Comparative transcriptomic analysis of long noncoding RNAs in Leishmania-infected human macrophages

Abstract

It is well established that infection with Leishmania alters the host cell’s transcriptome. Since mammalian cells have multiple mechanisms to control gene expression, different molecules, such as noncoding RNAs, can be involved in this process. MicroRNAs have been extensively studied upon Leishmania infection, but whether long noncoding RNAs (lncRNAs) are also altered in macrophages is still unexplored. We performed RNA-seq from THP-1-derived macrophages infected with Leishmania amazonensis (La), L. braziliensis (Lb), and L. infantum (Li), investigating a previously unappreciated fraction of macrophage transcriptome. We found that more than 24% of the total annotated transcripts and 30% of differentially expressed (DE) RNAs in Leishmania-infected macrophage correspond to lncRNAs. LncRNAs and protein coding RNAs with altered expression are similar among macrophages infected with the Leishmania species. Still, some species-specific alterations could occur due to distinct pathophysiology in which Li infection led to a more significant number of exclusively DE RNAs. The most represented classes among DE lncRNAs were intergenic and antisense lncRNAs. We also found enrichment for immune response-related pathways in the DE protein coding RNAs, as well as putative targets of the lncRNAs. We performed a coexpression analysis to explore potential cis regulation of coding and antisense noncoding transcripts. We identified that antisense lncRNAs are similarly regulated as its neighbor protein coding genes, such as the BAALC/BAALC-AS1, BAALC/BAALC-AS2, HIF1A/HIF1A-AS1, HIF1A/HIF1A-AS3 and IRF1/IRF1-AS1 pairs, which can occur as a species-specific modulation. These findings are a novelty in the field because, to date, no study has focused on analyzing lncRNAs in Leishmania-infected macrophage. Our results suggest that lncRNAs may account for a novel mechanism by which Leishmania can control macrophage function. Further research must validate putative lncRNA targets and provide additional prospects in lncRNA function during Leishmania infection.

Early Leishmania infectivity depends on miR-372/373/520d family-mediated reprogramming of polyamines metabolism in THP-1-derived macrophages

“…Recently, miR-372 and its mice homolog miR-294 were implicated in the deregulation of lipid metabolism when associated to the lncRNA NEAT1 51 . Whether lncRNA could mediate metabolic rewiring in our model is still an open question, since lncRNA expression during Leishmania infection was only recently reported 52 , 53 .…”

MAPPING CHANGES OF MIRNA-MRNA NETWORKS INLEISHMANIA-INFECTEDMACROPHAGES PREDICTS REGULATORY MIRNA-TF LOOPS AS NOVEL TARGETS OF PARASITE IMMUNE SUBVERSION

“…Here, we performed a dual RNAseq analysis to simultaneously profile changes in mRNA and miRNA abundances in primary, bone marrow-derived macrophages infected with lesion-isolated L. amazonensis amastigotes (Lemaire et al 2013, Martinez-Hernandez et al 2021, Rashidi et al 2021, Fernandes et al 2022. Computational analysis of these data sets allowed us to map putative miRNA-mRNA regulatory networks that are predicted to control the observed inhibition of the pro-inflammatory TLR / NF-κB signalling pathway and increased cholesterol biosynthesis, both of which are prerequisites for intracellular parasite survival , Gutierrez Sanchez et al 2023.…”

Papel de miRNAs na regulação da via de produção de poliaminas/NO em macrófagos derivados de THP-1 infectados com Leishmania amazonensis

“…A análise de precursores não mostrou modulação diferencial dos pri-miR-372/373 ou pre-miR-372/373 (Figura 13). Ainda, o lncRNA C19MC-HG, que abriga o miR-520d, não foi diferencialmente expresso no transcriptoma de THP-1 infectada com L. amazonensis (Fernandes et al 2023). A ausência de modulação dos pri-e pre-miRNAs quantificados pode ter ocorrido devido ao fato de que o processo de biogênese dos miRNAs é completado rapidamente (Reichholf et al 2019).…”