scholarly journals Engineered Liposomes Protect Immortalized Immune Cells from Cytolysins Secreted by Group A and Group G Streptococci

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 166
Author(s):  
Hervé Besançon ◽  
Yu Larpin ◽  
Viktoria S. Babiychuk ◽  
René Köffel ◽  
Eduard B. Babiychuk
Keyword(s):  
Immune Cells ◽  
Bacterial Infections ◽  
Bacterial Pathogens ◽  
Host Cells ◽  
Human Pathogens ◽  
Efficient Treatment ◽  
Group G Streptococci ◽  
Cell Plasma ◽  
Successful Infection ◽  
Life Threatening

The increasing antibiotic resistance of bacterial pathogens fosters the development of alternative, non-antibiotic treatments. Antivirulence therapy, which is neither bacteriostatic nor bactericidal, acts by depriving bacterial pathogens of their virulence factors. To establish a successful infection, many bacterial pathogens secrete exotoxins/cytolysins that perforate the host cell plasma membrane. Recently developed liposomal nanotraps, mimicking the outer layer of the targeted cell membranes, serve as decoys for exotoxins, thus diverting them from attacking host cells. In this study, we develop a liposomal nanotrap formulation that is capable of protecting immortalized immune cells from the whole palette of cytolysins secreted by Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis—important human pathogens that can cause life-threatening bacteremia. We show that the mixture of cholesterol-containing liposomes with liposomes composed exclusively of phospholipids is protective against the combined action of all streptococcal exotoxins. Our findings pave the way for further development of liposomal antivirulence therapy in order to provide more efficient treatment of bacterial infections, including those caused by antibiotic resistant pathogens.

scholarly journals Symbiosis Comes of Age at the 10th Biennial Meeting of Wolbachia Researchers

2019 ◽  
Vol 85 (8) ◽  
Author(s):  
Irene L. G. Newton ◽  
Barton E. Slatko
Keyword(s):  
Cell Biology ◽  
Rna Virus ◽  
Host Cells ◽  
Human Pathogens ◽  
Content Type ◽  
New Science ◽  
Successful Infection ◽  
Filarial Nematodes ◽  
Insect Populations ◽  
Basic Biology

ABSTRACT Wolbachia pipientis is an alphaproteobacterial obligate intracellular microbe and arguably the most successful infection on our planet, colonizing 40% to 60% of insect species. Wolbachia spp. are also present in most, but not all, filarial nematodes, where they are obligate mutualists and are the targets for antifilarial drug discovery. Although Wolbachia spp. are related to important human pathogens, they do not infect mammals but instead are well known for their reproductive manipulations of insect populations, inducing the following phenotypes: male killing, feminization, parthenogenesis induction, and cytoplasmic incompatibility (CI). The most common of these, CI, results in a sperm-egg incompatibility and increases the relative fecundity of infected females in a population. In the last decade, Wolbachia spp. have also been shown to provide a benefit to insects, where the infection can inhibit RNA virus replication within the host. Wolbachia spp. cannot be cultivated outside host cells, and no genetic tools are available in the symbiont, limiting approaches available for their study. This means that many questions fundamental to our understanding of Wolbachia basic biology remained unknown for decades. The 10th biennial international Wolbachia conference, Wolbachia Evolution, Ecology, Genomics and Cell Biology: A Chronicle of the Most Ubiquitous Symbiont, was held on 17 to 22 June 2018 in Salem, MA. In this review, we highlight the new science presented at the meeting, link it to prior efforts to answer these questions across the Wolbachia genus, and present the importance of these findings to the field of symbiosis. The topics covered in this review are based on the presentations at the conference.

scholarly journals Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

2012 ◽  
Vol 56 (11) ◽  
pp. 5433-5441 ◽  
Author(s):  
Miles C. Duncan ◽  
Roger G. Linington ◽  
Victoria Auerbuch
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Bacterial Pathogens ◽  
Secretion System ◽  
Effector Proteins ◽  
Host Cells ◽  
Magic Bullet ◽  
Antimicrobial Drugs ◽  
Type Three Secretion System ◽  
Type Three Secretion

