American tegumentary leishmaniasis is a vector-borne parasitic disease caused by Leishmania protozoans. Innate immune cells undergo long-term functional reprogramming in response to infection or Bacillus Calmette-Guérin (BCG) vaccination via a process called trained immunity, conferring non-specific protection from secondary infections. Here, we demonstrate that monocytes trained with the fungal cell wall component β-glucan confer enhanced protection against infections caused by Leishmania braziliensis through the enhanced production of proinflammatory cytokines. Mechanistically, this augmented immunological response is dependent on increased expression of interleukin 32 (IL-32). Studies performed using a humanized IL-32 transgenic mouse highlight the clinical implications of these findings in vivo. This study represents a definitive characterization of the role of IL-32γ in the trained phenotype induced by β-glucan or BCG, the results of which improve our understanding of the molecular mechanisms governing trained immunity and Leishmania infection control.

Interleukin 32 (IL-32) is a proinflammatory cytokine, expressed as 9 distinct isoforms. The most active isoform is the predominantly intracellular-functioning IL-32γ. Involvement of IL-32 in infectious diseases is increasingly being appreciated. Production of IL-32 promotes pathways that serve to control bacterial infection, especially those caused by mycobacteria. A similar role for this cytokine is observed in the cellular response to viral infections. In addition to its protective effects against microorganisms, IL-32 is involved in immunopathogenesis of some infectious diseases. In parasitic diseases, it has been demonstrated that this cytokine is induced by Leishmania infection. In this review, we summarize the present data on the role of IL-32 in infectious diseases, highlighting this cytokine as new target for control of infections.

Interleukin-32 (IL-32) is expressed in lesions of patients with American Tegumentary Leishmaniasis (ATL), but its precise role in the disease remains unknown. In the present study, silencing and overexpression of IL-32 was performed in THP-1-derived macrophages infected with Leishmania (Viannia) braziliensis or L. (Leishmania) amazonensis to investigate the role of IL-32 in infection. We report that Leishmania species induces IL-32γ, and show that intracellular IL-32γ protein production is dependent on endogenous TNFα. Silencing or overexpression of IL-32 demonstrated that this cytokine is closely related to TNFα and IL-8. Remarkably, the infection index was augmented in the absence of IL-32 and decreased in cells overexpressing this cytokine. Mechanistically, these effects can be explained by nitric oxide cathelicidin and β-defensin 2 production regulated by IL-32. Thus, endogenous IL-32 is a crucial cytokine involved in the host defense against Leishmania parasites. Leishmania (V.) braziliensis and L. (L.) amazonensis are protozoa that infect macrophages and cause cutaneous and mucosal leishmaniasis. Here we showed that both Leishmania species induce the production of IL-32γ in human macrophages. This intracellular and pro-inflammatory cytokine mediates the production of cytokines, especially TNFα and IL-8, in Leishmania-infected macrophages. Differential effects of IL-32γ on TNFα, IL-10 and IL-1Ra production after infection with distinct Leishmania species were detected, consistent with the concept that IL-32γ can differently influence the outcome of inflammatory process in leishmaniasis lesions. Moreover, IL-32γ upregulates microbicidal molecules, antimicrobial peptides, as well as NO, which are known as important factors in parasite control. These results underscore IL-32γ as a crucial cytokine to host defense against leishmaniasis.

Background: Even during long-term combination antiretroviral therapy (cART), people living with HIV (PLHIV) have a dysregulated immune system, characterized by persistent immune activation, accelerated immune ageing and increased risk of non-AIDS comorbidities. A multi-omics approach is applied to a large cohort of PLHIV to understand pathways underlying these dysregulations in order to identify new biomarkers and novel genetically validated therapeutic drugs targets.Methods: The 2000HIV study is a prospective longitudinal cohort study of PLHIV on cART. In addition, untreated HIV spontaneous controllers were recruited. In-depth multi-omics characterization will be performed, including genomics, epigenomics, transcriptomics, proteomics, metabolomics and metagenomics, functional immunological assays and extensive immunophenotyping. Furthermore, the latent viral reservoir will be assessed through cell associated HIV-1 RNA and DNA, and full-length individual proviral sequencing on a subset. Clinical measurements include an ECG, carotid intima-media thickness and plaque measurement, hepatic steatosis and fibrosis measurement as well as psychological symptoms and recreational drug questionnaires. Additionally, considering the developing pandemic, COVID-19 history and vaccination was recorded. Participants return for a two-year follow-up visit. The 2000HIV study consists of a discovery and validation cohort collected at separate sites to immediately validate any finding in an independent cohort.Results: Overall, 1895 PLHIV from four sites were included for analysis, 1559 in the discovery and 336 in the validation cohort. The study population was representative of a Western European HIV population, including 288 (15.2%) cis-women, 463 (24.4%) non-whites, and 1360 (71.8%) MSM (Men who have Sex with Men). Extreme phenotypes included 114 spontaneous controllers, 81 rapid progressors and 162 immunological non-responders. According to the Framingham score 321 (16.9%) had a cardiovascular risk of >20% in the next 10 years. COVID-19 infection was documented in 234 (12.3%) participants and 474 (25.0%) individuals had received a COVID-19 vaccine.Conclusion: The 2000HIV study established a cohort of 1895 PLHIV that employs multi-omics to discover new biological pathways and biomarkers to unravel non-AIDS comorbidities, extreme phenotypes and the latent viral reservoir that impact the health of PLHIV. The ultimate goal is to contribute to a more personalized approach to the best standard of care and a potential cure for PLHIV.

Studies in IL‐32 transgenic mice and in vitro suggest that IL‐32 may have protective effects against Mycobacterium tuberculosis, but so far there are barely any studies in humans. We studied the role of IL‐32 and its splice variants in tuberculosis (TB) in vivo and in vitro. Blood transcriptional analysis showed lower total IL‐32 mRNA levels in pulmonary TB patients compared to patients with latent TB infection and healthy controls. Also, among Indonesian household contacts who were heavily exposed to an infectious TB patient, IL‐32 mRNA levels were higher among those who remained uninfected compared to those who became infected with M. tuberculosis. In peripheral blood mononuclear cells from healthy donors, we found that IL‐32γ, the most potent isoform, was down‐regulated upon M. tuberculosis stimulation. This decrease in IL‐32γ was mirrored by an increase of another splice variant, IL‐32β. Also, a higher IL‐32γ/IL‐32β ratio correlated with IFN‐γ production, whereas a lower ratio correlated with production of IL‐1Ra, IL‐6, and IL‐17. These data suggest that IL‐32 contributes to protection against M. tuberculosis infection, and that this effect may depend on the relative abundance of different IL‐32 isoforms.