An alloy of zinc and innate immunity: Galvanising host defence against infection

Pein, Jessica B. von; Stocks, Claudia J.; Schembri, Mark A.; Kapétanovic, Ronan; Sweet, Matthew J.

doi:10.1111/cmi.13268

Cited by 20 publications

(17 citation statements)

References 107 publications

(186 reference statements)

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“…Likewise, zinc serves as an important agent for the development of cell structure and functions. It may promote the survival and virulence of bacteria, viruses, or other microbes and participate in host defence by modulating various modes of signal transduction and inflammation in a concentrationdependent way [5,22,72,98].…”

Section: Discussionmentioning

confidence: 99%

“…APN has also been described as a cancer-specific biomarker and reported to be involved in the progression of tumour metastasis, angiogenesis and prognosis, as well as protein overexpression in cancer cells, while tissue invasion and metastasis in human prostate cancer could be attenuated by using Zn 2+ to inhibit APN biological activity in a dose-dependent manner [95][96][97]. Zinc is also closely related to some transmembrane receptor proteins, including B cell receptors (BCRs), TLRs and nucleotide-binding oligomerization domain (NOD)-like receptors, which are responsible for the recognition of microbes or antigen molecules and involved in the development and modulation of intestinal homeostasis [72,98,99]. ZIP9 increased the intracellular zinc level and enhanced Akt and Erk phosphorylation in response to BCR activation [100].…”

Section: Zinc Affects the Activity Of Host Receptors And Immune Respomentioning

confidence: 99%

“…Interestingly, the antimicrobial roles of macrophages vary in defending against different pathogens. Macrophages deploy both zinc starvation and/or zinc toxicity as an antimicrobial strategy [72,98,105]. The clearance of Streptococcus in macrophages is promoted by both calprotectin-mediated zinc starvation and intracellular zinc toxicity [106], whereas zinc starvation is utilized as a strategy against Histoplasma capsulatum infection, and excessive zinc poisoning within the macrophage phagolysosome exerts direct bactericidal effects on M. tuberculosis and UPEC [98,107,108].…”

Section: Zinc Affects the Activity Of Host Receptors And Immune Respomentioning

confidence: 99%

“…Macrophages deploy both zinc starvation and/or zinc toxicity as an antimicrobial strategy [72,98,105]. The clearance of Streptococcus in macrophages is promoted by both calprotectin-mediated zinc starvation and intracellular zinc toxicity [106], whereas zinc starvation is utilized as a strategy against Histoplasma capsulatum infection, and excessive zinc poisoning within the macrophage phagolysosome exerts direct bactericidal effects on M. tuberculosis and UPEC [98,107,108]. In addition, continuous stimulation of TLRs and NOD2 alters the expression of MT and increases the level of intracellular zinc, leading to increased autophagy and enhanced bacterial clearance of S. typhimurium, S. aureus, and adherent invasive E. coli in intestinal macrophages [98,[109][110][111].…”

Section: Zinc Affects the Activity Of Host Receptors And Immune Respomentioning

confidence: 99%

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Zinc is an important inter-kingdom signal between the host and microbe

Xia

Lian

et al. 2021

Vet Res

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Zinc (Zn) is an essential trace element in living organisms and plays a vital role in the regulation of both microbial virulence and host immune responses. A growing number of studies have shown that zinc deficiency or the internal Zn concentration does not meet the needs of animals and microbes, leading to an imbalance in zinc homeostasis and intracellular signalling pathway dysregulation. Competition for zinc ions (Zn2+) between microbes and the host exists in the use of Zn2+ to maintain cell structure and physiological functions. It also affects the interplay between microbial virulence factors and their specific receptors in the host. This review will focus on the role of Zn in the crosstalk between the host and microbe, especially for changes in microbial pathogenesis and nociceptive neuron-immune interactions, as it may lead to new ways to prevent or treat microbial infections.