ABSTRACTThe recent and dramatic rise of antibiotic resistance among bacterial pathogens underlies the fear that standard treatments for infectious disease will soon be largely ineffective. Resistance has evolved against nearly every clinically used antibiotic, and in the near future, we may be hard-pressed to treat bacterial infections previously conquered by “magic bullet” drugs. While traditional antibiotics kill or slow bacterial growth, an important emerging strategy to combat pathogens seeks to block the ability of bacteria to harm the host by inhibiting bacterial virulence factors. One such virulence factor, the type three secretion system (T3SS), is found in over two dozen Gram-negative pathogens and functions by injecting effector proteins directly into the cytosol of host cells. Without T3SSs, many pathogenic bacteria are unable to cause disease, making the T3SS an attractive target for novel antimicrobial drugs. Interdisciplinary efforts between chemists and microbiologists have yielded several T3SS inhibitors, including the relatively well-studied salicylidene acylhydrazides. This review highlights the discovery and characterization of T3SS inhibitors in the primary literature over the past 10 years and discusses the future of these drugs as both research tools and a new class of therapeutic agents.

scholarly journals Glycobiology of syndecan-1 in bacterial infections

2018 ◽  
Vol 46 (2) ◽  
pp. 371-377 ◽  
Author(s):  
Rafael S. Aquino ◽  
Yvonne Hui-Fang Teng ◽  
Pyong Woo Park
Keyword(s):  
Cell Surface ◽  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Bacterial Pathogens ◽  
Innate Immune ◽  
Host Cells ◽  
Innate Defense ◽  
Immune Clearance ◽  
Bacterial Adhesins ◽  
A Cell

Syndecan-1 (Sdc1) is a major cell surface heparan sulfate (HS) proteoglycan of epithelial cells, a cell type targeted by many bacterial pathogens early in their pathogenesis. Loss of Sdc1 in mice is a gain-of-function mutation that significantly decreases the susceptibility to several bacterial infections, suggesting that subversion of Sdc1 is an important virulence strategy. HS glycosaminoglycan (GAG) chains of cell surface Sdc1 promote bacterial pathogenesis by facilitating the attachment of bacteria to host cells. Engagement of cell surface Sdc1 HS chains by bacterial adhesins transmits signal through the highly conserved Sdc1 cytoplasmic domain, which can lead to uptake of intracellular bacterial pathogens. On the other hand, several bacteria that do not require Sdc1 for their attachment and invasion stimulate Sdc1 shedding and exploit the capacity of Sdc1 ectodomain HS GAGs to disarm innate defense mechanisms to evade immune clearance. Recent data suggest that select HS sulfate motifs, and not the overall charge of HS, are important in the inhibition of innate immune mechanisms. Here, we discuss several examples of Sdc1 subversion in bacterial infections.

scholarly journals Mycobacterium tuberculosis Infection Drives Mitochondria-Biased Dysregulation of Host Transfer RNA–Derived Fragments

2020 ◽  
Author(s):  
Monika M Looney ◽  
Yin Lu ◽  
Petros C Karakousis ◽  
Marc K Halushka
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Messenger Rna ◽  
Noncoding Rna ◽  
Bacterial Infections ◽  
Bacterial Pathogens ◽  
Transfer Rna ◽  
Host Cells ◽  
Analysis Tool ◽  
Mycobacterium Tuberculosis Infection ◽  
Micro Rnas

Abstract Background Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis, causes 10 million infections and 1.5 million deaths per year worldwide. The success of Mtb as a human pathogen is directly related to its ability to suppress host responses, which are critical for clearing intracellular pathogens. Emerging evidence suggests that key response pathways may be regulated by a novel class of small noncoding RNA, called transfer RNA (tRNA)–derived fragments (tRFs). tRFs can complex with Argonaute proteins to target and degrade messenger RNA targets, similarly to micro RNAs, but have thus far been overlooked in the context of bacterial infections. Methods We generated a novel miRge2.0-based tRF-analysis tool, tRFcluster, and used it to analyze independently generated and publicly available RNA-sequencing datasets to assess tRF dysregulation in host cells following infection with Mtb and other intracellular bacterial pathogens. Results We found that Mtb and Listeria monocytogenes drive dramatic tRF dysregulation, whereas other bacterial pathogens do not. Interestingly, Mtb infection uniquely increased the expression of mitochondria-derived tRFs rather than genomic-derived tRFs, suggesting an association with mitochondrial damage in Mtb infection. Conclusions tRFs are dysregulated in some, but not all, bacterial infections. Biased dysregulation of mitochondria-derived tRFs in Mtb infection suggests a link between mitochondrial distress and tRF production.

scholarly journals Evasion of Early Antiviral Responses by Herpes Simplex Viruses

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Paula A. Suazo ◽  
Francisco J. Ibañez ◽  
Angello R. Retamal-Díaz ◽  
Marysol V. Paz-Fiblas ◽  
Susan M. Bueno ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Host Cells ◽  
Type I ◽  
Human Pathogens ◽  
Herpes Simplex Viruses ◽  
Antiviral Responses ◽  
Simplex Virus

