Infergen Stimulated Macrophages Restrict Mycobacterium tuberculosis Growth by Autophagy and Release of Nitric Oxide

Pahari, Susanta; Khan, Nargis; Aqdas, Mohammad; Negi, Shikha; Kaur, Jagdeep; Agrewala, Javed N.

doi:10.1038/srep39492

Cited by 26 publications

(28 citation statements)

References 52 publications

(73 reference statements)

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“…43 Treatment of macrophages with recombinant IFNab results in the restriction of M. tuberculosis growth by NO. 44 Our in vitro experiments revealed that Ifnb induction by M. smegmatis and even the low response induced by MAP takes place via the cytosolic cGAS-STING-TBK1-IRF3/7 pathway. Activation required viability and cellular uptake.…”

Section: Discussionmentioning

confidence: 74%

cGAS-STING-TBK1-IRF3/7 induced interferon-β contributes to the clearing of non tuberculous mycobacterial infection in mice

Ruangkiattikul¹,

Nerlich²,

Abdissa

et al. 2017

Virulence

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Type I interferons (IFN-I), such as IFN-α and IFN-β are important messengers in the host response against bacterial infections. Knowledge about the role of IFN-I in infections by nontuberculous mycobacteria (NTM) is limited. Here we show that macrophages infected with pathogens of the Mycobacterium avium complex produced significantly lower amounts of IFN-β than macrophages infected with the opportunistic pathogen M. smegmatis. To dissect the molecular mechanisms of this phenomenon, we focused on the obligate pathogen Mycobacterium avium ssp paratuberculosis (MAP) and the opportunistic M. smegmatis. Viability of both bacteria was required for induction of IFN-β in macrophages. Both bacteria induced IFN-β via the cGAS-STING-TBK1-IRF3/7-pathway of IFN-β activation. Stronger phosphorylation of TBK1 and higher amounts of extracellular bacterial DNA in the macrophage cytosol were found in M. smegmatis infected macrophages than in MAP infected macrophages. After intraperitoneal infection of mice, a strong Ifnb induction by M. smegmatis correlated with clearance of the bacteria. In contrast, MAP only induced weak Ifnb expression which correlated with bacterial persistence and increased number of granulomas in the liver. In mice lacking the type I interferon receptor we observed improved survival of M. smegmatis while survival of MAP was similar to that in wildtype mice. On the other hand, treatment of MAP infected wildtype mice with the IFN-I inducer poly(I:C) or recombinant IFN-β impaired the survival of MAP. This indicates an essential role of IFN-I in clearing infections by MAP and M. smegmatis. The expression level of IFN-I is decisive for transient versus persistent NTM infection.

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Section: Discussionmentioning

confidence: 74%

cGAS-STING-TBK1-IRF3/7 induced interferon-β contributes to the clearing of non tuberculous mycobacterial infection in mice

Ruangkiattikul¹,

Nerlich²,

Abdissa

et al. 2017

Virulence

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“…DprE1 is the flavoprotein subunit of the enzyme, decaprenyl‐phosphoryl D‐ribose epimerase, that produces decaprenyl‐phosphoryl arabinose (DPA), which catalyzes the FAD‐dependent oxidation of decaprenylphosphoryl‐ β ‐D‐ribose (DPR) to decaprenylphosphoryl‐2‐keto‐D‐erythro‐pentofuranose (DPX). The NADH‐dependent enzyme DprE2 then converts DPX to decaprenylphosphoryl‐ β ‐D‐arabinose (DPA), a unique sugar donor for biogenesis of the vital mycobacterial cell wall polysaccharides arabinogalactan and lipoarabinomannan . Epimerization of DPR to DPA is accomplished by the concerted action of DprE1 and DprE2 enzymes wherein DprE1 uses FAD to oxidize DPR to a keto intermediate, which, in turn, is reduced to DPA by DprE2 using NADH as a cofactor.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Triazole Derivatives of 9‐Ethyl‐9H‐carbazole and Dibenzo[b,d]furan and Evaluation of Their Antimycobacterial and Immunomodulatory Activity

et al. 2017

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1,4‐Disubstituted 1,2,3‐triazole derivatives of 9‐ethyl‐9H‐carbazole and dibenzo[b,d]furan were synthesized by the Huisgen's 1,3‐dipolar cycloaddition reaction between azides and terminal alkynes. The synthesized derivatives 7d, 8a, 8b, 9e, and 10c exhibited good MIC values, especially against Mycobacterium smegmatis and these compounds were further evaluated for their immunomodulatory activity. Majority of the compounds exhibited no toxicity on splenocytes and macrophages and the compounds 8a and 8b are proved as induced proliferator. These compounds have shown decreased production of TNF‐α from LPS stimulated RAW 264.7 cells and among all these compounds, 7d has shown significant inhibition of TNF‐α production. Molecular docking studies into the active site of mycobacterial DprE1 enzyme helped to establish a structural basis for inhibition of Mycobacterium tuberculosis and understand the type of ligand‐protein interactions governing the binding affinity.

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“…Recruitment and activation of many signaling molecules in cascade lead to nuclear translocation of NF-κB, which eventually causes the activation of MPCs. In a different setup, the activated macrophages have the capability to carry out macro-autophagy to take care of intracellular Mtb ( 72 , 73 ). In a similar phenomenon known as “programmed necroptosis,” MPCs controls the intracellular replication of Mtb .…”

Section: Prrs-mediated Bolstering Of Mps Activity Against Mmentioning

confidence: 99%

Reinforcing the Functionality of Mononuclear Phagocyte System to Control Tuberculosis

et al. 2018

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The mononuclear phagocyte system (MPS) constitutes dendritic cells, monocytes, and macrophages. This system contributes to various functions that are essential for maintaining homeostasis, activation of innate immunity, and bridging it with the adaptive immunity. Consequently, MPS is highly important in bolstering immunity against the pathogens. However, MPS is the frontline cells in destroying Mycobacterium tuberculosis (Mtb), yet the bacterium prefers to reside in the hostile environment of macrophages. Therefore, it may be very interesting to study the struggle between Mtb and MPS to understand the outcome of the disease. In an event when MPS predominates Mtb, the host remains protected. By contrast, the situation becomes devastating when the pathogen tames and tunes the host MPS, which ultimately culminates into tuberculosis (TB). Hence, it becomes extremely crucial to reinvigorate MPS functionality to overwhelm Mtb and eliminate it. In this article, we discuss the strategies to bolster the function of MPS by exploiting the molecules associated with the innate immunity and highlight the mechanisms involved to overcome the Mtb-induced suppression of host immunity. In future, such approaches may provide an insight to develop immunotherapeutics to treat TB.

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Infergen Stimulated Macrophages Restrict Mycobacterium tuberculosis Growth by Autophagy and Release of Nitric Oxide

Cited by 26 publications

References 52 publications

cGAS-STING-TBK1-IRF3/7 induced interferon-β contributes to the clearing of non tuberculous mycobacterial infection in mice

cGAS-STING-TBK1-IRF3/7 induced interferon-β contributes to the clearing of non tuberculous mycobacterial infection in mice

Synthesis of Triazole Derivatives of 9‐Ethyl‐9H‐carbazole and Dibenzo[b,d]furan and Evaluation of Their Antimycobacterial and Immunomodulatory Activity

Reinforcing the Functionality of Mononuclear Phagocyte System to Control Tuberculosis

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