Effects of miR-302 on the Immune Response of Macrophages During Infection with Leishmania infantum

• Grant number: 25/12707-9
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2025
• End date: October 31, 2026
• Field of knowledge: Biological Sciences - Parasitology
• Principal Investigator: Sandra Marcia Muxel
• Grantee: Sandra Marcia Muxel
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated research grant: 24/08802-3 - Integrative study of Long noncoding RNAs and microRNAs in Leishmania infection, AP.R
• Associated scholarship(s): 25/22576-9 - Effects of miR-302 on Macrophage Immune Response During Leishmania infantum Infection, BP.IC

Abstract

In this project, we aim to investigate the function of miR-302 in regulating the response of macrophages infected with L. infantum. The network of microRNA-mediated signals alters macrophage activation and cytokine production, enhancing resistance to infection. MicroRNAs are small non-coding RNAs that regulate gene expression by pairing their seed (6-9 nt) with the complementary 3'UTR sequence of the target mRNA, promoting degradation or inhibition of mRNA translation. miR-302 plays a role in regulating Tnf and Nos2 mRNA, reducing NO production and increasing infection with L. amazonensis. Transforming growth factor beta (TGF-¿), with a dual role in immunosuppression and pathogenesis, acts as a key regulator of anti-leishmania immune responses. During Leishmania infection, TGF-¿ induces immunological deviation, increasing the differentiation of regulatory T cells (T-reg) and inhibiting macrophage activation, thereby suppressing critical anti-parasitic responses. TGF-¿, along with IL-6, induces Th17 differentiation, increasing tissue inflammation in lesions. During visceral leishmaniasis, high expression of TGF-¿ and positively regulated TGF-¿RI/TGF-¿RII is observed in macrophages. Often, the expression of TGF-¿ and TGF-¿R increases in severe cases. The miR-302/367 cluster contains a coding sequence located in intron 8 of the LARP7 gene and encodes 5 miRNAs, including miR302a, miR302b, miR302c, miR302d, and miR367. According to the literature, the overexpression of miR-302/367 in human breast cancer cells reduces the expression of TGFBR2 and RHOC. Additionally, the expressions of TGFBR2, BUB1, RHOC, AKT1, MAPK1, MAPK14, and SMAD3 were significantly negatively regulated after the overexpression of the miR-302/367 cluster in cancer cells. Therefore, it is important to understand the correlation between parasite survival and the expression of miRNAs and their target genes in macrophages infected with Leishmania, as well as how the modulation of these molecules impacts the activation of the pro-inflammatory response and the subversion of the host's response to the parasite. miR-302 may help elucidate how microRNAs regulate the immune response in different contexts. This knowledge can be applied to other infections, allowing us to understand how pathogens manipulate the host's response. (AU)