LncRNA Malat1 in Cytokine Regulation and Macrophage Polarization in Canine Visceral Leishmaniasis

• Grant number: 25/19625-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: November 01, 2025
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Valéria Marçal Felix de Lima
• Grantee: Lucas Takeshi Siqueira Ito
• Host Institution: Faculdade de Medicina Veterinária (FMVA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil
• Associated research grant: 25/08317-0 - LncRNAs and mRNA in splenic macrophages of dogs with visceral leishmaniasis and immune regulation by Malat-1, AP.R

Abstract

Canine visceral leishmaniasis (CVL) is caused by the protozoan Leishmania (L.) infantum and is a serious zoonosis in Brazil. It represents a major public health problem, since dogs are potent transmitters of the parasite to humans and usually precede human cases. Therefore, the dog is an important target in control measures. Protection against the disease is associated with the Th1 cellular immune response, which stimulates the production of cytokines such as interleukin (IL)-12, interferon-gamma (IFN-¿), and tumor necrosis factor-alpha (TNF-¿), activating macrophages to eliminate the parasite. Conversely, the progression of CVL is related to a Th2-type humoral response, characterized by antibodies and anti-inflammatory cytokines such as IL-10 and transforming growth factor beta (TGF-¿), which suppress effector immunity and favor parasite multiplication. Since Leishmania replicates and lives obligatorily inside macrophages, it manipulates their metabolism by promoting the expression of arginase-1, essential for its growth, instead of inducible nitric oxide synthase (iNOS), which generates nitric oxide (NO), lethal to the parasite. In addition, the expression of the inhibitory molecule PD-1 on lymphocytes contributes to immune dysfunction in infected dogs. Recent studies have highlighted the role of epigenetic mechanisms in regulating immunity in CVL. Changes in the global expression of messenger RNAs (mRNAs) may shed light on the immune response against a wide range of pathogens. Transcriptomic studies have been conducted in dogs, mice, and humans infected with different Leishmania species. Long non-coding RNAs (lncRNAs) regulate physiological and immunological processes, acting either in the nucleus at the transcriptional level or in the cytoplasm at the post-transcriptional level. Although still poorly studied in leishmaniasis, evidence indicates that infection can modulate lncRNA expression, as observed in blood and serum samples from human patients. However, no data are available regarding their role in the spleen, the main target organ in canine disease. Understanding the molecular mechanisms underlying the function of lncRNAs in the immune response may therefore contribute to the development of potential therapeutic targets for various treatments. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long intergenic non-coding RNA associated with cancer progression and metastasis. Recently, differential expression of MALAT1 has been reported in mononuclear cells from patients with visceral leishmaniasis and in experimental models, but its functional role in regulating immunity has not yet been characterized in CVL. MALAT1 can inhibit the inflammatory response through interaction with NF-¿B and reduce the production of cytokines such as TNF-¿ and IL-6. Furthermore, it negatively regulates type I IFN in viral infections and promotes IL-10 expression via activation of the transcription factor Maf in CD4+ T cells. It also favors macrophage polarization toward the M2 profile, associated with parasite persistence, and regulates molecules such as PD-L1 and B7-H4, which are linked to suppression of the cytotoxic response. To date, no study has evaluated the functional role of lncRNA MALAT1 in the immunological regulation of dogs with leishmaniasis. Therefore, we will assess the differential expression of lncRNA MALAT1 in splenic macrophages from dogs with leishmaniasis, as well as its regulatory role in splenic leukocytes and in target molecules already described. Knowledge of the factors associated with disease progression may provide relevant insights for the development of new treatment strategies in canine leishmaniasis. (AU)