MicrobiologyBytes

Bacterial virulence results from the interaction between bacteria and their hosts. This interaction provides selection pressure for bacterial adaptation towards increased fitness or virulence. Basic mechanisms involved in bacterial adaptation at the genetic level are point mutations and recombination. As bacterial genome plasticity is higher in vivo than in vitro, host-pathogen interaction may facilitate bacterial adaptation. Comparative genomics has so far been almost entirely focused on genomic changes upon prolonged bacterial growth in vitro.

To achieve a better comprehension of bacterial genome plasticity and the capacity to adapt in response to their host, researchers studied bacterial genome evolution in vivo. They analyzed the impact of individual hosts on genome-wide bacterial adaptation under controlled conditions, by administration of an asymptomatic E. coli isolate to several hosts. Interestingly, the different hosts appeared to personalize their microflora. Adaptation at the genomic level included point mutations in several metabolic and virulence-related genes, often affecting pleiotropic regulators, but re-isolates from each patient showed a distinct pattern of genetic alterations in addition to random changes. These results provide new insights into bacterial traits under selection during E. coli in vivo growth, further explaining the mechanisms of bacterial adaptation to specific host environments.

Host Imprints on Bacterial Genomes – Rapid, Divergent Evolution in Individual Patients. (2010) PLoS Pathog 6(8): e1001078. doi:10.1371/journal.ppat.1001078
Bacterial virulence results from the interaction between bacteria and their hosts. This interaction provides selection pressure for bacterial adaptation towards increased fitness or virulence. Basic mechanisms involved in bacterial adaptation at the genetic level are point mutations and recombination. As bacterial genome plasticity is higher in vivo than in vitro, host-pathogen interaction may facilitate bacterial adaptation. Comparative genomics has so far been almost entirely focused on genomic changes upon prolonged bacterial growth in vitro. To achieve a better comprehension of bacterial genome plasticity and the capacity to adapt in response to their host, we studied bacterial genome evolution in vivo. We analyzed the impact of individual hosts on genome-wide bacterial adaptation under controlled conditions, by administration of asymptomatic bacteriuria E. coli isolate 83972 to several hosts. Interestingly, the different hosts appeared to personalize their microflora. Adaptation at the genomic level included point mutations in several metabolic and virulence-related genes, often affecting pleiotropic regulators, but re-isolates from each patient showed a distinct pattern of genetic alterations in addition to random changes. Our results provide new insights into bacterial traits under selection during E. coli in vivo growth, further explaining the mechanisms of bacterial adaptation to specific host environments.

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Researchers examined the responses of various microorganisms (viruses, bacterial cells, bacterial and fungal spores, and lichens) to selected factors of space (microgravity, galactic cosmic radiation, solar UV radiation, and space vacuum) in space and laboratory simulation experiments. In general, microorganisms tend to thrive in the space flight environment in terms of enhanced growth parameters and a demonstrated ability to proliferate in the presence of normally inhibitory levels of antibiotics. The mechanisms responsible for the observed biological responses, however, are not yet fully understood. A hypothesized interaction of microgravity with radiation-induced DNA repair processes was experimentally refuted.

The survival of microorganisms in outer space was investigated to tackle questions on the upper boundary of the biosphere and on the likelihood of interplanetary transport of microorganisms. It was found that extraterrestrial solar UV radiation was the most deleterious factor of space. Among all organisms tested, only lichens (Rhizocarpon geographicum and Xanthoria elegans) maintained full viability after 2 weeks in outer space, whereas all other test systems were inactivated by orders of magnitude. Using optical filters and spores of Bacillus subtilis as a biological UV dosimeter, it was found that the current ozone layer reduces the biological effectiveness of solar UV by 3 orders of magnitude. If shielded against solar UV, spores of B. subtilis were capable of surviving in space for up to 6 years, especially if embedded in clay or meteorite powder (artificial meteorites). The data support the likelihood of interplanetary transfer of microorganisms within meteorites, the so-called lithopanspermia hypothesis.

Space microbiology. (2010) Microbiol Mol Biol Rev. 74(1): 121-56

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An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence. Such changes are mediated by chemical modifications to chromatin on both DNA and DNA-associated histones. Post-translational covalent modifications to the flexible NH2 terminus (tail) of histones include methylation, acetylation, phosphorylation and ubiquitylation, and these are associated with the structural organization of chromatin and its transcriptional status. However, not all histone modifications are truly epigenetic, as very few satisfy the heritable part of the definition. To establish and mediate epigenetic memory, such modifications must be transmitted during DNA replication. Methylation of cytosine in CpG dinucleotides (often referred to as DNA methylation) also contributes to the epigenetic status of a gene locus. When this occurs in a CpG island adjacent to a transcription initiation site, it is generally associated with repression or silencing of transcription. Histone modification, DNA methylation and the resulting reorganisation of chromatin are closely interlinked enzyme-driven processes that determine the transcriptional status of genes, gene clusters and noncoding RNAs such as micro (mi)RNAs. Most of the epigenetic markers mentioned above are associated with transcriptional repression. Multiple additional covalent modifications to histones exist in parallel to these, resulting in a complex and context-influenced ‘histone code’ that dictates transcriptional state.

One of the key questions in the study of mammalian gene regulation is how epigenetic methylation patterns on histones and DNA are initiated and established. These stable, heritable, covalent modifications are largely associated with the repression or silencing of gene transcription, and when deregulated can be involved in the development of human diseases such as cancer. This article reviews examples of viruses and bacteria known or thought to induce epigenetic changes in host cells, and how this might contribute to disease. The heritable nature of these processes in gene regulation suggests that they could play important roles in chronic diseases associated with microbial persistence; they might also explain so-called ‘hit-and-run’ phenomena in infectious disease pathogenesis.

