MicrobiologyBytes

An unfailing observation over the past 70 years is that resistance to all antibiotics emerges eventually after use in the clinic. Where does this resistance come from? Recent work has shown that antibiotic resistance genes are common in metagenomes of ancient sediments. This prevalence of resistance, well before the use of antibiotics, denotes the importance of taking microbial chemical ecology and deep metagenomic profiling into account in the development and use of antibiotics.

Antibiotic resistance is ancient: implications for drug discovery. Trends Microbiol. 25 Jan 2012

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First it was foot and mouth virus.
Then it was bluetongue virus.
Now it is Schmallenberg virus.
So here’s 10 things you didn’t know about Schmallenberg virus:

1. Schmallenberg virus was first isolated in Schmallenberg, Germany, in November 2011.
2. Schmallenberg virus is a Bunyavirus, one of a large group of of negative-stranded RNA viruses.
3. Why should I care? In cows, Schmallenberg virus causes fever and a drastic reduction in milk production. In sheep it causes congenital malformations and stillborn lambs (also stillborn calves in cows).
4. Schmallenberg virus was first identifed in the UK on 23rd January 2012.
5. Like Bluetongue, Schmallenberg virus is transmitted by midges (Culicoides spp.), which means we will be unlikely to be able to eradicate it – vaccination of anaimals is the only likely effective response.
6. Where did Schmallenberg virus come from? The virus genome is most closely related to sequences of a different Orthobunyavirus called Shamonda virus which belongs to the so-called Simbu serogroup known to infect ruminants and be transmitted by midges. In other words, it has form. But whether it is newly evolved (unlikely) or just newly discovered we don’t yet know.
7. How did Schmallenberg virus reach the UK? We don’t know. It could have been due to animal movements, but since it was first identifed in eastern England, it’s possible that it arrived in midges travelling under their own steam.
8. Is Schmallenberg virus going to spread to other parts of the UK and other countries? Yes, you can bet on that (just like bluetongue did).
9. Can I catch Schmallenberg virus? Honest answer: We don’t know. Possibly, but there have been no reports of human illness from areas where the virus is known to exist, so I wouldn’t worry too much.
10. Where can I find the latest news about Schmallenberg virus? Right here.
11. OK, one last time, why should I care? Because Schmallenberg virus is going to cost European and probably worldwide ecomonies millions of pounds. And that will affect you.

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Traditional approaches to phage therapy rely on the ability of viruses to kill their bacterial prey. However, the narrow host range or most bacteriophages and the ability of bacteria to become resistant to infection mean that in practice, using phage to simply replace antibiotics is not feasible. We need smarter approaches, which is where a recent paper comes in. Using phages to engineer sensitivity to antibiotics is a promising approach, but whether this proof-of-principle experiment ever makes it to the clinic is another matter.

Reversing bacterial resistance to antibiotics by phage-mediated delivery of dominant sensitive genes. (2011)Appl. Environ. Microbiol. 23 Nov 2011 doi: 10.1128/AEM.05741-11
Pathogen resistance to antibiotics is a rapidly growing problem, leading to an urgent need for novel antimicrobial agents. Unfortunately, development of new antibiotics faces numerous obstacles, and a method that will resensitize pathogens to approved antibiotics therefore holds key advantages. We present a proof-of-principle for a system that restores antibiotic efficiency by reversing pathogen resistance. This system uses temperate phages to introduce, by lysogenization, genes rpsL and gyrA conferring sensitivity in a dominant fashion to two antibiotics, streptomycin and nalidixic acid, respectively. Unique selective pressure is generated to enrich for bacteria that harbor the phages encoding the sensitizing constructs. This selection pressure is based on a toxic compound, tellurite, and therefore does not forfeit any antibiotic for the sensitization procedure. We further demonstrate a possible way of reducing undesirable recombination events by synthesizing dominant sensitive genes with major barriers to homologous recombination. Such synthesis does not significantly reduce the gene’s sensitization ability. Unlike conventional bacteriophage therapy, the system does not rely on the phage’s ability to kill pathogens in the infected host, but instead, to deliver genetic constructs into the bacteria, and thus render them sensitive to antibiotics prior to host infection. We believe that transfer of the sensitizing cassette by the constructed phages will significantly enrich for antibiotic-treatable pathogens on hospital surfaces. Broad usage of the proposed system, in contrast to antibiotics and phage therapy, will potentially change the nature of nosocomial infections toward being more susceptible to antibiotics rather than more resistant.

