Posts Tagged ‘Bacteria’

Helicobacter pylori and stomach lesions

Friday, July 18th, 2014

Helicobacter pylori Helicobacter pylori infection promotes stomach ulcers and cancer. How H. pylori initially interacts with and irritates gastric tissue is not well understood.

A new article describes how H. pylori rapidly identifies and colonizes sites of minor injuries in the stomach, almost immediately interferes with healing at those injury sites, and so promotes sustained gastric damage.

Smoking, alcohol, excessive salt intake, and non-steroidal anti-inflammatory drugs cause damage to the tissue lining the stomach, and are associated with stomach ulcers. Scientists asked whether H. pylori can sense and respond to such damage and so contribute to disease development.

The researchers induced small stomach lesions in mice and observed that H. pylori bacteria can rapidly detect the injury site and navigate toward it. Within minutes, accumulation of bacteria interferes with repair of the tissue damage.

To examine how the bacteria accomplish this, the researchers also studied mice with larger stomach lesions (ulcers) that were subsequently infected with H. pylori. They found that H. pylori preferentially colonizes stomach tissue at injured ulcer sites, and there impairs healing of the damaged tissue. Selective colonization requires both bacterial motility and chemotaxis (the ability to change direction of movement in response to environmental cues), and higher levels of bacterial accumulation cause slower healing. However, when extremely high levels of immotile or chemotaxis-deficient bacteria are added to damaged tissue, they can also slow healing.

While the signals that attract H. pylori (but not benign stomach bacteria) toward injured tissue are not yet known, the researchers hope that their ability to rapidly measure H. pylori accumulation at the injured site now provides an experimental set-up to determine the factor(s) involved.

 

Motility and Chemotaxis Mediate the Preferential Colonization of Gastric Injury Sites by Helicobacter pylori. (2014) PLoS Pathog 10(7): e1004275. doi:10.1371/journal.ppat.1004275

 

Mosquitoes infected Wolbachia more likely to transmit West Nile virus

Friday, July 11th, 2014

Wolbachia Mosquitoes infected with the bacteria Wolbachia are more likely to become infected with West Nile virus and more likely to transmit the virus to humans, according to a new paper.

Previous research has shown that Wolbachia – a genus of bacteria that live in insects – renders mosquitoes resistant to pathogen infection, preventing the mosquitoes from infecting humans with the pathogens. As a result, researchers are currently releasing Wolbachia-infected mosquitoes into the wild as part of a strategy to control Dengue virus. They also are investigating Wolbachia as a possible control strategy for malaria.

Expecting to find that Wolbachia would block infection by West Nile virus in the same way that it blocks Dengue virus, injected the Wolbachia into adult female Culex tarsalis mosquitoes, allowed them to grow, then fed the mosquitoes a meal of blood infected with West Nile virus. Wolbachia infection did not block West Nile virus in the mosquito, instead these mosquitoes had significantly higher West Nile virus infection rates seven days after they were fed the infected blood. Wolbachia infection allowed the mosquitoes to become infected with West Nile virus faster than the controls.

These results point to a previously unforeseen complication – the possibility that mosquitoes rendered resistant to one pathogen by Wolbachia infection might become better vectors of an alternative pathogen. The team also found that West Nile virus enhancement in the Wolbachia-infected mosquitoes occurred in conjunction with the suppression of genes associated with the mosquitoes’ anti-viral immune response.

This is the first study to demonstrate that Wolbachia can enhance a human pathogen in a mosquito. The results suggest that caution should be used when releasing Wolbachia-infected mosquitoes into nature to control vector-borne diseases of humans.

 

Wolbachia Enhances West Nile Virus (WNV) Infection in the Mosquito Culex tarsalis. (2014) PLoS Negl Trop Dis 8(7): e2965. doi:10.1371/journal.pntd.0002965
Novel strategies are required to control mosquitoes and the pathogens they transmit. One attractive approach involves maternally inherited endosymbiotic Wolbachia bacteria. After artificial infection with Wolbachia, many mosquitoes become refractory to infection and transmission of diverse pathogens. We evaluated the effects of Wolbachia (wAlbB strain) on infection, dissemination and transmission of West Nile virus (WNV) in the naturally uninfected mosquito Culex tarsalis, which is an important WNV vector in North America. After inoculation into adult female mosquitoes, Wolbachia reached high titers and disseminated widely to numerous tissues including the head, thoracic flight muscles, fat body and ovarian follicles. Contrary to other systems, Wolbachia did not inhibit WNV in this mosquito. Rather, WNV infection rate was significantly higher in Wolbachia-infected mosquitoes compared to controls. Quantitative PCR of selected innate immune genes indicated that REL1 (the activator of the antiviral Toll immune pathway) was down regulated in Wolbachia-infected relative to control mosquitoes. This is the first observation of Wolbachia-induced enhancement of a human pathogen in mosquitoes, suggesting that caution should be applied before releasing Wolbachia-infected insects as part of a vector- borne disease control program.

