Distinct host-immune response toward species related intracellular mycobacterial killing: A transcriptomic study

Madhvi, Abhilasha; Mishra, Hridesh; Chegou, Novel N.; Tromp, Gerard; Heerden, Carel Jacobus Van; Pietersen, Ray-Dean; Leisching, Gina; Baker, Bienyameen

doi:10.1080/21505594.2020.1726561

Cited by 11 publications

(14 citation statements)

References 56 publications

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“…Contrary to our in vitro macrophage infection studies with Mtb amidase mutants, it is clear that Ami1 promotes the bacterial survival of M. smegmatis within macrophages possibly through Ami1-mediated reduction of host inflammation [39]. These differences could be potentially attributed to the induction of distinct host-immune responses within macrophages infected between nonpathogenic M. smegmatis and pathogenic M. tuberculosis [40].…”

Section: Discussioncontrasting

confidence: 91%

Deletion of N-acetylmuramyl-L-alanine amidases alters the host immune response to Mycobacterium tuberculosis infection

et al. 2021

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Peptidoglycan (PG), a heteropolysaccharide component of the mycobacterial cell wall can be shed during tuberculosis infection with immunomodulatory consequences. As such, changes in PG structure are expected to have important implications on disease progression and host responses during infection with Mycobacterium tuberculosis. Mycobacterial amidases have important roles in remodeling of PG during cell division and are implicated in susceptibility to antibiotics. However, their role in modulating host immunity remains unknown. We assessed the bacterial burden and host immune responses to M. tuberculosis mutants defective for either one of two PG N-acetylmuramyl-L-alanine amidases, Ami1 and Ami4, in bone marrow-derived macrophages (BMDM) and C57BL/6 mice. In infected BMDM, the single deletion of both genes resulted in increased proinflammatory cytokine responses. In mice, infection with the Δami1 mutant led to differential induction of pro-inflammatory cytokines and chemokines, decreased cellular recruitment and reduced lung pathology during the acute phase of the infection. While increased proinflammatory cytokines production was observed in BMDM infected with the Δami4 mutant, these effects did not prevail in mice. Infection using the Δami1 and Δami4 Mtb mutants showed that these genes are dispensable for intracellular mycobacterial growth in macrophages and mycobacterial burden in mice. These findings suggest that both Ami1 and Ami4 in M. tuberculosis are not essential for mycobacterial growth within the host. In summary, we show that amidases are important for modulating host immunity during Mtb infection in murine macrophages and mice.

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Section: Discussioncontrasting

confidence: 91%

Deletion of N-acetylmuramyl-L-alanine amidases alters the host immune response to Mycobacterium tuberculosis infection

et al. 2021

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“…Top 20 enriched pathways ranked by significance include TNF signalling pathway, JAK/STAT signalling pathway and NFκB signalling pathway, as well as inflammatory diseases, including inflammatory bowel disease (Figure 3B). Using IPA analysis, 35 relationships between significant DEGs with disease and function were summarized (Figure 3C). Multiple inflammatory factors related to LPS stimulation were up‐regulated, including Toll‐like receptor 4 (TLR4), TNF, IL1β, IFNG (IFNγ), CHUK (IKKα) and interleukin 17A (IL17A) (in red colour), which matched well with RT‐PCR results shown in Figure 2E‐G.…”

Section: Resultsmentioning

confidence: 99%

“…In order to further elaborate the influence of L971 from different aspects, we performed further analysis using IPA 35 by comparative analysis. In canonical pathway comparison (Figure 5A), various signalling pathways up‐regulated by LPS were inhibited after treatment by L971, especially in proinflammatory signalling pathways, such as NFκB signalling, leukocyte extravasation signalling, acute phase response signalling, IL17 and interleukin 8 (IL8) signalling.…”

Section: Resultsmentioning

confidence: 99%

Scaffold compound L971 exhibits anti‐inflammatory activities through inhibition of JAK/STAT and NFκB signalling pathways