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Cystic fibrosis is caused by mutations in the CFTR gene leading to a disrupted chloride channel. It is well established that the greatest contributor to patient morbidity and mortality is chronic lung disease, caused by a constant cycle of infection and inflammation throughout the patient’s life. The CFTR mutation leads to defective regulation of chloride and sodium, resulting in increased water absorption, depletion of airway surface liquid and dehydrated mucous. Consequently, the purulent sputum and mucus plugs together with an ineffective inflammatory response, all contribute to the chronic infections that are central to CF lung disease. From early childhood, CF patients experience recurrent pulmonary infections from a range of pathogens.

In spite of intensive antibiotic therapy, certain organisms persist, leading to pulmonary exacerbations, hospitalizations and patient death. These include Pseudomonas aeruginosa, Burkholderia cepacia complex (Bcc) and Achromobacter xylosoxidans, with Bcc being the most problematic. It was recently demonstrated that chronic colonisation by Bcc resulted in a greater lung function decline than by the other two pathogens. CF patients are also susceptible to colonisation by other pathogens, including Staphylococcus aureus (both methicillin-resistant and sensitive), genus Pandoraea, Stenotrophomonas maltophilia and non-tuberculous Mycobacteria, although the role of these latter four pathogens in CF lung disease is unclear. Furthermore, the identification of high levels of anaerobic organisms in CF sputum has added to the complex microbial population in the CF lung. These CF-associated anaerobes were not susceptible to antibiotics with known efficacy against anaerobes and the clinical significance of anaerobes in CF is not yet fully understood.

Bacterial host interactions in cystic fibrosis. Curr Opin Microbiol. Dec 1 2011
Chronic infection is a hallmark of cystic fibrosis (CF) and the main contributor to morbidity. Microbial infection in CF is complex, due to the number of different species that colonise the CF lung. Their colonisation is facilitated by a host response that is impaired or compromised by highly viscous mucous, zones of hypoxia and the lack of the cystic fibrosis transmembrane regulator (CFTR). Successful dominant CF pathogens combine an effective arsenal to establish infection and counter-attack the host response, together with an ability to adapt readily to an unfavourable environment. Hypermutability is common among CF pathogens facilitating adaptation and as the host response persists, progressive destruction of the normal architecture of lung tissue ensues with catastrophic consequences for the host.

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Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host-encoded cellular prion protein, PrPC. They have occurred in a wide range of mammalian species including human. Human prion diseases can arise sporadically, be hereditary or be acquired. Sporadic human prion diseases include Cruetzfeldt-Jacob disease (CJD), fatal insomnia and variably protease-sensitive prionopathy. Genetic or familial prion diseases are caused by autosomal dominantly inherited mutations in the gene encoding for PrPC and include familial or genetic CJD, fatal familial insomnia and Gerstmann-Straussler-Scheinker syndrome. Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD and a new variant form of CJD that was transmitted to humans from affected cattle via meat consumption especially brain. This review presents information on the epidemiology, etiology, clinical assessment, neuropathology and public health concerns of human prion diseases. The role of the PrP encoding gene (PRNP) in conferring susceptibility to human prion diseases is also discussed.

An overview of human prion diseases. (2011) Virology Journal 8: 559 doi:10.1186/1743-422X-8-559

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It was my privilege to work with Phil Minor during my PhD. 25 years later (gulp), Phil looks back and forward to the polio endgame.

The Polio-Eradication programme and issues of the end game. J Gen Virol. Nov 29 2011
Poliovirus causes paralytic poliomyelitis, an ancient disease of humans that became a major public health issue in the 20th century. The primary site of infection is the gut where virus replication is entirely harmless; the two very effective vaccines developed in the 1950s (Oral Polio Vaccine, or OPV and Inactivated Polio Vaccine, or IPV) induce humoral immunity which prevents viraemic spread and disease. The success of vaccination in developing countries and in middle income countries encouraged the World Health Organization to commit itself to an eradication programme which has made great advances. The features of the infection including its largely silent nature and the ability of the live vaccine (OPV) to evolve and change in vaccine recipients and their contacts make eradication particularly challenging. Understanding the pathogenesis and virology of the infections is of major significance as the programme reaches its conclusion.

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The delightful NCBI ROFL carried this item recently. Certainly something to think about over the “festive” season.

