The Secretome of Vibrio cholerae

Vibrio cholerae is a facultative human pathogen responsible for the cholera disease which infects millions of people worldwide each year. V. cholerae is a natural inhabitant of aquatic environments and the infection usually occurs after ingestion of contaminated water or food. The virulence factors of V. cholerae have been extensively studied in the last decades and include the cholera toxin and the coregulated pilus. Most of the virulence factors of V. cholerae belong to the secretome, which corresponds to all the molecules secreted in the extracellular environment such as proteins, exopolysaccharides, extracellular DNA or membrane vesicles. In this chapter, we review the current knowledge of the secretome of V. cholerae and its role in virulence, colonization and resistance. In the first section, we focus on the proteins secreted through conventional secretion systems. The second and third sections emphasize on the membrane vesicles and on the secretome associated with biofilms.

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Cholera Toxin Encapsulated within Several Vibrio cholerae O1 Serotype Inaba Outer Membrane Vesicles Lacks a Functional B-Subunit

Toxins ◽

10.3390/toxins11040207 ◽

2019 ◽

Vol 11 (4) ◽

pp. 207 ◽

Cited By ~ 2

Author(s):

Elnaz Rasti ◽

Angela Brown

Keyword(s):

Outer Membrane ◽

Cholera Toxin ◽

Vibrio Cholerae ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Biologically Active ◽

Host Cells ◽

Free Form ◽

Type Ii Secretion ◽

Secondary Mechanism

Cholera toxin (CT), the major virulence factor of Vibrio cholerae, is an AB5 toxin secreted through the type II secretion system (T2SS). Upon secretion, the toxin initiates endocytosis through the interaction of the B pentamer with the GM1 ganglioside receptor on small intestinal cells. In addition to the release of CT in the free form, the bacteria secrete CT in association with outer membrane vesicles (OMVs). Previously, we demonstrated that strain 569B releases OMVs that encapsulate CT and which interact with host cells in a GM1-independent mechanism. Here, we have demonstrated that OMV-encapsulated CT, while biologically active, does not exist in an AB5 form; rather, the OMVs encapsulate two enzymatic A-subunit (CTA) polypeptides. We further investigated the assembly and secretion of the periplasmic CT and found that a major fraction of periplasmic CTA does not participate in the CT assembly process and instead is continuously encapsulated within the OMVs. Additionally, we found that the encapsulation of CTA fragments in OMVs is conserved among several Inaba O1 strains. We further found that under conditions in which the amount of extracellularly secreted CT increases, the concentration of OMV-encapsulated likewise CTA increases. These results point to a secondary mechanism for the secretion of biologically active CT that does not depend on the CTB-GM1 interaction for endocytosis.

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Type III Secretion Is Essential for the Rapidly Fatal Diarrheal Disease Caused by Non-O1, Non-O139 Vibrio cholerae

mBio ◽

10.1128/mbio.00106-11 ◽

2011 ◽

Vol 2 (3) ◽

Cited By ~ 37

Author(s):

Ok S. Shin ◽

Vincent C. Tam ◽

Masato Suzuki ◽

Jennifer M. Ritchie ◽

Roderick T. Bronson ◽

...

Keyword(s):

