Nabeeha Qazi

Background: Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis infection (TB), remains a significant global health burden, with an estimated 10 million new cases diagnosed annually worldwide.^1,2 Mtb evades the innate and adaptive immune response and persists in alveolar macrophages as latent TB (LTB) within a granuloma.² Only 5-10% of infected individuals progress to transmissible active TB (ATB).^1,2 Patients present with a spectrum of symptoms including cough, fever, and fatigue.¹ TB is diagnosed via the Tuberculin skin test (TST) and whole blood interferon-gamma (IGRAs). TST can show false positive results in people vaccinated with BCG or false negatives in immunocompromised individuals. IGRAs are unaffected by BCG. However, neither test can differentiate between ATB and LTB.¹ First-line antibiotics include rifampin, isoniazid, pyrazinamide, and ethambutol.^1,3 The dangers of TB are compounded by multi-drug resistant (MDR) TB, which resists antibiotic treatment.^1,3 MicroRNAs (miRNAs) are small non-coding RNAs that modulate host defense mechanisms against pathogens.^4,5,6 In TB, some miRNAs restrict host-mediated antibacterial signaling that allows Mtb to persist and resist treatment, while others induce autophagy to limit the infection.^4,6 Host-directed therapy (HDT) with miRNAs has the potential to combat TB without resulting in resistance.^4,5

Objective: In this narrative review, we explored the mechanisms by which miRNAs modulate the host immune response to Mtb infection, focusing on metabolism, autophagy, and apoptosis.

Search Methods: An online search in the PubMed database was conducted from 2018-2024 using the following keywords: “tuberculosis,” “microRNA in tuberculosis,” and “host-directed therapy.”

Results: Studies have demonstrated that changes in miRNA expression levels correlate with TB treatment response, predicting patient prognosis.⁷A five-miRNA signature (miRs -29a, -99b, -21, -146a, and -652) was found to be a potential biomarker for active TB and could predict treatment success.⁷ miR-21 has been shown to limit host glycolysis in murine studies. By dampening host glycolytic activity via targeting of enzyme PFK-M, miR-21 creates a metabolic environment conducive to Mtb persistence.⁶ Autophagy, a cellular recycling process involved in the degradation of intracellular pathogens, is regulated by miRNAs during TB infection. miR-27a was found to be upregulated in PBMCs of patients with ATB, promoting Mtb survival. It was determined that miR-27a is a negative regulator of Cacna2d3, which leads to increased Mtb survival in macrophages by decreasing autophagy. Cacna2d3 knockout mice infected with Mtb showed improved outcomes when compared with wildtype mice. In addition, only infection of wildtype macrophages had decreased CFU when treated with a miR-27a inhibitor, but not Cacna2d3 knockout macrophages suggesting miR-27a modulation as a potential host-directed therapy.⁸ miRNAs, notably miR-27b, have been shown to accelerate macrophage apoptosis.⁹ Mtb infected macrophages upregulate miR-27b, which targets Bag2 transcripts causing an increase in apoptosis. Bag2 limits apoptosis by interacting with p53; Bag2 knockout macrophages infected with Mtb showed enhanced apoptosis. ⁹ Blocking p53 prevented apoptosis in Mtb-infected macrophages treated with miR-27b mimics, suggesting the miR-27b/Bag2/p53 pathway as a potential host-directed therapy target.⁹

Conclusions: MDR-TB poses a formidable challenge to global TB control efforts, necessitating innovative therapeutic approaches. HDT has emerged as a promising strategy to augment conventional antibiotic treatments. miRNAs play a pivotal role in modulating host immune responses and can be targeted for HDT in MDR-TB.^6,7,9 By modulating miRNA expression profiles, researchers aim to bolster host defense mechanisms, overcome drug resistance, and improve diagnostic accuracy.

Works Cited:

1.  Rahlwes KC, Dias BRS, Campos PC, Alvarez-Arguedas S, Shiloh MU. Pathogenicity and virulence of Mycobacterium tuberculosis. Virulence. 2023 Dec;14(1):2150449. doi: 10.1080/21505594.2022.2150449
2. Chandra P, Grigsby SJ, Philips JA. Immune evasion and provocation by Mycobacterium tuberculosis. Nat Rev Microbiol. 2022 Dec;20(12):750-766. doi: 10.1038/s41579-022-00763-4. Epub 2022 Jul 25.
3. Liebenberg D, Gordhan BG, Kana BD. Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management. Front Cell Infect Microbiol. 2022 Sep 23;12:943545. doi: 10.3389/fcimb.2022.943545.
4. Kundu M, Basu J. The Role of microRNAs and Long Non-Coding RNAs in the Regulation of the Immune Response to Mycobacterium tuberculosis Front Immunol. 2021 Jun 24;12:687962. doi: 10.3389/fimmu.2021.687962.
5. Sinigaglia A, Peta E, Riccetti S, Venkateswaran S, Manganelli R, Barzon L. Tuberculosis-Associated MicroRNAs: From Pathogenesis to Disease Biomarkers. 2020 Sep 24;9(10):2160. doi: 10.3390/cells9102160.
6. Hackett EE, Charles-Messance H, O’Leary SM, et al. Mycobacterium tuberculosis limits host glycolysis and il-1β by restriction of PFK-M via microrna-21. Cell Reports. 2020;30(1). doi:10.1016/j.celrep.2019.12.015
7. Barry SE, et al. Identification of a plasma microRNA profile in untreated pulmonary tuberculosis patients that is modulated by anti-bacterial therapy. Journal of Infection. 2018
8. Liu F, Chen J, et al. MicroRNA-27a controls the intracellular survival of Mycobacterium tuberculosis by regulating calcium-associated autophagy. Nature Communications. 2018;9:4295: doi: 10.1038/s41467-018-06836-4
9. Liang S, et al. MicroRNA-27b modulates inflammatory response and apoptosis during Mycobacterium tuberculosis J Immunol. 2018;200 (10): 3506–3518. https://doi.org/10.4049/jimmunol.1701448