 

Honing in on enteric fever

Thursday, July 3rd, 2014

Salmonella typhimurium Enteric fever (typhoid), affects about 22 million people and causes about 200,000 deaths every year, according to conservative estimates. Enteric fever is spread by bacteria belonging to the Salmonella genus, with two sub-species – Salmonella Typhi and Salmonella Paratyphi A – being responsible for most cases of the disease. And although the number of cases of enteric fever has fallen significantly over recent decades, there is a clear need for a diagnostic test for Salmonella that is rapid, affordable and accurate. It is important to be able to distinguish between enteric fever caused by Salmonella Typhi and enteric fever caused by Salmonella Paratyphi A in order to ensure that the correct drugs are prescribed and to combat the development of antibiotic resistance.

The application of metabolomics is relatively new in infectious diseases research compared to the application of genomics and proteomics. Despite this, screening the metabolome in blood plasma has identified useful prognostic profiles of several diseases, including sepsis. One of the major benefits of this technique is that it utilizes a pattern of biomarkers (that is, the various metabolites), as opposed to relying on just one host biomarker, as has been the focus of previous approaches.

A new paper in eLife applies this promising new approach to this challenge. Instead of trying to detect Salmonella in the blood during infection, they used a technique called metabolomics. The basic idea of this approach is that infection leads to metabolic changes, such that a person with enteric fever (or any infection) could have a profile of metabolites in their blood that is different to the metabolite profile of a healthy person. The challenge, therefore, is to identify a ‘metabolic fingerprint’ that can be used to detect enteric fever with high levels of sensitivity and specificity.

 

eLife: Host-pathogen interactions: Honing in on enteric fever

 

Antibiotics – let’s clean up our act

Tuesday, May 27th, 2014
East Penobscot Bay, Maine by Jason Mrachina

Beautiful Penobscot Bay

Last week I wrote about a new type of antibiotic which targets bacteria in biiofilms. Ron Huber (Friends of Penobscot Bay) left an interesting comment:

“Of concern to us as … conservationists is whether these broad spectrum peptide antibiotics are digested by standard sewage treatment plant technology or pass essentially unscathed through the patient and the wastewater treatment facility and into the receiving waters. We want and absolutely need vigorous marine biofilms, an at a variety of scales and species mixes, if we are to have mussels, lobsters, clams, oysters and other organisms at all… Sewage plants are adaptable; can something be added that would bind with the antibiotic or otherwise render it harmless before discharge We would really like to know!” (full comment)

There has been much discussion about the misuse of antibiotics in agriculture and the impact of such careless use on human health. There has been rather less public discuss on on the environmental impact of antibiotic resides in sewage effluent. So apart from the environment, do antibiotic residues which survive sewage pose a risk to human health?

Yes they do (Selective pressure of antibiotic pollution on bacteria of importance to public health. (2012) Environmental health perspectives, 120(8), 1100). Consequently, there is a fair amount of research being carried out in this area – it just doesn’t make it into the press. Standard sewage treatment processes reduce but don’t eliminate antibiotics in sewage and these can contribute to the evolution and persistence of resistant pathogens in the environment (The effectiveness of sewage treatment processes to remove faecal pathogens and antibiotic residues. (2012) Journal of Environmental Science and Health, Part A, 47(2), 289-297). This paper shows that more advanced treatments such as membrane bioreactor technology reduce antibiotic resides more than the conventional activated sludge process, but still do not eliminate them completely from the wastewater.

What effect do these residues have on the environment? We really don’t know, but it seems likely that legislators are more likely to respond to the costs involved in improving sewage treatment via the human health argument rather than the environmental argument. Sad, but that’s how it is. As far as the new peptide antibiotic I wrote about last week is concerned, we simply don’t know yet how it will be affected by sewage treatment processes. But should we be worried about such criteria when introducing new compounds for therapeutic use? Yes we should. Of course, it’s not just antibiotics we have to worry about.

 

New Broad-Spectrum Peptide Antibiotic Targets Biofilms

Friday, May 23rd, 2014

Biofilm Biofilms are structured multicellular communities of microorganisms associated with surfaces. They have been widely studied, in part because they cause at least 65% of all human infections, being particularly prevalent in device-related infections, on body surfaces and in chronic infections. Biofilms represent a major health problem worldwide due to their resistance to host defence mechanisms and to conventional antimicrobials, which generally target free-swimming (planktonic) bacteria. So there is an urgent need to identify compounds that effectively clear biofilm-related infections.

