Envelope stress responses: balancing damage repair and toxicity

Mitchell, Angela M.; Silhavy, Thomas J.

doi:10.1038/s41579-019-0199-0

Cited by 162 publications

(184 citation statements)

References 165 publications

(242 reference statements)

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“…We also observed higher fitness scores for a number of genes involved in LPS biosynthesis (waaC, waaD, waaE, waaF, lpcA) in the presence of T4, LZ4 and λ phages when grown on solid plates. These results suggest that LPS components either play an important role in efficient phage infection cycle or these LPS truncations lead to a destabilized membrane and probably decrease outer membrane protein levels via envelope stress response [101,[106][107][108][109]. A detailed description about many of the genes we identified in this study is included as a Supplemental Note.…”

Section: Rb-tnseq Identifies Known Receptors and Host Factors For Allmentioning

confidence: 91%

“…For example, it is known that the downregulation of genes involved in transcription antitermination (nusB, nusG) and Sec translocon subunit E (secE) shows high fitness in presence of λ phage, and are crucial for the phage growth cycle [118][119][120]. lptABC, kdsC, and lpxAC are known to impact outer membrane biogenesis, LPS synthesis and transport [108,109,121,122]; while the RNA binding global regulator CsrA is known to be involved in carbohydrate metabolism and regulation of biofilm [123,124]. Downregulation of these genes likely leads to pleiotropic effects leading to enhanced fitness in the presence of phages.…”

Section: A Crispri Screen Provides Deeper View Of Phage Resistance Dementioning

confidence: 99%

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High-throughput mapping of the phage resistance landscape inE. coli

Mutalik¹,

Adler²,

Rishi³

et al. 2020

Preprint

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Bacteriophages (phages) are critical players in the dynamics and function of microbial communities and drive processes as diverse as global biogeochemical cycles and human health. Phages tend to be predators finely tuned to attack specific hosts, even down to the strain level, which in turn defend themselves using an array of mechanisms. However, to date, efforts to rapidly and comprehensively identify bacterial host factors important in phage infection and resistance have yet to be fully realized. Here, we globally map the host genetic determinants involved in resistance to 14 phylogenetically diverse double-stranded DNA phages using two model Escherichia coli strains (K-12 and BL21) with known sequence divergence to demonstrate strain-specific differences. Using genome-wide loss-of-function and gain-of-function genetic technologies, we are able to confirm previously described phage receptors as well as uncover a number of previously unknown host factors that confer resistance to one or more of these phages. We uncover differences in resistance factors that strongly align with the susceptibility of K-12 and BL21 to specific phage. We also identify both phage specific mechanisms, such as the unexpected role of cyclic-di-GMP in host sensitivity to phage N4, and more generic defenses, such as the overproduction of colanic acid capsular polysaccharide that defends against a wide array of phages. Our results indicate that host responses to phages can occur via diverse cellular mechanisms. Our systematic and highthroughput genetic workflow to characterize phage-host interaction determinants can be extended to diverse bacteria to generate datasets that allow predictive models of how phagemediated selection will shape bacterial phenotype and evolution. The results of this study and future efforts to map the phage resistance landscape will lead to new insights into the coevolution of hosts and their phage, which can ultimately be used to design better phage therapeutic treatments and tools for precision microbiome engineering.3 Introduction:

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Section: Rb-tnseq Identifies Known Receptors and Host Factors For Allmentioning

confidence: 91%

Section: A Crispri Screen Provides Deeper View Of Phage Resistance Dementioning

confidence: 99%

High-throughput mapping of the phage resistance landscape inE. coli

Mutalik¹,

Adler²,

Rishi³

et al. 2020

Preprint

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“…The ESR has evolved to sense environmental insults (e.g immune system, temperature, pH and antibiotics) and monitor the defects or the damage to the cell envelope in order to restore its homeostasis (Mitchell and Silhavy, ). Accordingly, we were not surprised to observe that the ESR was induced in the a/e2 mutant and showed that Gna‐Gne2 are key players in the maintenance of the cell envelope homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…As inactivation of gna-gne2 altered the cell envelope integrity and lipid A biosynthesis, we tested whether the envelope stress response (ESR) was induced in the double a/e2 mutant. The ESR senses environmental changes and stresses, and stimulates the cell's adaption to restore the cell envelope homeostasis (reviewed in (Mitchell and Silhavy, 2019)). Expression of the A. baumannii ESR genes (dsbA, degP, baeR, rstA) (Crépin et al, 2018) was quantified by qRT-PCR.…”

