Emerging evidence has suggested a potential role for long non-coding RNAs (lncRNAs) in transcriptome dysregulation during Mycobacterium tuberculosis (Mtb) infection. Understanding the regulatory functions of lncRNAs can provide further insight into the interaction between Mtb and the host. In this study, we sought to explore the lncRNA signature in the Mtb-infected THP1 macrophages (H37Rv, H37Ra, and BCG strains) using the publicly available RNA sequencing dataset of GSE162729. Our analysis identified 6202 putative lncRNAs, with the majority being novel lncRNAs, indicating their significant involvement in the Mtb-infected macrophages. We also identified several differentially expressed lncRNA genes specifically induced in each infected group. Reactome enrichment pathway analysis on cis target genes of lncRNAs revealed that inflammatory immune responses were the predominant features of lncRNAs induced during the H37Rv infection compared to H3Ra and BCG infection. Scavenging by class A receptors and inflammasomes were also highlighted as the common enriched terms among Mtb- and BCG-infected groups. Moreover, we highlighted several potential lncRNAs as hub genes in the predicted regulatory network between the differentially expressed lncRNAs and miRNAs in Mtb-infected THP-1 cells. These findings suggested a possible diverse regulatory role for lncRNAs in the macrophage response to different Mycobacterium strain infections. Further functional study of the lncRNA genes in Mtb infection, while considering the genetic background of the Mtb strain, will be a promising focus for future research.

Department of Immunotherapy and Leishmania Vaccine Research Pasteur Institute of Iran Tehran Iran

Nuclear Agriculture Research School Nuclear Science and Technology Research Institute Karaj Iran

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Arish M, Naz F (2022) Macrophage plasticity as a therapeutic target in tuberculosis. Eur J Immunol 52:696–704. https://doi.org/10.1002/eji.202149624 PubMed DOI

Chakraborty P, Kulkarni S, Rajan R, Sainis K (2013) Drug resistant clinical isolates of Mycobacterium tuberculosis from different genotypes exhibit differential host responses in THP-1 cells. PLoS ONE 8:e62966 PubMed DOI PMC

Chen Y-C, Lin M-C, Lee C-P, Zheng Y-X, Fang W-F (2019) Decreased miR-150–5p and miR-23a-3p expressions in patients with active pulmonary tuberculosis (TB) disease. Eur Respir J 54:PA4594. https://doi.org/10.1183/13993003.congress-2019.PA4594 DOI

Hmama Z, Peña-Díaz S, Joseph S, Av-Gay Y (2015) Immunoevasion and immunosuppression of the macrophage by Mycobacterium tuberculosis. Immunol Rev 264:220–232 PubMed DOI

Hu X, Liao S, Bai H, Gupta S, Zhou Y, Zhou J et al (2020) Long noncoding RNA and predictive model to improve diagnosis of clinically diagnosed pulmonary tuberculosis. J Clin Microbiol 58:e01973–e02019 PubMed DOI PMC

Huleihel L, Dziki JL, Bartolacci JG, Rausch T, Scarritt ME, Cramer MC et al (2017) Macrophage phenotype in response to ECM bioscaffolds. Semin Immunol 29:2–13. https://doi.org/10.1016/j.smim.2017.04.004 PubMed DOI PMC

Kim YS, Kim JK, Hanh BTB, Kim SY, Kim HJ, Kim YJ et al (2020) The peroxisome proliferator-activated receptor α- agonist gemfibrozil promotes defense against Mycobacterium abscessus infections. Cells 9:648. https://doi.org/10.3390/cells9030648 PubMed DOI PMC

Kohl M, Wiese S, Warscheid B (2011) Cytoscape: software for visualization and analysis of biological networks. Methods Mol Biol 696:291–303. https://doi.org/10.1007/978-1-60761-987-1_18 PubMed DOI

Kopp F, Mendell JT (2018) Functional classification and experimental dissection of long noncoding RNAs. Cell 172:393–407. https://doi.org/10.1016/j.cell.2018.01.011 PubMed DOI PMC

Kumar M, Sahu Sanjaya K, Kumar R, Subuddhi A, Maji Ranjan K, Jana K et al (2015) MicroRNA let-7 modulates the immune response to Mycobacterium tuberculosis infection via control of A20, an inhibitor of the NF-κB pathway. Cell Host Microbe 17:345–356. https://doi.org/10.1016/j.chom.2015.01.007 PubMed DOI