A new report in PLoS Pathogens identifies a potent anti-biofilm peptide that works by blocking (p)ppGpp, an important signal in biofilm development. The peptide had at least three effects on biofilms, which might reflect the role of (p)ppGpp in cells. First when added prior to initiation of biofilms it prevented biofilm formation, second it specifically led to cell death in biofilms at concentrations that were not lethal for planktonic (free-swimming) cells, and third it promoted biofilm dispersal even in maturing (2-day old) biofilms. This anti-biofilm strategy represents a significant advance in the search for new agents that specifically target many bacterial species.

 

Broad-Spectrum Anti-biofilm Peptide That Targets a Cellular Stress Response. (2014) PLoS Pathog 10(5): e1004152. doi:10.1371/journal.ppat.1004152
Bacteria form multicellular communities known as biofilms that cause two thirds of all infections and demonstrate a 10 to 1000 fold increase in adaptive resistance to conventional antibiotics. Currently, there are no approved drugs that specifically target bacterial biofilms. Here we identified a potent anti-biofilm peptide 1018 that worked by blocking (p)ppGpp, an important signal in biofilm development. At concentrations that did not affect planktonic growth, peptide treatment completely prevented biofilm formation and led to the eradication of mature biofilms in representative strains of both Gram-negative and Gram-positive bacterial pathogens including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, methicillin resistant Staphylococcus aureus, Salmonella Typhimurium and Burkholderia cenocepacia. Low levels of the peptide led to biofilm dispersal, while higher doses triggered biofilm cell death. We hypothesized that the peptide acted to inhibit a common stress response in target species, and that the stringent response, mediating (p)ppGpp synthesis through the enzymes RelA and SpoT, was targeted. Consistent with this, increasing (p)ppGpp synthesis by addition of serine hydroxamate or over-expression of relA led to reduced susceptibility to the peptide. Furthermore, relA and spoT mutations blocking production of (p)ppGpp replicated the effects of the peptide, leading to a reduction of biofilm formation in the four tested target species. Also, eliminating (p)ppGpp expression after two days of biofilm growth by removal of arabinose from a strain expressing relA behind an arabinose-inducible promoter, reciprocated the effect of peptide added at the same time, leading to loss of biofilm. NMR and chromatography studies showed that the peptide acted on cells to cause degradation of (p)ppGpp within 30 minutes, and in vitro directly interacted with ppGpp. We thus propose that 1018 targets (p)ppGpp and marks it for degradation in cells. Targeting (p)ppGpp represents a new approach against biofilm-related drug resistance.

 

CRISPRs and bacterial pathogenesis

Friday, April 25th, 2014

CRISPRs have taken microbiology by storm in the last few years. If you haven’t caught up yet, there’s a short introductory primer here. CRISPRs (or CRISPR-Cas systems as they are now tending to be called) protect bacteria from infection by bacteriophages and other mobile genetic elements including plasmids. Because they are barriers to horizontal gene transfer, CRISPRs reduce the speed of eviolution of pathogens. but CRISPRs can increase also virulence by modulating gene expression. A recent short review discusses the “love-hate relationship between bacterial pathogens and their CRISPR-Cas systems“.

CRISPR-Cas system

Impact of CRISPR immunity on the emergence and virulence of bacterial pathogens. (2014) Current Opinion in Microbiology, 17, 82-90.
CRISPR-Cas systems protect prokaryotes from viruses and plasmids and function primarily as an adaptive immune system in these organisms. Recent discoveries, however, revealed unexpected roles for CRISPR loci as barriers to horizontal gene transfer and as modulators of gene expression. We review how both of these functions of CRISPR-Cas systems can affect the emergence and virulence of human bacterial pathogens.

 

 

Exploiting bacteriophages for human health

Thursday, March 27th, 2014

Exploiting bacteriophages for human health Whenever I write about phage therapy – using bacteriophages to treat bacterial infections – readers get overly enthusiastic about injecting patients with phages to produce a miracle cure. Look at it this way – that hasn’t worked for the last 100 years and it’s not likely to suddenly start working now. This short review is worth reading because it takes a much more thoughtful and holistic approach to the idea of phage therapy than the simple minded “phage as wonder cure” idea.

Exploiting gut bacteriophages for human health. Trends Microbiol. 20 Mar 2014 pii: S0966-842X(14)00045-6. doi: 10.1016/j.tim.2014.02.010
The human gut contains approximately 1015 bacteriophages (the ‘phageome’), probably the richest concentration of biological entities on earth. Mining and exploiting these potential ‘agents of change’ is an attractive prospect. For many years, phages have been used to treat bacterial infections in humans and more recently have been approved to reduce pathogens in the food chain. Phages have also been studied as drug or vaccine delivery vectors to help treat and prevent diseases such as cancer and chronic neurodegenerative conditions. Individual phageomes vary depending on age and health, thus providing a useful biomarker of human health as well as suggesting potential interventions targeted at the gut microbiota.