Cholera Toxin ◽

Vibrio Cholerae ◽

Intestinal Epithelium ◽

Type Iii Secretion ◽

Diarrheal Disease ◽

Secretion Systems ◽

Content Type ◽

Type Iii ◽

Severe Diarrhea ◽

Toxin Coregulated Pilus

ABSTRACTCholera is a severe diarrheal disease typically caused by O1 serogroup strains ofVibrio cholerae. The pathogenicity of all pandemicV. choleraeO1 strains relies on two critical virulence factors: cholera toxin, a potent enterotoxin, and toxin coregulated pilus (TCP), an intestinal colonization factor. However, certain non-O1, non-O139V. choleraestrains, such as AM-19226, do not produce cholera toxin or TCP, yet they still cause severe diarrhea. The molecular basis for the pathogenicity of non-O1, non-O139V. choleraehas not been extensively characterized, but many of these strains encode related type III secretion systems (TTSSs). Here, we used infant rabbits to assess the contribution of the TTSS to non-O1, non-O139V. choleraepathogenicity. We found that all animals infected with wild-type AM-19226 developed severe diarrhea even more rapidly than rabbits infected withV. choleraeO1. UnlikeV. choleraeO1 strains, which do not damage the intestinal epithelium in rabbits or humans, AM-19226 caused marked disruptions of the epithelial surface in the rabbit small intestine. TTSS proved to be essential for AM-19226 virulence in infant rabbits; an AM-19226 derivative deficient for TTSS did not elicit diarrhea, colonize the intestine, or induce pathological changes in the intestine. Deletion of either one of the two previously identified or two newly identified AM-19226 TTSS effectors reduced but did not eliminate AM-19226 pathogenicity, suggesting that at least four effectors contribute to this strain’s virulence. In aggregate, our results suggest that the TTSS-dependent virulence in non-O1, non-O139V. choleraerepresents a new type of diarrheagenic mechanism.IMPORTANCECholera, which is caused byVibrio cholerae, is an important cause of diarrheal disease in many developing countries. The mechanisms of virulence of nonpandemic strains that can cause a diarrheal illness are poorly understood. AM-19226, like several other pathogenic, nonpandemicV. choleraestrains, carries genes that encode a type III secretion system (TTSS), but not cholera toxin (CT) or toxin coregulated pilus (TCP). In this study, we used infant rabbits to study AM-19226 virulence. Infant rabbits orally inoculated with this strain rapidly developed a fatal diarrheal disease, which was accompanied by marked disruptions of the intestinal epithelium. This strain’s TTSS proved essential for its pathogenicity, and there was no diarrhea, intestinal pathology, or colonization in rabbits infected with a TTSS mutant. The effector proteins translocated by the TTSS all appear to contribute to AM-19226 virulence. Thus, our study provides insight intoin vivomechanisms by which a novel TTSS contributes to diarrheal disease caused by nonpandemic strains ofV. cholerae.

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Pathogenic Acinetobacter: from the Cell Surface to Infinity and Beyond

Journal of Bacteriology ◽

10.1128/jb.00906-15 ◽

2015 ◽

Vol 198 (6) ◽

pp. 880-887 ◽

Cited By ~ 59

Author(s):

Brent S. Weber ◽

Christian M. Harding ◽

Mario F. Feldman

Keyword(s):

Virulence Factors ◽

Current Knowledge ◽

Multidrug Resistant ◽

Protein Glycosylation ◽

Opportunistic Pathogens ◽

Secretion Systems ◽

Content Type ◽

Bacterial Surface ◽

Acinetobacter Pittii ◽

New Strategies

The genusAcinetobacterencompasses multiple nosocomial opportunistic pathogens that are of increasing worldwide relevance because of their ability to survive exposure to various antimicrobial and sterilization agents. Among these,Acinetobacter baumannii,Acinetobacter nosocomialis, andAcinetobacter pittiiare the most frequently isolated in hospitals around the world. Despite the growing incidence of multidrug-resistantAcinetobacterspp., little is known about the factors that contribute to pathogenesis. New strategies for treating and managing infections caused by multidrug-resistantAcinetobacterstrains are urgently needed, and this requires a detailed understanding of the pathobiology of these organisms. In recent years, some virulence factors important forAcinetobactercolonization have started to emerge. In this review, we focus on several recently described virulence factors that act at the bacterial surface level, such as the capsule,O-linked protein glycosylation, and adhesins. Furthermore, we describe the current knowledge regarding the type II and type VI secretion systems present in these strains.

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The Cyclic Dipeptide Cyclo(Phe-Pro) Inhibits Cholera Toxin and Toxin-Coregulated Pilus Production in O1 El Tor Vibrio cholerae

Journal of Bacteriology ◽

10.1128/jb.00191-10 ◽

2010 ◽

Vol 192 (14) ◽

pp. 3829-3832 ◽

Cited By ~ 21

Author(s):

Xiaowen R. Bina ◽

James E. Bina

Keyword(s):

Cholera Toxin ◽

Vibrio Cholerae ◽

Virulence Factors ◽

Virulence Gene ◽

Cyclic Dipeptide ◽

Present Evidence ◽

Toxin Coregulated Pilus ◽

El Tor ◽

Virulence Regulator

ABSTRACT Cyclo(Phe-Pro) is a cyclic dipeptide produced by multiple Vibrio species. In this work, we present evidence that cyclo(Phe-Pro) inhibits the production of the virulence factors cholera toxin (CT) and toxin-coregulated pilus (TCP) in O1 El Tor Vibrio cholerae strain N16961 during growth under virulence gene-inducing conditions. The cyclo(Phe-Pro) inhibition of CT and TCP production correlated with reduced transcription of the virulence regulator tcpPH and was alleviated by overexpression of tcpPH.

