to fatal visceral leishmaniasis if the infection goes untreated. Leishmania species infect phagocytes cells like macrophages. Interferon gamma (IFN-γ)–activated macrophages control the replication of the parasite, suggesting that a T1 response is needed to avoid disease development. However, an imbalanced overexaggerated immune T1 response liberating high IFN-γ and tumor necrosis factor alpha (TNF-α) may contribute to the pathogenesis associated with Leishmania infection despite the presence of very few parasites in the lesions [5, 6]. Naive CD4 + T helper cells can diferentiate into several subsets of T helpers upon entering in contact with antigens. In the presence of interleukin (IL) 12, naive CD4 + T-helper cells diferentiate into T1 cells to mediate cellular immunity and produce IFN-γ. When stimulated with IL-4, these cells progress to T2 cells and are involved in humoral immunity producing IL-4, IL-5, and IL-13 while upon exposition to tumor growth factor beta (TGF-β), IL-6 and IL-23 evolve to T17 cells that produce IL-17. IL-23, a heterodimeric cytokine comprised of IL-23p19 and IL-12p40, is the main cytokine that, upon binding to its receptor, IL-23 receptor (IL-23R), is involved in the difer- entiation and maintenance of CD4 + T helper cells, the IL-17– producing efector T17 cells [7]. T17 cells secrete IL-17, TNF-α, and IL-6 but not IFN-γ and IL-4. Te T17 pathway plays key role in controlling acute micro- bial infections [8, 9]. IL-23R is described as the essential com- ponent for the terminal diferentiation of T17 cells [7]. 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