March of Mycobacterium: miRNAs intercept host cell CD40 signalling

Abstract

The disease tuberculosis is fatal if untreated. It is caused by the acid-fast bacilli Mycobacterium tuberculosis. Mycobacterium resides and replicates within the alveolar macrophages, causing inflammation and granuloma, wherein macrophage-T cell interactions enhance the inflammation-causing pulmonary caseous lesions. The first interactions between Mycobacterium and the receptors on macrophages decide the fate of Mycobacterium because of phagolysosomal impairments and the expression of several miRNAs, which may regulate CD40 expression on macrophages. While the altered phagolysosomal functions impede antigen presentation to the T cell-expressed antigen receptor, the interactions between the macrophage-expressed CD40 and the T cell-expressed CD40-ligand (CD40L or CD154) provide signals to T cells and Mycobacterium-infected macrophages. These two functions significantly influence the resolution or persistence of Mycobacterium infection. CD40 controls T-cell polarisation and host-protective immunity by eliciting interleukin-12p40, nitric oxide, reactive oxygen species and IFN-c production. Indeed, CD40deficient mice succumb to low-dose aerosol infection with Mycobacterium because of deficient interleukin (IL)-12 production leading to impaired IFN-c-secreting T-cell response. In contrast, despite generating fewer granulomas, the CD40L-deficient mice developed anti-mycobacterial T-cell responses to the levels observed in the wild-type mice. These host-protective responses are significantly subdued by the Mycobacterium-infected macrophage produced TGF-b and IL-10, which promote promycobacterial T-cell responses. The CD40-CD40L-induced counteractive immune responses against Mycobacterium thus present a conundrum that we explain here with a reconciliatory hypothesis. Experimental validation of the hypothesis will provide a rationale for designing anti-tubercular immunotherapy.

Tuberculosis dissemination in kidney transplant recipient treated with anti-CD40 monoclonal antibody: a case report

“…Interaction between the CD40 receptor and CD40L on activated T cells upregulates the production of IL-12, reactive oxygen species and IFN-γ production. Thus, it plays a crucial role in eliciting cell-mediated immunity important in the defence against intracellular infection [15,16]. As a result, transplant recipients treated with costimulatory signal blockers are likely to be at higher risk of tuberculosis than those on calcineurin inhibitors.…”

MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity

“…The M. tuberculosis H37Rv, M. bovis Bacillus Calmette-Guerin (BCG) Danish strain (ATCC35733), and M. smegmatis [ATCC700084/mc ( 2 )155] were grown at 37°C in Difco Middlebrook 7H9 broth (Cat: 90003-876, Becton Dickinson) or on Middlebrook 7H10 agar (Cat: 90003-728, Becton Dickinson) supplemented with 10% oleic acid-albumin-dextrose-catalase-enriched Middlebrook (OADC, Cat: 90000-418, Becton Dickinson), 0.2% glycerol, and 0.05% Tween-80. Slow-growing H37Rv and BCG reach logarithmic phase for 3–4-week culture.…”

“…In 2018, there were about 10 million new TB cases, and 1.2 million deaths ( 1 ). Mtb is spread or transmitted via aerosol from active TB patients, and the bacilli can survive or grow in lung macrophages or epithelial cells of susceptible hosts ( 2 ). The balance between host immune response and TB infection determines the potential clinical outcomes of the resulting active TB, latent TB infection (LTBI), or resister status with early clearance of TB bacillus without immune signature of infection ( 3 ).…”