Abstract

Authors summary

Citation: Guerra MVdF, de Souza JL, da Silva LS, Júnior JdES, de Mesquita TGR, Queiroz KLGD, et al. (2025) Genetic analysis of IFNG-AS1 implicates opposite effects to Leishmania guyanensis-cutaneous leishmaniasis: rs4913269 confers protection while rs7134599 enhances susceptibility and correlates with high plasma IL-4 and IL-10 levels. PLoS Negl Trop Dis 19(7): e0013318. https://doi.org/10.1371/journal.pntd.0013318

Editor: Vyacheslav Yurchenko, University of Ostrava: Ostravska univerzita, CZECHIA

Received: March 27, 2025; Accepted: July 3, 2025; Published: July 14, 2025

Copyright: © 2025 Guerra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All the data are in the manuscript and contains all raw data required to replicate the results of the study in the supporting information.

Funding: This work was supported by the Brazilian Council for Scientific and Technological Development (CNPq), grant number 404181/2012-0 to RR, Fundação de Amparo e Pesquisa do Estado do Amazonas (FAPEAM), grant numbers 06200151/2020, 01.02.016301.03393/2021-80 and 01.02.016301.01090/2023-94 to RR, and FAPEAM RESOLUÇÃO N. 002/2023-POSGRAD – Coordenador/Auxilio Financeiro. JJ, JS, LS and KLGDQ have fellowships from FAPEAM. JPN and RR are CNPq fellows. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist

Background

Leishmaniasis is a vector-borne disease caused by the flagellated protozoan Leishmania spp. The extracellular promastigote form is transmitted through the bites of phlebotomine sandflies and transforms into the intracellular amastigote form within the mammalian host following blood meals. Leishmaniasis presents a wide range of clinical manifestations, ranging from asymptomatic cases and self-healing or non-healing cutaneous leishmaniasis (CL) to severe mucosal involvement or life-threatening visceral leishmaniasis (VL). CL is the most common form of human leishmaniasis, characterized by inflammatory ulcerative cutaneous lesions with elevated borders, confined to the skin.

Leishmaniasis is a neglected tropical disease despite it is endemic in 99 countries across Africa, Asia, Southern Europe, the Middle East and South America according to WHO in 2022 [1]. In 2023, 272098 cases of new CL and 11922 new VL cases were reported to WHO [2]. This disease, associated with poverty, malnutrition, population displacement and poor housing conditions, has a significant global burden and affects predominantly vulnerable populations living in remote regions with limited access to healthcare. Leishmaniasis is a parasitic zoonosis, and its transmission patterns are changing with increasing urbanization due to deforestation and human invasion. To date, there is no vaccine and treatment efficacy is low.

The involvement of the immune system in leishmaniasis has been extensively demonstrated in the resistant C57BL/6 and the susceptible BALB/c mouse strains infected with L. major. BALB/c mice exhibit a robust T-helper 2 (Th2)-type response to L. major, leading to disease progression, in contrast to resistant C57BL/6 mice, which develop a strong T-helper 1 (Th-1)-type response, predominantly dependent on the interleukin-12 (IL-12)/interferon-γ (IFN-γ)/tumor necrosis factor-alpha (TNF-α) axis [3]. IFN-γ plays a critical role in controlling Leishmania growth during infection. IFNG knock-out C57BL/6 mice are unable to control L. major infection. Blocking IFN-γ signaling results in increased lesion size and parasite burden [4].

In Brazil, L. braziliensis (Lb), L. guyanensis (Lg), L. lainsoni, L. amazonensis, L. shawi, L. naiffi and L. lindenbergi are the major species causing tegumentary leishmaniasis. In the state of Amazonas, Lg is the primary etiological agent of CL, accounting for approximately 95% of CL cases. In regions where L. braziliensis is endemic, individuals with a positive delayed-type hypersensitivity (DTH+) response to Leishmania antigen but without a history of disease occurrence have been observed, indicating the presence of subclinical or asymptomatic infection [5].

In regions endemic for leishmaniasis, not all individuals develop disease following bites from Leishmania-infected phlebotomine sandflies, suggesting that host genetic factors significantly influence clinical outcomes. Notably, the host-pathogen interaction has several layers of complexity, including the genetic background of the host, the virulence and genotype of the parasite, the Leishmania-phlebotomine vector and an environment favorable for the development of lesions. There is evidence of a major recessive gene controlling susceptibility to Lb-CL among migrants to an endemic area of leishmaniasis in Bolivia [6]. Family-based genetic epidemiological studies have demonstrated the role of genetic components in controlling susceptibility to L. peruviana-CL, particularly at an early age of onset in Peru [7]. Familial aggregation of CL and ML, caused by L. braziliensis, in endemic regions supports the hypothesis of heritability and genetic susceptibility of clinical forms of leishmaniasis [8]. Genetic variants within the IFNG are suggested to influence cytokine levels of IFN-γ [9–11]. Our findings indicate that the IFNG variant rs2069705 may serve as a genetic modifier of the clinical outcome of L. guyanensis-infection and individuals with a haplotype of several single nucleotide variants (SNVs) within IFNG, associated with low IFN-γ plasma levels, have a 60% increased risk of developing Lg-CL [11].