Kundu M, Basu J (2021) The role of microRNAs and long non-coding RNAs in the regulation of the immune response to Mycobacterium tuberculosis infection. Front Immunol 12:687962 PubMed DOI PMC

Liu M, Li W, Song F, Zhang L, Sun X (2021) Silencing of lncRNA MIAT alleviates LPS-induced pneumonia via regulating miR-147a/NKAP/NF-κB axis. Aging (Albany NY) 13:2506 DOI

Pu W, Zhao C, Wazir J, Su Z, Niu M, Song S et al (2021) Comparative transcriptomic analysis of THP-1-derived macrophages infected with Mycobacterium tuberculosis H37Rv, H37Ra and BCG. J Cell Mol Med 25:10504–10520 PubMed DOI PMC

Ravan P, Nejad Sattari T, Siadat SD, Vaziri F (2019) Evaluation of the expression of cytokines and chemokines in macrophages in response to rifampin-monoresistant Mycobacterium tuberculosis and H37Rv strain. Cytokine 115:127–134. https://doi.org/10.1016/j.cyto.2018.12.004 PubMed DOI

Sinigaglia A, Peta E, Riccetti S, Venkateswaran S, Manganelli R, Barzon L (2020) Tuberculosis-associated microRNAs: from pathogenesis to disease biomarkers. Cells 9:2160. https://doi.org/10.3390/cells9102160 PubMed DOI PMC

Statello L, Guo C-J, Chen L-L, Huarte M (2021) Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 22:96–118 PubMed DOI

Subuddhi A, Kumar M, Majumder D, Sarkar A, Ghosh Z, Vasudevan M et al (2020) Unraveling the role of H3K4 trimethylation and lncRNA HOTAIR in SATB1 and DUSP4-dependent survival of virulent Mycobacterium tuberculosis in macrophages. Tuberculosis 120:101897. https://doi.org/10.1016/j.tube.2019.101897 PubMed DOI

Taniue K, Akimitsu N (2021) The functions and unique features of LncRNAs in cancer development and tumorigenesis. Int J Mol Sci 22:632 PubMed DOI PMC

Team R C (2020) RA language and environment for statistical computing, R Foundation for Statistical. Computing

Walther K, Schulte LN (2021) The role of lncRNAs in innate immunity and inflammation. RNA Biol 18:587–603. https://doi.org/10.1080/15476286.2020.1845505 PubMed DOI

Wang Z, Xu H, Wei Z, Jia Y, Wu Y, Qi X et al (2020) The role of non-coding RNA on macrophage modification in tuberculosis infection. Microb Pathog 149:104592 PubMed DOI

Wei L, Liu K, Jia Q, Zhang H, Bie Q, Zhang B (2021) The roles of host noncoding RNAs in Mycobacterium tuberculosis infection. Front Immunol 12:664787

WHO (2022) Global tuberculosis report 2022. World Health Organization, Geneva

Wu M, Aung H, Hirsch CS, Toossi Z (2012) Inhibition of Mycobacterium tuberculosis-induced signalling by transforming growth factor-β in human mononuclear phagocytes. Scand J Immunol 75:301–304. https://doi.org/10.1111/j.1365-3083.2011.02668.x PubMed DOI PMC

Yang X, Yang J, Wang J, Wen Q, Wang H, He J et al (2016) Microarray analysis of long noncoding RNA and mRNA expression profiles in human macrophages infected with Mycobacterium tuberculosis. Sci Rep 6:38963 PubMed DOI PMC

Zheng L, Leung E, Lee N, Lui G, To KF, Chan RC et al (2015) Differential microRNA expression in human macrophages with Mycobacterium tuberculosis infection of Beijing/W and non-Beijing/W strain types. PLoS ONE 10:e0126018. https://doi.org/10.1371/journal.pone.0126018 PubMed DOI PMC

Zihad S, Sifat N, Islam MA, Monjur-Al-Hossain ASM, Sikdar K, Sarker MMR et al (2023) Role of pattern recognition receptors in sensing Mycobacterium tuberculosis. Heliyon 9:e20636. https://doi.org/10.1016/j.heliyon.2023.e20636 PubMed DOI PMC