Yan

Zhang

et al. 2021

J Cellular Molecular Medi

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JAK/STAT and NFκB signalling pathways play essential roles in regulating inflammatory responses, which are important pathogenic factors of various serious immune‐related diseases, and function individually or synergistically. To find prodrugs that can treat inflammation, we performed a preliminary high‐throughput screening of 18 840 small molecular compounds and identified scaffold compound L971 which significantly inhibited JAK/STAT and NFκB driven luciferase activities. L971 could inhibit the constitutive and stimuli‐dependent activation of STAT1, STAT3 and IκBα and could significantly down‐regulate the proinflammatory gene expression in mouse peritoneal macrophages stimulated by LPS. Gene expression profiles upon L971 treatment were determined using high‐throughput RNA sequencing, and significant differentially up‐regulated and down‐regulated genes were identified by DESeq analysis. The bioinformatic studies confirmed the anti‐inflammatory effects of L971. Finally, L971 anti‐inflammatory character was further verified in LPS‐induced sepsis shock mouse model in vivo. Taken together, these data indicated that L971 could down‐regulate both JAK/STAT and NFκB signalling activities and has the potential to treat inflammatory diseases such as sepsis shock.

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“…As such, the authors speculate that PKR induces anti-BCG cytokine production via downstream activation of ERK1/2 and NF-κB ( 95 ). Other studies have shown that EIF2AK2 mRNA increases during infection with BCG and M. tuberculosis ( 113 , 114 ). The findings that PKR expression and activation is triggered by mycobacterial infections suggest that PKR plays a role in the immune response to mycobacteria.…”

Section: Pkr In Mycobacterial Infectionsmentioning

confidence: 86%

“…Although most studies on PKR during mycobacterial infection used M. tuberculosis or BCG, there is limited evidence to indicate that PKR also plays a role during NTM infections. For instance, Madhvi et al recently reported that EIF2AK2 mRNA increases during infection with the nonpathogenic Mycobacterium smegmatis (114). In addition, there is evidence to loosely suggest that PKR plays a role in the immune response to Mycobacterium ulcerans, the causative agent of the tropical disease Buruli ulcer.…”

Section: Non-tuberculosis Mycobacteriamentioning

confidence: 99%

Protein Kinase R in Bacterial Infections: Friend or Foe?

Smyth

Sun

2021

Front. Immunol.

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The global antimicrobial resistance crisis poses a significant threat to humankind in the coming decades. Challenges associated with the development of novel antibiotics underscore the urgent need to develop alternative treatment strategies to combat bacterial infections. Host-directed therapy is a promising new therapeutic strategy that aims to boost the host immune response to bacteria rather than target the pathogen itself, thereby circumventing the development of antibiotic resistance. However, host-directed therapy depends on the identification of druggable host targets or proteins with key functions in antibacterial defense. Protein Kinase R (PKR) is a well-characterized human kinase with established roles in cancer, metabolic disorders, neurodegeneration, and antiviral defense. However, its role in antibacterial defense has been surprisingly underappreciated. Although the canonical role of PKR is to inhibit protein translation during viral infection, this kinase senses and responds to multiple types of cellular stress by regulating cell-signaling pathways involved in inflammation, cell death, and autophagy – mechanisms that are all critical for a protective host response against bacterial pathogens. Indeed, there is accumulating evidence to demonstrate that PKR contributes significantly to the immune response to a variety of bacterial pathogens. Importantly, there are existing pharmacological modulators of PKR that are well-tolerated in animals, indicating that PKR is a feasible target for host-directed therapy. In this review, we provide an overview of immune cell functions regulated by PKR and summarize the current knowledge on the role and functions of PKR in bacterial infections. We also review the non-canonical activators of PKR and speculate on the potential mechanisms that trigger activation of PKR during bacterial infection. Finally, we provide an overview of existing pharmacological modulators of PKR that could be explored as novel treatment strategies for bacterial infections.

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Distinct host-immune response toward species related intracellular mycobacterial killing: A transcriptomic study

Cited by 11 publications

References 56 publications

Deletion of N-acetylmuramyl-L-alanine amidases alters the host immune response to Mycobacterium tuberculosis infection

Deletion of N-acetylmuramyl-L-alanine amidases alters the host immune response to Mycobacterium tuberculosis infection

Scaffold compound L971 exhibits anti‐inflammatory activities through inhibition of JAK/STAT and NFκB signalling pathways

Protein Kinase R in Bacterial Infections: Friend or Foe?

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