Scent Recognition of Infected Status in Humans. J Sex Med. Dec 6 2011. doi: 10.1111/j.1743-6109.2011.02562.x
There is a body of experimental evidence that mice and rats use chemical signals to avoid sexual contact with infected conspecifics. In contrast to animals, body scent of sick humans is employed only in medical diagnostics. A modification of human body odor, due to an infection, has not been studied as a potential signal for choice of a sexual partner. It might, however, be especially important for sexually transmitted infections (STI) because many such infections have no obvious external manifestations.
Aim: In this study, we have investigated odor pleasantness of young men infected with gonorrhea, Neisseria gonorrhoeae.
Methods:We collected armpit sweat and saliva from young men (17-25 years old) belonging to three groups: healthy persons (N=16), young men infected with gonorrhea, Neisseria gonorrhoeae (N=13), and persons recovered due to specific therapy (N=5). The sweat samples odor was then assessed by healthy young women (17-20 years old). Concentrations of cortisol, testosterone, immunoglobulin A (IgA), and immunoglobulin G (IgG) were measured in saliva by means of enzyme-linked immunosorbent assay.
Main Outcome Measures: Subjective rates of odor pleasantness, association of scent of armpit sweat with odor descriptors, stepwise regression of odor pleasantness and salivary cortisol, testosterone, IgA, and IgG. Results: The odor from infected individuals was reported as less pleasant in comparison with the odor of healthy and recovered young men. The scent of infected men was more frequently associated by raters with the descriptor “putrid.” Odor pleasantness of the male sweat correlated negatively with concentration of the nonspecific salivary IgA and IgG, which was measured as an indicator of current immunoenhancement.
Conclusion: Perhaps, the immune-dependent reduction of the scent pleasantness in the acute phase of STI is part of an evolutionary mechanism ensuring, unconsciously, avoidance of a risky romantic partner.

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During the past decade, there has been a striking increase in Clostridium difficile infections worldwide predominantly due to the emergence of epidemic or hypervirulent isolates, leading to an increased research focus on this bacterium. Particular interest has surrounded the two large clostridial toxins encoded by most virulent isolates, known as toxin A and toxin B. Toxin A was thought to be the major virulence factor for many years; however, it is becoming increasingly evident that toxin B plays a much more important role than anticipated. It is clear that further experiments are required to accurately determine the relative roles of each toxin in disease, especially in more clinically relevant current epidemic isolates.

The role of toxin A and toxin B in the virulence of Clostridium difficile. Trends in Microbiology, 7 December 2011

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Prematurity is the leading cause of neonatal deaths and long-term infant disability, with the rate of preterm births continuing to rise. Despite improved medical and respiratory management, the mortality rate for the most premature infants remains high. Extremely low birth weight infants are at increased risk for complications such as sepsis, meningitis, necrotizing enterocolitis and poor growth- problems, all associated with high risk for neurodevelopmental impairment, and all of which may be impacted by the microbial communities in their gut. Among premature infants, frequently used treatments, such as antibiotics and histamine-2 blockers are associated with an increased risk of necrotizing enterocolitis and may exert their influence via alternations in gut microbiota.

This paper uses molecular methods to resolve the microbial constituents of the gut-associated microbiome in premature babies. The study highlights unprecedented early fungal diversity, evidence of roundworms, human and bacterial viruses, and a bacterial community harboring many potential pathogens.

Beyond Bacteria: A Study of the Enteric Microbial Consortium in Extremely Low Birth Weight Infants. (2011) PLoS ONE 6(12): e27858
Extremely low birth weight (ELBW) infants have high morbidity and mortality, frequently due to invasive infections from bacteria, fungi, and viruses. The microbial communities present in the gastrointestinal tracts of preterm infants may serve as a reservoir for invasive organisms and remain poorly characterized. We used deep pyrosequencing to examine the gut-associated microbiome of 11 ELBW infants in the first postnatal month, with a first time determination of the eukaryote microbiota such as fungi and nematodes, including bacteria and viruses that have not been previously described. Among the fungi observed, Candida sp. and Clavispora sp. dominated the sequences, but a range of environmental molds were also observed. Surprisingly, seventy-one percent of the infant fecal samples tested contained ribosomal sequences corresponding to the parasitic organism Trichinella. Ribosomal DNA sequences for the roundworm symbiont Xenorhabdus accompanied these sequences in the infant with the greatest proportion of Trichinella sequences. When examining ribosomal DNA sequences in aggregate, Enterobacteriales, Pseudomonas, Staphylococcus, and Enterococcus were the most abundant bacterial taxa in a low diversity bacterial community (mean Shannon-Weaver Index of 1.02±0.69), with relatively little change within individual infants through time. To supplement the ribosomal sequence data, shotgun sequencing was performed on DNA from multiple displacement amplification (MDA) of total fecal genomic DNA from two infants. In addition to the organisms mentioned previously, the metagenome also revealed sequences for gram positive and gram negative bacteriophages, as well as human adenovirus C. Together, these data reveal surprising eukaryotic and viral microbial diversity in ELBW enteric microbiota dominated bytypes of bacteria known to cause invasive disease in these infants.

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