The long non-coding RNA (lncRNA) interferon gamma antisense-1 (IFNG-AS1), also known as TMEVPG1 and NEST, is adjacent to IFNG on chromosome 12q14. In a murine model of multiple sclerosis, IFNG-AS1 was identified as a susceptibility locus for Theiler’s virus-induced demyelinating disease (TMEV-IDD) [12]. Subsequently, the homologous region on human chromosome 12q14–15 was associated with multiple sclerosis in humans [13]. IFNG-AS1 is induced in response to Th1 differentiation through mechanisms dependent on Signal Transducer and Activator of Transcription 4 (STAT4) and T-box expressed in T cells (T-bet) [14–16], and IFNG-AS1 cooperates with T-bet to promote IFNG transcription. T-bet binds to the IFNG-AS1 promoter/proximal enhancer, as well as to upstream distal enhancers in both developing and differentiated effector Th1 cells, playing a critical role in epigenetic remodeling of these regions [17 ]. IFNG-AS1 is essential for Th1 lineage-specific expression of IFNG and is co-expressed with IFNG. IFNG-AS1 contributes to IFNG expression, and the human IFNG-AS1 is selectively expressed in Th1 cells, particularly in effector Th1 cells, and is regulated by the Th1 transcription factors STAT4 and T-bet [17]. IFNG-AS1 expression is downregulated after in vitro stimulation of murine CD4+ or CD8 + splenocytes, while IFNG expression is upregulated [17]. T-bet guides the epigenetic remodeling of IFNG-AS1 proximal and distal enhancers, leading to recruitment of the stimulus-inducible transcription factors nuclear factor-kappa B (NF-κB) and ETS proto-oncogene (Ets-1) to the locus [18]. The enhancer-specific activity of IFNG-AS1 and its transcriptional regulation depend on NF-κB.

Gene expression profiling of colonic tissue surgical samples from patients with ulcerative colitis revealed high expression of IFNG-AS1 [19], and bioinformatics analysis suggests that the IFNG-AS1 is associated with the inflammatory bowel disease (IBD) susceptibility locus SNV rs7134599 [20]. Moreover, its genomic location is adjacent to the inflammatory cytokine, IFNG. The IFNG-AS1 SNV rs4913269 is associated with susceptibility to L. braziliensis-CL [21]. Considering the importance of IFNG-AS1 in regulating the expression of IFNG, this study investigated whether the variants of IFNG-AS1 rs4913269 C/G and rs7134599 A/G may be associated with L. guyanensis-CL in the state of Amazonas, Brazil.

Materials and methods

Biological materials

Results

The study population consisted of 1,714 unrelated individuals, including 855 patients with Lg-CL and 859 HCs. A total of 639 were male patients with Lg-CL (mean age ± standard error of the mean 34.29 ± 0.53 years) and 216 were female patients with Lg-CL (37.19 ± 1.05 years). In the HCs group, 591 were male (42 ± 0.72 years) and 268 were female (40 ± 1.04 years). Male HCs were significantly older than male patients with Lg-CL (p < 0.0001).

The IFNG-AS1 gene, located on chromosome 12q14, is adjacent to IFNG. IFNG-AS-1 is approximately 165 kb upstream of the IFNG coding region on the opposite strand to IFNG, spanning nucleotide 67,989,447–68,234,686 covering IFNG, IL26 and part of IL22, as shown in Fig 1. The variant rs4913269 is in the third intron at nucleotide 68,014,065 and rs7134599 is positioned at nucleotide 68,106,295 and 48,474 bp upstream of IFNG.

Discussion

Individuals from the same endemic areas are more likely to share similar socio-epidemiological and ecological characteristics. However, only a subset of these individuals develops Lg-CL, highlighting the role of host genetic factors in disease susceptibility. To advance the understanding of the molecular mechanisms underlying the immunopathogenesis of Lg-CL, we conducted a case-control genetic analysis of IFNG-AS1 variants.

Previous studies have indicated that IFNG-AS1 positively regulates IFNG expression in immune cells such as CD8+ and CD4 + T cells [14–16]. IFN-γ is a key immunoregulatory cytokine produced by T cells and innate lymphoid cells, playing a pivotal role in host-defense against invading pathogens. LncRNA, including IFNG-AS1, are sequences exceeding 200 nucleotides in length, transcribed from genes lacking open reading frames for protein translation. They are involved in transcriptional regulation by modulating RNA polymerase II activity, promoter activation [34], chromatin remodeling, telomere activity, subcellular structural organization [35], and post-transcriptional mRNA processing, including splicing, editing, transport, translation, and degradation [36].