Besides overcoming physical constraints, such as extreme temperatures, reduced humidity, elevated pressure, and natural predators, human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection, replication and optimally, reinfection. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) infect humans at a high frequency and persist within the host for life by establishing latency in neurons. To gain access to these cells, herpes simplex viruses (HSVs) must replicate and block immediate host antiviral responses elicited by epithelial cells and innate immune components early after infection. During these processes, infected and noninfected neighboring cells, as well as tissue-resident and patrolling immune cells, will sense viral components and cell-associated danger signals and secrete soluble mediators. While type-I interferons aim at limiting virus spread, cytokines and chemokines will modulate resident and incoming immune cells. In this paper, we discuss recent findings relative to the early steps taking place during HSV infection and replication. Further, we discuss how HSVs evade detection by host cells and the molecular mechanisms evolved by these viruses to circumvent early antiviral mechanisms, ultimately leading to neuron infection and the establishment of latency.

scholarly journals Tailored Liposomal Nanotraps for the Treatment of Streptococcal Infections

2020 ◽  
Author(s):  
Hervé Besançon ◽  
Viktoriia Babiychuk ◽  
Yu Larpin ◽  
René Köffel ◽  
Dominik Schittny ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Diagnostic Delay ◽  
Host Cells ◽  
Streptococcal Toxic Shock Syndrome ◽  
Streptococcal Infections ◽  
Antibiotic Resistant ◽  
Bacterial Diseases ◽  
Life Threatening ◽  
Streptococcus Dysgalactiae Subspecies Equisimilis ◽  
Pathogen Clearance

Abstract Background: Streptococcal infections are associated with life-threatening pneumonia and sepsis. The rise in antibiotic resistance calls for novel approaches to treat bacterial diseases. Anti-virulence strategies promote a natural way of pathogen clearance by eliminating the advantage provided to bacteria by their virulence factors. In contrast to antibiotics, anti-virulence agents are less likely to exert selective evolutionary pressure, which is a prerequisite for the development of drug resistance. As part of their virulence mechanism, many bacterial pathogens secrete cytolytic exotoxins that destroy the host cell by destabilizing their plasma membrane. Liposomal nanotraps, mimicking plasmalemmal structures of host cells that are specifically targeted by bacterial toxins are being developed in order to neutralize - by competitive sequestration - numerous exotoxins. Results: In this study, the liposomal nanotrap technology is further developed to simultaneously neutralize the whole palette of cytolysins produced by Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis - pathogens that can cause life-threatening streptococcal toxic shock syndrome. We show that the mixture of liposomes containing high amounts of cholesterol and liposomes composed exclusively of choline-containing phospholipids is fully protective against the combined action of exotoxins secreted by these pathogens. Conclusions: Unravelling the universal mechanisms that define targeting of host cells by streptococcal cytolysins paves the way for a broad-spectrum anti-toxin therapy that can be applied without a diagnostic delay for the treatment of bacterial infections including those caused by antibiotic-resistant pathogens.

scholarly journals Pathogenicity Islands in Bacterial Pathogenesis

2004 ◽  
Vol 17 (1) ◽  
pp. 14-56 ◽  
Author(s):  
Herbert Schmidt ◽  
Michael Hensel
Keyword(s):  
Cell Biology ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Human Life ◽  
Bacterial Pathogens ◽  
Genomic Islands ◽  
Model Systems ◽  
Host Cells ◽  
Pathogenicity Islands ◽  
Molecular Features

SUMMARY In this review, we focus on a group of mobile genetic elements designated pathogenicity islands (PAI). These elements play a pivotal role in the virulence of bacterial pathogens of humans and are also essential for virulence in pathogens of animals and plants. Characteristic molecular features of PAI of important human pathogens and their role in pathogenesis are described. The availability of a large number of genome sequences of pathogenic bacteria and their benign relatives currently offers a unique opportunity for the identification of novel pathogen-specific genomic islands. However, this knowledge has to be complemented by improved model systems for the analysis of virulence functions of bacterial pathogens. PAI apparently have been acquired during the speciation of pathogens from their nonpathogenic or environmental ancestors. The acquisition of PAI not only is an ancient evolutionary event that led to the appearance of bacterial pathogens on a timescale of millions of years but also may represent a mechanism that contributes to the appearance of new pathogens within a human life span. The acquisition of knowledge about PAI, their structure, their mobility, and the pathogenicity factors they encode not only is helpful in gaining a better understanding of bacterial evolution and interactions of pathogens with eukaryotic host cells but also may have important practical implications such as providing delivery systems for vaccination, tools for cell biology, and tools for the development of new strategies for therapy of bacterial infections.

