STING-Dependent 2′-5′ Oligoadenylate Synthetase–Like Production Is Required for IntracellularMycobacterium lepraeSurvival

Abstract

Cytosolic detection of nucleic acids elicits a type I interferon (IFN) response and plays a critical role in host defense against intracellular pathogens. Herein, a global gene expression profile of Mycobacterium leprae-infected primary human Schwann cells identified the genes differentially expressed in the type I IFN pathway. Among them, the gene encoding 2'-5' oligoadenylate synthetase-like (OASL) underwent the greatest upregulation and was also shown to be upregulated in M. leprae-infected human macrophage cell lineages, primary monocytes, and skin lesion specimens from patients with a disseminated form of leprosy. OASL knock down was associated with decreased viability of M. leprae that was concomitant with upregulation of either antimicrobial peptide expression or autophagy levels. Downregulation of MCP-1/CCL2 release was also observed during OASL knock down. M. leprae-mediated OASL expression was dependent on cytosolic DNA sensing mediated by stimulator of IFN genes signaling. The addition of M. leprae DNA enhanced nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin intracellular survival, downregulated antimicrobial peptide expression, and increased MCP-1/CCL2 secretion. Thus, our data uncover a promycobacterial role for OASL during M. leprae infection that directs the host immune response toward a niche that permits survival of the pathogen.

The Association of OASL and Type I Interferons in the Pathogenesis and Survival of Intracellular Replicating Bacterial Species

“…Moreover, OASL is also produced as a result of signaling through this axis and aids in promoting a favorable intracellular milieu for bacterial survival. In line with this, the biological role of OASL during mycobacterial infection, specifically with the vacuolar pathogen M. leprae was recently elucidated (de Toledo-Pinto et al, 2016). The authors suggest that the presence of OASL is required for intracellular M. leprae survival which appears to be dependent on inhibiting autophagic mechanisms, thus preventing clearance of the microbe.…”

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

“…4.8.2.0 software (Carl Zeiss). The number of fluorescent LC3 puncta was quantified using the Particle Analyzer plugin of ImageJ software after image thresholding [14,32]. ImageJ was also used for colocalization analysis.…”

“…Briefly, the red, green, and blue channels were extracted from RGB images and converted to binary images (grayscale) by automatic thresholding. Afterwards, the background pixelation was removed from the analysis, and then merged channels were analyzed using the Colocalization and Analyze Particles built-in functions of the software [32]. For both analysis, a minimum of 100 cells per sample were scored by each experiment.…”

“…A newly published paper has suggested that the killing of M . leprae in human macrophages was associated with the targeting of mycobacteria to autophagy [32]. Interestingly, several molecules that trigger autophagy, like VDR, TLR2, and NOD2 receptors [13,16,33], are preferentially expressed in T-lep skin lesions [6,34,35], while the polymorphisms in these genes are associated with susceptibility to L-lep [36–38].…”

The Emerging Roles of STING in Bacterial Infections

“…This protein is related to anti-RNA viral response in humans [103]. Surprisingly, OASL was greatly upregulated following M. leprae infection and its function was associated with reduced autophagy and antimicrobial response, promoting bacilli viability [104]. …”