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Delivery of Toxins and Effectors by Bacterial Membrane Vesicles

Toxins ◽

10.3390/toxins13120845 ◽

2021 ◽

Vol 13 (12) ◽

pp. 845

Author(s):

Adrian Macion ◽

Agnieszka Wyszyńska ◽

Renata Godlewska

Keyword(s):

Virulence Factors ◽

Pathogenic Bacteria ◽

Membrane Vesicles ◽

Cell Types ◽

Oral Bacteria ◽

Host Cells ◽

Target Cells ◽

Tissue Destruction ◽

Secretion Systems ◽

The Central Nervous System

Pathogenic bacteria interact with cells of their host via many factors. The surface components, i.e., adhesins, lipoproteins, LPS and glycoconjugates, are particularly important in the initial stages of colonization. They enable adhesion and multiplication, as well as the formation of biofilms. In contrast, virulence factors such as invasins and toxins act quickly to damage host cells, causing tissue destruction and, consequently, organ dysfunction. These proteins must be exported from the bacterium and delivered to the host cell in order to function effectively. Bacteria have developed a number of one- and two-step secretion systems to transport their proteins to target cells. Recently, several authors have postulated the existence of another transport system (sometimes called “secretion system type zero”), which utilizes extracellular structures, namely membrane vesicles (MVs). This review examines the role of MVs as transporters of virulence factors and the interaction of toxin-containing vesicles and other protein effectors with different human cell types. We focus on the unique ability of vesicles to cross the blood–brain barrier and deliver protein effectors from intestinal or oral bacteria to the central nervous system.

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Role of Cholera Toxin in Vibrio cholerae Infection in Humans - A Review

International Letters of Natural Sciences ◽

10.18052/www.scipress.com/ilns.22.22 ◽

2014 ◽

Vol 22 ◽

pp. 22-32 ◽

Cited By ~ 1

Author(s):

Partha Pal

Keyword(s):

Cholera Toxin ◽

Vibrio Cholerae ◽

Indian Subcontinent ◽

Bacterial Species ◽

Human Pathogen ◽

Watery Stool ◽

The Past ◽

Contaminated Food ◽

El Tor

Vibrio cholerae, the causative agent of Asiatic cholera, is a gram-negative motile bacterial species acquired via oral ingestion of contaminated food or water sources. Cholera has spread from the Indian subcontinent where it is endemic to involve nearly the whole world seven times during the past 185 years. V. cholerae serogroup O1, biotype El Tor, has moved from Asia to cause pandemic disease in Africa and South America during the past 35 years. A new serogroup, O139, appeared in south Asia in 1992, has become endemic there, and threatens to start the next pandemic. The facultative human pathogen V. cholerae represents a paradigm that evolved from environmental non-pathogenic strains by acquisition of virulence genes. The major virulence factors of V. cholerae, cholera toxin (CTX) encoded by the ctxAB genes residing in the genome of filamentous lysogenic bacteriophage (CTXɸ) and toxin coregulated pilus (TCP) encoded by vibrio pathogenicity island (VPI). CTX, a potent stimulator of adenylate cyclase, causes the intestine to secrete watery fluid rich in sodium, bicarbonate, and potassium, in volumes far exceeding the intestinal absorptive capacity, by ADP-ribosylation of the alpha subunit of the GTP-binding protein. Thus intestinal infection with V. cholerae results in the loss of large volumes of watery stool, leading to severe and rapidly progressing dehydration and shock. Without adequate and appropriate rehydration therapy, severe cholera kills about half of affected individuals. Today, cholera still remains a burden mainly for underdeveloped countries, which cannot afford to establish or to maintain necessary hygienic and medical facilities. During the last three decades, intensive research has been undertaken to unravel the virulence properties and to study the epidemiology of this significant human pathogen. This review provides an overview of the role of CTX in the occurrence of this disease in humans.