In this study, we identified distinct roles for two IFNG-AS1 variants in modulating susceptibility to Lg-CL. Notably, individuals homozygous for the G allele at rs4913269 in the LncRNA IFNG-AS1 appear to be protected from developing Lg-CL, in contrast to findings in Lb-CL where the same G allele was associated with disease susceptibility [21]. Peripheral blood mononuclear cells from heterozygous (A/G) patients with Lb-CL, stimulated with soluble Leishmania promastigote antigens, showed a significantly higher percentage of IFN-γ and TNFα–producing T cells compared with G/G homozygotes, suggesting that G/G homozygotes are at higher risk of developing Lb-CL [21]. However, no significant differences of IFN-γ and TNFα–producing T cells was observed between the AA genotypes and GG homozygotes [21].

We observed that homozygous individuals for the rs4913269 G allele exhibited lower plasma levels of IL-10 and IL-12p70. IL-12 is essential for the expression of IFNG and IFN-γ plays a central role in host-defense against intracellular pathogen. In IL10-knockout mice with spontaneous colitis, elevated expression of IFNG-AS1 was noted [17]. The protective effect of rs4913269 is noteworthy, particularly considering the prior findings in Lb-CL where the same allele was linked to susceptibility [21]. The rs4913269 G allele may promote a controlled Th1 response, suppressing IL-10 and limiting IL-12p40 as part of a feedback effect of early parasite clearance. Indeed, these immunological profiles may suggest that bearers of the rs4913269 G/G genotype achieve parasite control without excessive inflammation.

IL-10 is an anti-inflammatory cytokine that can inactivate macrophages, inhibit the elimination and multiplication of intracellular pathogens, and impair Th-1 immune responses, including the production of IFN-γ and TNF-α and avoid tissue damage. IL-12-p70, known to promote Th1 differentiation, is produced primarily by dendritic cells and macrophages in response to infection. In rs4913269 G/G carriers, a reduced IL-10 level may preserve macrophage activation and enhance parasite elimination. Meanwhile, lower IL-12p70 may indicate that the immune system achieves sufficient IFN-γ levels early in infection, limiting the need for continued IL-12 driven stimulation to avoid exacerbating proinflammatory reaction, while keeping in check the parasites. This is consistent with the broader understanding that genes involved in immune responses must be precisely coordinated and tightly regulated to ensure rapid expression of multiple genes to control microbial pathogens while mitigating host tissue damage [37]. The IFNG-AS1 gene is selectively expressed in Th1 effector cells, and we hypothesized that reduced IL-12 and IL-10 levels may facilitate an adequate IFN-γ response, ensuring sufficient macrophage activation to control intracellular pathogens, thereby preventing tissue damage following parasites clearance or control during early infection.

Interestingly, our findings align observations from biopsy lesion specimens of Lb-CL patients that exhibited high expression of pro-inflammatory chemokines and cytokines, primarily associated with the activation and migration of monocytes, polymorphonuclear cells, and Th1 CD4 + T cells [38], as well as elevated cytolytic activity mediated by CD8 + T cells [39]. Additionally, increased frequencies of NK cells have been observed in the peripheral blood cells of Lb-CL patients, with these cells expressing higher IFN-γ, TNF-α, granzyme B, and perforin than CD8⁺ T cells. Granzyme B expression positively correlates with lesion-size, suggesting NK cells contribute to CL immunopathology [40]. In Lb-CL, a positive correlation exists between lesion size and the number of CD4 + T cells expressing IFN-γ and TNF-α [41]. In Plasmodium falciparum, children whose cells produced higher IFN-γ following stimulation with Plasmodium falciparum antigen in vitro were more likely to experience the clinical manifestations of malaria infection [42]. IFNG-AS1 expression enhances IFN-γ expression in CD8 + T cells, in response to Salmonella infection [16]. Elevated IFNG-AS1 expression has been shown to augment Th1 responses in Hashimoto’s Thyroiditis (HT) patients and may contribute to HT pathogenesis [43]. Conversely, the increased IFNG-AS1 expression has been associated with decreased Th1 cells and increased Treg cells population in experimental autoimmune Myasthenia gravis models [44].