scholarly journals Taming the Triskelion: Bacterial Manipulation of Clathrin

2019 ◽  
Vol 83 (2) ◽  
Author(s):  
Eleanor A. Latomanski ◽  
Hayley J. Newton
Keyword(s):  
Bacterial Infections ◽  
Viral Infections ◽  
Bacterial Pathogens ◽  
Eukaryotic Cell ◽  
Bacterial Attachment ◽  
Host Cells ◽  
Intracellular Growth ◽  
Traditional Role ◽  
Content Type ◽  
Cell Spread

SUMMARYThe entry of pathogens into nonphagocytic host cells has received much attention in the past three decades, revealing a vast array of strategies employed by bacteria and viruses. A method of internalization that has been extensively studied in the context of viral infections is the use of the clathrin-mediated pathway. More recently, a role for clathrin in the entry of some intracellular bacterial pathogens was discovered. Classically, clathrin-mediated endocytosis was thought to accommodate internalization only of particles smaller than 150 nm; however, this was challenged upon the discovery thatListeria monocytogenesrequires clathrin to enter eukaryotic cells. Now, with discoveries that clathrin is required during other stages of some bacterial infections, another paradigm shift is occurring. There is a more diverse impact of clathrin during infection than previously thought. Much of the recent data describing clathrin utilization in processes such as bacterial attachment, cell-to-cell spread and intracellular growth may be due to newly discovered divergent roles of clathrin in the cell. Not only does clathrin act to facilitate endocytosis from the plasma membrane, but it also participates in budding from endosomes and the Golgi apparatus and in mitosis. Here, the manipulation of clathrin processes by bacterial pathogens, including its traditional role during invasion and alternative ways in which clathrin supports bacterial infection, is discussed. Researching clathrin in the context of bacterial infections will reveal new insights that inform our understanding of host-pathogen interactions and allow researchers to fully appreciate the diverse roles of clathrin in the eukaryotic cell.

scholarly journals Ribosome Protection Proteins—“New” Players in the Global Arms Race with Antibiotic-Resistant Pathogens

2021 ◽  
Vol 22 (10) ◽  
pp. 5356
Author(s):  
Rya Ero ◽  
Xin-Fu Yan ◽  
Yong-Gui Gao
Keyword(s):  
Bacterial Infections ◽  
Significant Proportion ◽  
Resistance Mechanism ◽  
Inhibitory Effect ◽  
Resistance Mechanisms ◽  
Human Pathogens ◽  
Antibiotic Resistant ◽  
Long Time ◽  
Life Threatening ◽  
A Minor

Bacteria have evolved an array of mechanisms enabling them to resist the inhibitory effect of antibiotics, a significant proportion of which target the ribosome. Indeed, resistance mechanisms have been identified for nearly every antibiotic that is currently used in clinical practice. With the ever-increasing list of multi-drug-resistant pathogens and very few novel antibiotics in the pharmaceutical pipeline, treatable infections are likely to become life-threatening once again. Most of the prevalent resistance mechanisms are well understood and their clinical significance is recognized. In contrast, ribosome protection protein-mediated resistance has flown under the radar for a long time and has been considered a minor factor in the clinical setting. Not until the recent discovery of the ATP-binding cassette family F protein-mediated resistance in an extensive list of human pathogens has the significance of ribosome protection proteins been truly appreciated. Understanding the underlying resistance mechanism has the potential to guide the development of novel therapeutic approaches to evade or overcome the resistance. In this review, we discuss the latest developments regarding ribosome protection proteins focusing on the current antimicrobial arsenal and pharmaceutical pipeline as well as potential implications for the future of fighting bacterial infections in the time of “superbugs.”

scholarly journals Secretory System Components as Potential Prophylactic Targets for Bacterial Pathogens

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 892
Author(s):  
Wieslaw Swietnicki
Keyword(s):  
Small Molecules ◽  
Bacterial Infections ◽  
Bacterial Pathogens ◽  
Human Pathogens ◽  
Current Review ◽  
System Components ◽  
Secretory System

Bacterial secretory systems are essential for virulence in human pathogens. The systems have become a target of alternative antibacterial strategies based on small molecules and antibodies. Strategies to use components of the systems to design prophylactics have been less publicized despite vaccines being the preferred solution to dealing with bacterial infections. In the current review, strategies to design vaccines against selected pathogens are presented and connected to the biology of the system. The examples are given for Y. pestis, S. enterica, B. anthracis, S. flexneri, and other human pathogens, and discussed in terms of effectiveness and long-term protection.

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