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Virulence of Cholera Toxin Gene-Positive Vibrio cholerae Non-O1/non-O139 Strains Isolated From Environmental Water in Kolkata, India

Frontiers in Microbiology ◽

10.3389/fmicb.2021.726273 ◽

2021 ◽

Vol 12 ◽

Author(s):

Eizo Takahashi ◽

Sadayuki Ochi ◽

Tamaki Mizuno ◽

Daichi Morita ◽

Masatomo Morita ◽

...

Keyword(s):

Cholera Toxin ◽

Vibrio Cholerae ◽

Virulence Factors ◽

Culture Supernatant ◽

Diarrheal Disease ◽

Histopathological Examination ◽

Pond Water ◽

Volume Of Fluid ◽

Toxin Gene ◽

Intestinal Loop

Cholera toxin (CT)-producing Vibrio cholerae O1 and O139 cause acute diarrheal disease and are proven etiological agents of cholera epidemics and pandemics. On the other hand, V. cholerae non-O1/non-O139 are designated as non-agglutinable (NAG) vibrios and are not associated with epidemic cholera. The majority of NAG vibrios do not possess the gene for CT (ctx). In this study, we isolated three NAG strains (strains No. 1, 2, and 3) with ctx from pond water in Kolkata, India, and examined their pathogenic properties. The enterotoxicity of the three NAG strains in vivo was examined using the rabbit ileal intestinal loop test. Strain No. 1 induced the accumulation of fluid in the loop, and the volume of fluid was reduced by simultaneous administration of anti-CT antiserum into the loop. The volume of fluid in the loop caused by strains No. 2 and 3 was small and undetectable, respectively. Then, we cultured these three strains in liquid medium in vitro at two temperatures, 25°C and 37°C, and examined the amount of CT accumulated in the culture supernatant. CT was accumulated in the culture supernatant of strain No.1 when the strain was cultured at 25°C, but that was low when cultured at 37°C. The CT amount accumulated in the culture supernatants of the No. 2 and No. 3 strains was extremely low at both temperature under culture conditions examined. In order to clarify the virulence properties of these strains, genome sequences of the three strains were analyzed. The analysis showed that there was no noticeable difference among three isolates both in the genes for virulence factors and regulatory genes of ctx. However, vibrio seventh pandemic island-II (VSP-II) was retained in strain No. 1, but not in strains No. 2 or 3. Furthermore, it was revealed that the genotype of the B subunit of CT in strain No. 1 was type 1 and those of strains No. 2 and 3 were type 8. Histopathological examination showed the disappearance of villi in intestinal tissue exposed to strain No. 1. In addition, fluid accumulated in the loop due to the action of strain No. 1 had hemolytic activity. This indicated that strain No. 1 may possesses virulence factors to induce severe syndrome when the strain infects humans, and that some strains of NAG vibrio inhabiting pond water in Kolkata have already acquired virulence, which can cause illness in humans. There is a possibility that these virulent NAG vibrios, which have acquired genes encoding factors involved in virulence of V. cholerae O1, may emerge in various parts of the world and cause epidemics in the future.

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Secretion Systems in Gram-Negative Bacterial Fish Pathogens

Frontiers in Microbiology ◽

10.3389/fmicb.2021.782673 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sophanit Mekasha ◽

Dirk Linke

Keyword(s):

Virulence Factors ◽

Infection Process ◽

Host Cells ◽

Secretion Systems ◽

Fish Pathogens ◽

Gram Negative ◽

Different Types ◽

Single Protein ◽

Available Information ◽

Extracellular Environment

Bacterial fish pathogens are one of the key challenges in the aquaculture industry, one of the fast-growing industries worldwide. These pathogens rely on arsenal of virulence factors such as toxins, adhesins, effectors and enzymes to promote colonization and infection. Translocation of virulence factors across the membrane to either the extracellular environment or directly into the host cells is performed by single or multiple dedicated secretion systems. These secretion systems are often key to the infection process. They can range from simple single-protein systems to complex injection needles made from dozens of subunits. Here, we review the different types of secretion systems in Gram-negative bacterial fish pathogens and describe their putative roles in pathogenicity. We find that the available information is fragmented and often descriptive, and hope that our overview will help researchers to more systematically learn from the similarities and differences between the virulence factors and secretion systems of the fish-pathogenic species described here.

