Immunotherapeutic Potential of Interleukin-32 and Trained Immunity for Leishmaniasis Treatment

Genetic variants in the IL-32 gene are linked to the clinical outcome of American tegumentary leishmaniasis (ATL) varying from higher susceptibility to protection. The post-transcriptional abilities of IL-32γ to stimulate the production of microbicidal substances decrease the infection index and parasite dissemination. β-Glucan-induced trained immunity improves protection against Leishmania braziliensis in an IL-32- and IL-1-dependent manner. Expression of genes associated with metabolism and inflammatory immune responses, such as RELA, BRD7, HNF1β, or TNFRSF8, is modulated by BCG vaccination. The upregulation of these genes is associated with certain IL-32 genotypes, stressing the pivotal role of IL-32 in regulating hematopoietic stem cell activity and its importance for trained immunity-induced protection against L. braziliensis. Neglected tropical diseases annually account for several million infections worldwide. Efficacious treatment for these poorly understood infectious diseases is often limited to ineffective, expensive, and toxic therapies such as the SbV used for leishmaniasis patients. Here, we review the latest discoveries and literature on the molecular pathways, cell types, and immune mediators involved in the immune response to infection with New World Leishmania spp. in humans and their interaction with the adaptive and innate immune system. Novel developments in the field of trained innate immunity and the recently described role of IL-32 are emphasized as potential immunotherapeutic treatments for the management of leishmaniasis. Neglected tropical diseases annually account for several million infections worldwide. Efficacious treatment for these poorly understood infectious diseases is often limited to ineffective, expensive, and toxic therapies such as the SbV used for leishmaniasis patients. Here, we review the latest discoveries and literature on the molecular pathways, cell types, and immune mediators involved in the immune response to infection with New World Leishmania spp. in humans and their interaction with the adaptive and innate immune system. Novel developments in the field of trained innate immunity and the recently described role of IL-32 are emphasized as potential immunotherapeutic treatments for the management of leishmaniasis. a collective term for leishmaniasis manifestations occurring in most areas of the New World, in particular Latin America. ATL is caused by protozoans of the genus Leishmania and is transmitted by sandflies of the genus Lutzomyia. It can be self-healing or become latent, chronic, or metastatic. a vaccine composed of live-attenuated Mycobacterium bovis used for approximately 80 years against tuberculosis caused by M. tuberculosis. a polysaccharide, present in yeast, fungi, bacteria, algae, barley, and oat, that can be derived from the cell walls of Candida albicans. a severe and chronic form of leishmaniasis caused by L. amazonensis, L. pifanoi, and L. mexicana in the New World, and by L. aethiopica in the Old World. DCL develops after an initial infection due to parasite dissemination and is characterized by multiple nodules and uncontrollable parasite growth. a form of leishmaniasis, commonly described as a form of ATL, caused by parasites of the Leishmania mexicana complex and of the subgenus Viannia in the New World. Infections with L. major and L. tropica in the Old World were reported in immunocompromised individuals. DL develops after an initial infection due to parasite dissemination and is characterized by multiple ulcerating, potentially necrotizing, cutaneous skin lesions. Mucosal involvement is frequent. a group of cytokines divided into 38 classes, most of which orchestrate the regulation of the immune system in a complex network of cells and proteins. a form of leishmaniasis caused by L. tropica and characterized by newly occurring nodules in scar tissues months after the initial infection. an abundant cell-surface glycolipid of Leishmania species. the initial and most common form of leishmaniasis characterized by localized, cutaneous lesions. It can be self-healing and is caused by members of the Leishmania tropica complex (Leishmania (Leishmania) tropica, L. (L.) major, L. (L.) minor, and L. (L.) aethiopica), the Leishmania mexicana complex (L. (L.) mexicana, L. (L.) amazonensis, L. (L.) pifanoi, and L. (L.) venezuelensis), and the subgenera Viannia (L. (Viannia) peruviana, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) braziliensis) and by Mundinia (L. (Mundinia) martiniquensis, and L. (M.) orientalis). a severe and chronic form of ATL characterized by skin and mucosal lesions affecting mucosal and surrounding tissues. ML is mainly caused by parasites of the subgenus Viannia. a form of leishmaniasis ranging from asymptomatic and paucisymptomatic to severe and life-threatening manifestations affecting visceral organs and the bone marrow. VL accounts for most Leishmania-related deaths per year and is caused by members of the Leishmania donovani complex (L. (L.) donovani and L. (L.) chagasi, synonym L. (L.) infantum), L. tropica, L. major, and also by L. (M.) martiniquensis and L. (M.) orientalis.