Section: Gna-gne2 Influences the Composition Of Lipid Amentioning

confidence: 99%

The UDP‐GalNAcA biosynthesis genes gna‐gne2 are required to maintain cell envelope integrity and in vivo fitness in multi‐drug resistant Acinetobacter baumannii

Crépin

Ottosen

Chandler

et al. 2019

Molecular Microbiology

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Acinetobacter baumannii infects a wide range of anatomic sites including the respiratory tract and bloodstream. Despite its clinical importance, littleis known about the molecular basis of A. baumannii pathogenesis. We previously identified the UDP-N-acetyl-d-galactosaminuronic acid (UDP-GalNAcA) biosynthesis genes, gna-gne2, as being critical for survival in vivo. Herein, we demonstrate that Gna-Gne2 are part of a complex network connecting in vivo fitness, cell envelope homeostasis and resistance to antibiotics. The ∆gna-gne2 mutant exhibits a severe fitness defect during bloodstream infection. Capsule production is abolished in the mutant strain, which is concomitant with its inability to survive in human serum. In addition, the ∆gna-gne2 mutant was more susceptible to vancomycin and unable to grow on MacConkey plates, indicating an alteration in cell envelope integrity. Analysis of lipid A by mass spectrometry showed that the hexa-and hepta-acylated species were affected in the gna-gne2 mutant. Finally, the ∆gna-gne2 mutant was more susceptible to several classes of antibiotics. Together, this study demonstrates the importance of UDP-GalNAcA in the pathobiology of A. baumannii. By interrupting its biosynthesis, we showed that this molecule plays a critical role in capsule biosynthesis and maintaining the cell envelope homeostasis.

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“…Some intracellular bacterial pathogens shed large amounts of outer membrane material inside the eukaryotic cells (Garcia-del Portillo, Stein, & Finlay, 1997) and they depend on the extra-cytoplasmic stress-responding sigma factor RpoE to survive inside the host cell (Cano et al, 2001). Consistently, RpoE stabilizes the membrane against host-damaging agents such as antimicrobial peptides or reactive oxygen and nitrogen species (Mitchell & Silhavy, 2019). Future studies should therefore analyze probable functional connections between RpoE and changes in PG structure, perhaps affecting the relative abundance of l,d-3-3-bridges.…”

Section: F I G U R Ementioning

confidence: 99%

Building peptidoglycan inside eukaryotic cells: A view from symbiotic and pathogenic bacteria

Portillo

2020

Molecular Microbiology

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The peptidoglycan (PG), as the exoskeleton of most prokaryotes, maintains a defined shape and ensures cell integrity against the high internal turgor pressure. These important roles have attracted researchers to target PG metabolism in order to control bacterial infections. Most studies, however, have been performed in bacteria grown under laboratory conditions, leading to only a partial view on how the PG is synthetized in natural environments. As a case in point, PG metabolism and its regulation remain poorly understood in symbiotic and pathogenic bacteria living inside eukaryotic cells. This review focuses on the PG metabolism of intracellular bacteria, emphasizing the necessity of more in vivo studies involving the analysis of enzymes produced in the intracellular niche and the isolation of PG from bacteria residing within eukaryotic cells. The review also points to persistent infections caused by some intracellular bacterial pathogens and the extent at which the PG could contribute to establish such physiological state. Based on recent evidences, I speculate on the idea that certain structural features of the PG may facilitate attenuation of intracellular growth. Lastly, I discuss recent findings in endosymbionts supporting a cooperation between host and bacterial enzymes to assemble a mature PG.

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Envelope stress responses: balancing damage repair and toxicity

Cited by 162 publications

References 165 publications

High-throughput mapping of the phage resistance landscape inE. coli

High-throughput mapping of the phage resistance landscape inE. coli

The UDP‐GalNAcA biosynthesis genes gna‐gne2 are required to maintain cell envelope integrity and in vivo fitness in multi‐drug resistant Acinetobacter baumannii

Building peptidoglycan inside eukaryotic cells: A view from symbiotic and pathogenic bacteria

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