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Section: Discussionmentioning

confidence: 99%

Section: Zinc Affects the Activity Of Host Receptors And Immune Respomentioning

confidence: 99%

Section: Zinc Affects the Activity Of Host Receptors And Immune Respomentioning

confidence: 99%

Section: Zinc Affects the Activity Of Host Receptors And Immune Respomentioning

confidence: 99%

See 2 more Smart Citations

Zinc is an important inter-kingdom signal between the host and microbe

Xia

Lian

et al. 2021

Vet Res

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“…In particular, zinc is essential for maintaining structure and catalytic activity of bacterial enzymes [86] and plays a role in signal transduction [87]. However, excessive zinc is cytotoxic, and immune cells can mobilize and deliver toxic concentrations of zinc to intracellular bacterial pathogens [47,88].…”

Section: Investigating Peptide Ability To Enhance Zinc Toxicitymentioning

confidence: 99%

Modified defence peptides from horseshoe crab target and kill bacteria inside host cells

Pein

Webb

et al. 2021

Preprint

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Bacteria that occupy an intracellular niche can evade extracellular host immune responses and antimicrobial molecules. In addition to classic intracellular pathogens, other bacteria including uropathogenic Escherichia coli (UPEC) can adopt both extracellular and intracellular lifestyles. UPEC intracellular survival and replication complicates treatment, as many therapeutic molecules do not effectively reach all components of the infection cycle. In this study, we explored cell penetrating antimicrobial peptides from distinct structural classes as alternative molecules for targeting bacteria. We identified two β-hairpin peptides from the horseshoe crab, tachyplesin I and polyphemusin I, with broad antimicrobial activity toward a panel of pathogenic and non-pathogenic bacteria in planktonic form. Peptide analogues [I11A]tachyplesin I and [I11S]tachyplesin I maintained activity toward bacteria, but were less toxic to mammalian cells than native tachyplesin I. This important increase in therapeutic window allowed treatment with higher concentrations of [I11A]tachyplesin I and [I11S]tachyplesin I, to significantly reduce intramacrophage survival of UPEC in an in vitro infection model. Mechanistic studies using bacterial cells, model membranes and cell membrane extracts, suggest that tachyplesin I and polyphemusin I peptides kill UPEC by selectively binding and disrupting bacterial cell membranes. Moreover, treatment of UPEC with sublethal peptide concentrations increased zinc toxicity and enhanced innate macrophage antimicrobial pathways. In summary, our combined data show that cell penetrating peptides are attractive alternatives to traditional small molecule antimicrobials for treating UPEC infection, and that optimization of native peptide sequences can deliver effective antimicrobials for targeting bacteria in extracellular and intracellular environments.

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Antimicrobial peptides provide wider coverage for targeting drug‐resistant bacterial pathogens

2021

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We need new treatment options to control bacterial infections. Bacteria use several strategies to resist drug treatment, including modification of the drug target, and adaptation to a different lifestyle, such as intracellular niches within host cells. Drugs that act on diverse targets are less likely to induce resistance in bacteria, than current antibiotics acting on a single molecular target. Antimicrobial peptides have been explored as a new class of antibiotics because they selectively kill bacteria via a mechanism that involves recognition of the negatively charged microbial surface. Furthermore, antimicrobial peptides with cell‐penetrating properties can cross host cell membranes and target bacteria in the cytosol or sequestered in vesicles. Therefore, bacteria in intracellular niches are less capable of evading treatment and the likelihood of establishing drug resistance is further reduced. This review highlights the potential of antimicrobial peptides as alternative therapeutics to target bacterial pathogens in both extracellular and intracellular environments, and to avoid acquired drug‐resistance.

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An alloy of zinc and innate immunity: Galvanising host defence against infection

Cited by 20 publications

References 107 publications

Zinc is an important inter-kingdom signal between the host and microbe

Zinc is an important inter-kingdom signal between the host and microbe

Modified defence peptides from horseshoe crab target and kill bacteria inside host cells

Antimicrobial peptides provide wider coverage for targeting drug‐resistant bacterial pathogens

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