Microbiology Today – microbial superheroes

Thursday, February 27th, 2014

The latest issue of Microbiology Today – microbial superheroes is available for download from http://www.sgm.ac.uk/en/publications/microbiology-today/current-issue.cfm

Microbiology Today - microbial superheroes

In this issue:

The shape-shifting superhero: Dictyostelium discoideum
This social amoeba has superhero, shape-shifting qualities, and is able to switch between a unicellular and a multicellular existence.

Diatoms: glass-dwelling dynamos
Superheroes have a reputation for being larger than life, but it is the unseen micro- organisms such as diatoms that can have a substantial impact on our lives.

The immortal, halophilic superhero: Halobacterium salinarum – a long-lived poly-extremophile
Halobacterium salinarum is an extremophile superhero on at least three counts: how are its extreme halophily, radiation resistance and longevity interconnected?

Heroic exertion of radiation-resistant extremophiles
An overview of ‘super’ radiation-resistant extremophiles and their potential uses in biotechnology and medicine.

Herpes simplex virus – master of disguise and invisibility
Invisibility would probably be high on anyone’s wish list of superpowers. But HSV has got there first.

 

Quorum Sensing Genes Discovered in a Bacteriophage

Thursday, January 30th, 2014

phiCDHM1 Some groundbreaking new research from my Leicester colleagues that’s too good to resist blogging about:

The incorporation of host DNA into phage genomes occurs across diverse bacteria, and acquisition of bacterial genes facilitates phage evolution. Although small, phage genomes have a high proportion of coding sequence relative to their size. The extent by which virus genomes can increase is constrained physically by the dimensions of their virion particles in which their DNA is packaged, by fitness costs associated with phage production, and by their packaging strategy. Although genetic material can be acquired via transduction and during DNA packaging, phage genomes are considered to be highly reduced and non-beneficial genes are lost through selective evolution. Therefore, discoveries of bacterial gene homologs in addition to the “core” phage genome are interesting, as is the diverse nature of these host associated genes.

Clostridium difficile is a major pathogen in healthcare settings, causing antibiotic associated diarrheal disease which can be fatal. Novel strains continue to emerge in clinical settings, and potential reservoirs of the bacterium include asymptomatic humans, wild and domesticated animals, and the natural environment. C. difficile pathogenicity can also be altered by the differential expression of their virulence genes, controlled via quorum sensing (QS) which is a form of bacterial communication. Through quorum sensing, cells communicate to the surrounding population via the release and detection of signalling molecules which elicit a physiological response. This paper describes the discivery of homologs of QS genes in a phage of C. difficile.

While the action and consequences of these phage QS genes is unclear, their presence and transcription during infection in a lysogenic and lytic background presents an exciting method by which phages can manipulate their hosts.

 

What Does the Talking?: Quorum Sensing Signalling Genes Discovered in a Bacteriophage Genome. (2014) PLoS ONE 9(1): e85131. doi:10.1371/journal.pone.0085131
The transfer of novel genetic material into the genomes of bacterial viruses (phages) has been widely documented in several host-phage systems. Bacterial genes are incorporated into the phage genome and, if retained, subsequently evolve within them. The expression of these phage genes can subvert or bolster bacterial processes, including altering bacterial pathogenicity. The phage phiCDHM1 infects Clostridium difficile, a pathogenic bacterium that causes nosocomial infections and is associated with antibiotic treatment. Genome sequencing and annotation of phiCDHM1 shows that despite being closely related to other C. difficile myoviruses, it has several genes that have not been previously reported in any phage genomes. Notably, these include three homologs of bacterial genes from the accessory gene regulator (agr) quorum sensing (QS) system. These are; a pre-peptide (AgrD) of an autoinducing peptide (AIP), an enzyme which processes the pre-peptide (AgrB) and a histidine kinase (AgrC) that detects the AIP to activate a response regulator. Phylogenetic analysis of the phage and C. difficile agr genes revealed that there are three types of agr loci in this species. We propose that the phage genes belonging to a third type, agr3, and have been horizontally transferred from the host. AgrB and AgrC are transcribed during the infection of two different strains. In addition, the phage agrC appears not to be confined to the phiCDHM1 genome as it was detected in genetically distinct C. difficile strains. The discovery of QS gene homologs in a phage genome presents a novel way in which phages could influence their bacterial hosts, or neighbouring bacterial populations. This is the first time that these QS genes have been reported in a phage genome and their distribution both in C. difficile and phage genomes suggests that the agr3 locus undergoes horizontal gene transfer within this species.