The rs7134599 in IFNGAS-1 has been suggested as a susceptibility locus for the IBD [20]. In a Tunisian population, the rs713599 A allele was associated with protection against asthma, a condition influenced by IL-4 expression [33]. In our study, we found that the A allele is associated with susceptibility to Lg-CL and correlates with higher circulating plasma levels of IL-10, IL-4, IL-1β and TNF-α. IL-10 and IL-4 are well-established inducers of Th2 response which has been linked to disease progression in Balb/c mice, contrasting with the protective Th1 response observed in C57Bl/6 mice [3]. Indeed, Lg-CL patients with predominant Th2 cytokines (IL-4 and IL-13) tend to develop lesions earlier than those with a Th1- dominant cytokine profile [45]. In Lb-CL patients, higher IFN-γ and IL-10 expressions have been observed in late-stage lesions compared with early-stage lesions [46]. Excess IL-1β has been associated with increased disease severity in patients with CL caused by L. peruviana [47]. IL-1β can suppress proinflammatory Th1 response by downregulating IL-12 receptor expression and interfering with IL-6-induced STAT1 phosphorylation [48].

It is important to consider that the observed association may also reflect differences in parasite burden and disease kinetics. It is plausible that rs4913269 G/G individuals mount a rapid and effective immune response, resulting in reduced parasite loads and shorter lesion duration. Conversely, rs713599 A carriers may experience delayed parasite clearance, leading to prolonged or more severe clinical manifestations. Future studies assessing parasite load and lesion healing time in relation to genotype will be valuable to validate these hypotheses.

Moreover, comorbid conditions such as malaria, malnutrition or HIV can profoundly influence immune homeostasis and cytokine profiles, influencing disease progression and treatment response. These conditions may interact synergistically with host genetic factors, including IFNG-AS1 variants, to increase susceptibility. For instance, HIV can induce immunosuppression and impair a Th1 response, while malaria might skew cytokine production through chronic immune action. The introduction of these variables in future multivariate models will enhance the accuracy of disease risk prediction, uncover gene-environment interactions and offer better clinical assessments in endemic populations. Of note, individuals with HIV were excluded in this study.

From a translational perspective, genotyping of IFNG-AS1 variants could enable risk stratification, identifying individuals more likely to develop disease upon exposure. For example, individuals with the rs7134599 A/A genotype may benefit from therapies aimed at modulating IL-10 or IL-4 in combination with conventional treatments.

In this study, we selected two SNVs (rs4913269 and rs7134599) based on their reported associations: rs4913269 with Lb-CL in Brazil [19], and rs7134599 with IBD [17,18]. The rs4913269 variant has been identified as a strong expression quantitative trait locus (eQTL) for IFNG-AS1 and a cis-acting eQTL for IFNG [19], while rs7134599 has been characterized as a strong eQTL in IBD [17,18]. The IFNG-AS1 gene region, located on chromosome 12q14, encompasses the genes IFNG, IL26 and IL22 as shown in Fig 1. Previously, we examined 9 SNVs spanning the IFNG gene region and demonstrated a similar LD structure between the patients with Lg-CL and HCs [11]. To mitigate the risk of spurious associations, we incorporated the two IFNG-AS1 SNVs along with eight IFNG SNVs to evaluate the LD structure consistency. The LD structure remains consistent between the patients with Lg-CL and HCs, suggesting a shared genetic background between the two groups, in line with STREGA guidelines (S2 Fig). Collectively, these findings indicate that allele frequency differences between the patients with Lg-CL and HCs are unlikely to be attributed to population stratification.

Our study population consists of approximately 50% to 60% of Native American, 40% to 50% European and around 10% African ancestry [27]. The minor allele frequency (MAF) for rs4913269 varies from 20% to 50% across different ethnic groups (https://snpinfo.niehs.nih.gov/snpinfo/snptag.html ). Notably, the frequency in Bahia (29%) aligns with that observed in the Admixed American population, whereas in Manaus (37%), it approximates the frequency observed in the Japanese population. Regarding rs7134599, the MAF ranges from 10% to 37%, depending on population ethnicity, with our study population exhibiting a MAF of 22%, like that observed in admixed American populations. In light of differences in MAF across ethnic groups, spurious associations may arise in case-control studies. In our study, this risk is minimized as the study population originates from the same endemic areas and the LD structure in this chromosomal region is similar between the patients and HCs group.

Nevertheless, the associations of rs4913269 G and rs7134599 A allele with CL are insufficient to fully explain protection against and susceptibility to Lg-CL, respectively. CL is a complex and multifactorial disease, influenced by multiple genetic and environmental factors. The immune response to infection is determined by the individual adaptive T-helper cell responses and disease progression also depends on the host-pathogen interaction which includes the host’s genetic background, parasite virulence, the Leishmania-vector phlebotomine characteristics and environmental factors.

In summary, our findings demonstrate that rs4913269 and rs7134599 are independently associated with decreased and increased risk of Lg-CL, respectively. These insights contribute to our understanding of the molecular basis of the disease and highlight its immunopathogenic mechanism of the disease, paving the way for the development of immunotherapeutic strategies.

Supporting information

Acknowledgments

The authors thank all the participants in the study.

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