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Staphylococcal Biofilms: Challenges and Novel Therapeutic Perspectives

Antibiotics ◽

10.3390/antibiotics10020131 ◽

2021 ◽

Vol 10 (2) ◽

pp. 131

Author(s):

Christian Kranjec ◽

Danae Morales Angeles ◽

Marita Torrissen Mårli ◽

Lucía Fernández ◽

Pilar García ◽

...

Keyword(s):

Virulence Factors ◽

Current Knowledge ◽

Three Dimensional ◽

Treatment Strategies ◽

Extracellular Dna ◽

Human Immune System ◽

Antibiotic Resistant ◽

New Treatment ◽

Biofilm Development ◽

Hospital Acquired

Staphylococci, like Staphylococcus aureus and S. epidermidis, are common colonizers of the human microbiota. While being harmless in many cases, many virulence factors result in them being opportunistic pathogens and one of the major causes of hospital-acquired infections worldwide. One of these virulence factors is the ability to form biofilms—three-dimensional communities of microorganisms embedded in an extracellular polymeric matrix (EPS). The EPS is composed of polysaccharides, proteins and extracellular DNA, and is finely regulated in response to environmental conditions. This structured environment protects the embedded bacteria from the human immune system and decreases their susceptibility to antimicrobials, making infections caused by staphylococci particularly difficult to treat. With the rise of antibiotic-resistant staphylococci, together with difficulty in removing biofilms, there is a great need for new treatment strategies. The purpose of this review is to provide an overview of our current knowledge of the stages of biofilm development and what difficulties may arise when trying to eradicate staphylococcal biofilms. Furthermore, we look into promising targets and therapeutic methods, including bacteriocins and phage-derived antibiofilm approaches.

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Campylobacter sp.: Pathogenicity factors and prevention methods—new molecular targets for innovative antivirulence drugs?

Applied Microbiology and Biotechnology ◽

10.1007/s00253-020-10974-5 ◽

2020 ◽

Vol 104 (24) ◽

pp. 10409-10436

Author(s):

Vanessa Kreling ◽

Franco H. Falcone ◽

Corinna Kehrenberg ◽

Andreas Hensel

Keyword(s):

Virulence Factors ◽

Current Knowledge ◽

Bacterial Species ◽

Bacterial Load ◽

Phase Variation ◽

Host Cells ◽

Poultry Production ◽

Secretion Systems ◽

Effective Phase ◽

Prevention Methods

Abstract Infections caused by bacterial species from the genus Campylobacter are one of the four main causes of strong diarrheal enteritis worldwide. Campylobacteriosis, a typical food-borne disease, can range from mild symptoms to fatal illness. About 550 million people worldwide suffer from campylobacteriosis and lethality is about 33 million p.a. This review summarizes the state of the current knowledge on Campylobacter with focus on its specific virulence factors. Using this knowledge, multifactorial prevention strategies can be implemented to reduce the prevalence of Campylobacter in the food chain. In particular, antiadhesive strategies with specific adhesion inhibitors seem to be a promising concept for reducing Campylobacter bacterial load in poultry production. Antivirulence compounds against bacterial adhesion to and/or invasion into the host cells can open new fields for innovative antibacterial agents. Influencing chemotaxis, biofilm formation, quorum sensing, secretion systems, or toxins by specific inhibitors can help to reduce virulence of the bacterium. In addition, the unusual glycosylation of the bacterium, being a prerequisite for effective phase variation and adaption to different hosts, is yet an unexplored target for combating Campylobacter sp. Plant extracts are widely used remedies in developing countries to combat infections with Campylobacter. Therefore, the present review summarizes the use of natural products against the bacterium in an attempt to stimulate innovative research concepts on the manifold still open questions behind Campylobacter towards improved treatment and sanitation of animal vectors, treatment of infected patients, and new strategies for prevention. Key points • Campylobacter sp. is a main cause of strong enteritis worldwide. • Main virulence factors: cytolethal distending toxin, adhesion proteins, invasion machinery. • Strong need for development of antivirulence compounds.

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