ESX-1 exploits type I IFN-signalling to promote a regulatory macrophage phenotype refractory to IFNγ-mediated autophagy and growth restriction of intracellular mycobacteria

Lienard, Julia; Movert, Elin; Valfridsson, Christine; Sturegård, Erik; Carlsson, Fredric

doi:10.1111/cmi.12594

Cited by 19 publications

(22 citation statements)

References 70 publications

(162 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…62 The induced IL-6 is responsible for the suppression of Th1 responses and the suppression of Mtb-infected and Mtbuninfected bystander macrophage responses to IFN-γ, which induces autophagy in Mtb-infected macrophages. 63,64 Mtb antigens expressed in latency, such as α-crystalline 1 (Acr1), can also interfere with the differentiation of DCs by targeting STAT3 pathways (Figure 1). 65 Continuous activation of STAT3 would inhibit the translocation of nuclear factor-κB (NF-κB) in DCs treated by Acr1.…”

Section: Mtb Microorganisms May Manipulate Th17-related Cytokine Signmentioning

confidence: 99%

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

2017

View full text Add to dashboard Cite

Interleukin-17 (IL-17), IL-21, IL-22 and IL-23 can be grouped as T helper 17 (Th17)-related cytokines because they are either produced by Th17/Th22 cells or involved in their development. Here, we review Th17-related cytokines/Th17-like cells, networks/signals and their roles in immune responses or immunity against Mycobacterium tuberculosis (Mtb) infection. Published studies suggest that Th17-related cytokine pathways may be manipulated by Mtb microorganisms for their survival benefits in primary tuberculosis (TB). In addition, there is evidence that immune responses of the signal transducer and activator of transcription 3 (STAT3) signal pathway and Th17-like T-cell subsets are dysregulated or destroyed in patients with TB. Furthermore, Mtb infection can impact upstream cytokines in the STAT3 pathway of Th17-like responses. Based on these findings, we discuss the need for future studies and the rationale for targeting Th17-related cytokines/signals as a potential adjunctive treatment.

show abstract

Section: Mtb Microorganisms May Manipulate Th17-related Cytokine Signmentioning

confidence: 99%

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

2017

View full text Add to dashboard Cite

show abstract

“…Multiple studies indicate that Mtb employs both active and passive mechanisms to induce T1-IFNs (74–76). The mycobacterial ESAT-6 secretion system (ESX-1) and its 6 kDa early secretory antigenic target (ESAT-6) are essential in this process, as mycobacteria lacking ESX-1 fail to induce T1-IFN production (67, 77–81).…”

Section: T1-ifns In Tbmentioning

confidence: 99%

“…Expression of CCL2 is reduced in the lungs of IFNAR −/− mice, and the pathogenic effects of poly-ICLC treatment are absent in Mtb-infected CCR2 −/− mice (72). Thus, preclinical TB studies indicate that T1-IFNs stimulate the influx of CCR2 + monocytes, but not PMN, to the site of infection in a CCR2-dependent way via the induction of CCL2 in parenchymal cells (74–76). …”

Section: T1-ifns In Tbmentioning

confidence: 99%

See 1 more Smart Citation

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

et al. 2017

View full text Add to dashboard Cite

The classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research.

show abstract

“…Our unpublished data suggest that boosting S1P level pharmacologically in host may offer therapeutic benefit in managing mycobacterial disease. However, among various species of mycobacteria, pathogenic species of mycobacteria particularly MDR/MTR strains contain their own type seventh secretion system, which they use to exploit macrophage defense mechanism for their replication (39–41). Kusner and Russell’s groups have already indicated the significance of ceramide/sphingolipid in establishing mycobacterial persistency (42, 43), which may contribute to the drug resistance.…”

Section: Sphingolipids In Mycobacterial Diseasementioning

confidence: 99%

Sphingolipids Are Dual Specific Drug Targets for the Management of Pulmonary Infections: Perspective

Sharma

Prakash

2017

Front. Immunol.

View full text Add to dashboard Cite

Sphingolipids are the major constituent of the mucus secreted by the cells of epithelial linings of lungs where they maintain the barrier functions and prevent microbial invasion. Sphingolipids are interconvertible, and their primary and secondary metabolites have both structural and functional roles. Out of several sphingolipid metabolites, sphingosine-1 phosphate (S1P) and ceramide are central molecules and decisive for sphingolipid signaling. These are produced by enzymatic activity of sphingosine kinase-1 (SK-1) upon the challenge with either biological or physiological stresses. S1P and ceramide rheostat are important for the progression of various pathologies, which are manifested by inflammatory cascade. S1P is a well-established secondary messenger and associated with various neuronal, metabolic, and inflammatory diseases other than respiratory infections such as Chlamydia pneumoniae, Streptococcus pneumoniae, and Mycobacterium tuberculosis. These pathogens are known to exploit sphingolipid metabolism for their opportunistic survival. Decreased sphingosine kinase activity/S1P content in the lung and peripheral blood of tuberculosis patients clearly indicated a dysregulation of sphingolipid metabolism during infection and suggest that sphingolipid metabolism is important for management of infection by the host. Our previous study has demonstrated that gain of SK-1 activity is important for the maturation of phagolysosomal compartment, innate activation of macrophages, and subsequent control of mycobacterial replication/growth in macrophages. Furthermore, S1P-mediated amelioration of lung pathology and disease severity in TB patients is believed to be mediated by the selective activation or rearrangement of various S1P receptors (S1PR) particularly S1PR2, which has been effective in controlling respiratory fungal pathogens. Therefore, such specificity of S1P–S1PR would be paramount for triggering inflammatory events, subsequent activation, and fostering bactericidal potential in macrophages for the control of TB. In this review, we have discussed and emphasized that sphingolipids may represent effective novel, yet dual specific drug targets for controlling pulmonary infections.

show abstract

ESX-1 exploits type I IFN-signalling to promote a regulatory macrophage phenotype refractory to IFNγ-mediated autophagy and growth restriction of intracellular mycobacteria

Cited by 19 publications

References 70 publications

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

Sphingolipids Are Dual Specific Drug Targets for the Management of Pulmonary Infections: Perspective

Contact Info

Product

Resources

About