Epigenetic reprogramming of host genes in viral and microbial pathogenesis. Trends Microbiol. Aug 17 2010

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The traditional route for identifying early hits in antibiotic research is to target multiplying bacteria. All current antibiotics have been generated this way. Activity of a potential antibiotic in such assays is predictive of an antimicrobial effect in humans (bearing in mind many compounds are not suitable due to undesirable characteristics such as toxicity). The disadvantage of this route is that the numbers of novel classes of non-toxic compounds which kill multiplying bacteria may have been almost exhausted and those that remain, may require substantial effort and expense to bring to market. Furthermore anti-multiplying agents are almost always either inactive or only partially active against non-multiplying or slowly multiplying or persister bacteria, which leads to the need for multiple doses of antibiotics in order to achieve cure of a bacterial infectious disease. This prolongs the duration of therapy and increases the emergence of resistance. Since bacterial resistance reduces the effectiveness of antibiotics, new ones are required at regular intervals, as the old ones lose their potency for most infections. However, the number of new antibiotics which reach the market each year is falling. Whilst at least 15 classes of antibiotics were introduced into the market between 1940 and 1962, only three new classes of antibiotics have been marketed since then. Together with their subsequent analogues, each class loses effectiveness, at least for some species of bacteria such as Gram-negatives, within 50 years after entry into the market. So, if we continue to use existing technologies for the next 50 years, it is unlikely that we will produce enough new classes to prevent the antibiotic era fading away. A fundamentally new route for antibiotic drug discovery is required if the antibiotic era is to continue. Bacterial molecules have been targeted, in order to create new drugs, but this has not produced any new classes of antibiotics which have reached the market. Another potential way to develop new antibacterials is to use bacteriophages. Although this method has been utilized for decades, no marketed bacteriophages are available in Western countries for licensed medicinal purposes.

In a clinical infection, multiplying and non-multiplying bacteria co-exist. Antibiotics kill multiplying bacteria, but they are very inefficient at killing non-multipliers which leads to slow or partial death of the total target population of microbes in an infected tissue. This prolongs the duration of therapy, increases the emergence of resistance and so contributes to the short life span of antibiotics after they reach the market. Targeting non-multiplying bacteria from the onset of an antibiotic development program is a new concept. This paper describes the proof of principle for this concept, which has resulted in the development of the first antibiotic using this approach. The antibiotic, called HT61, is a small quinolone-derived compound with a molecular mass of about 400 Daltons, and is active against non-multiplying bacteria, including methicillin sensitive and resistant, as well as Panton-Valentine leukocidin-carrying Staphylococcus aureus. It also kills mupirocin resistant MRSA. The mechanism of action of the drug is depolarisation of the cell membrane and destruction of the cell wall. The speed of kill is within two hours. In comparison to the conventional antibiotics, HT61 kills non-multiplying cells more effectively, 6 logs versus less than one log for major marketed antibiotics. HT61 kills methicillin sensitive and resistant S. aureus in the murine skin bacterial colonization and infection models. No resistant phenotype was produced during 50 serial cultures over a one year period. The antibiotic caused no adverse affects after application to the skin of minipigs. Targeting non-multiplying bacteria using this method should be able to yield many new classes of antibiotic. These antibiotics may be able to reduce the rate of emergence of resistance, shorten the duration of therapy, and reduce relapse rates.

A New Approach for the Discovery of Antibiotics by Targeting Non-Multiplying Bacteria: A Novel Topical Antibiotic for Staphylococcal Infections. 2010 PLoS ONE 5(7): e11818. doi:10.1371/journal.pone.0011818

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Mycobacterium tuberculosis is a remarkably successful human pathogen. The interaction with the human host is complex and much remains unknown. Recent advances in systems biology have allowed the integration of data from humans and animal models into computational approaches. For example, mathematical models provide a platform for in silico manipulation of host-pathogen interactions to gain insight into this infection across temporal and biologic scales. This article reviews recent studies on global approaches toward identifying comprehensive responses of both host and bacillus during infection, and the potential for incorporation of these data into many types of useful computational systems. Systems biology approaches provide a unique opportunity to study interventions that may improve therapy and vaccines against this major killer.

Tuberculosis: global approaches to a global disease. Curr Opin Biotechnol. Jul 14 2010

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Bacillus thuringiensis (Bt) is an insecticidal bacterium that has successfully been used as a biopesticide for many years. It is usually referred to as a soil-dwelling organism, as a result of the prevalence of its spores in this environment, but one that can act as an opportunistic pathogen under appropriate conditions. Our understanding of the biology of this organism has been challenged further by the publication of two reports that claim that Bt requires the co-operation of commensal bacteria within the gut of a susceptible insect for its virulence. Perhaps Bt is not primarily a saprophyte and does not require the assistance of commensal bacteria but is a true pathogen in its own right and furthermore that its primary means of reproduction is in an insect?

Bacillus thuringiensis: an impotent pathogen? Trends Microbiol. 2010 18 (5): 189-194

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The immune system of plants can be unstable in the face of rapidly evolving micro-organisms, and pathogens that can evade recognition can spread with alarming speed through a plant population. In this article in Microbiology Today, Gail Preston and Dawn Arnold ask, what is the reason for this inherent instability, and how can disease control be improved?

Plants, unlike animals, lack an adaptive immune system that allows them to recognize and defend against novel pathogenic micro-organisms. Instead they rely on a heritable, innate immune system in which plant receptors recognize the presence or activity of microbial molecules known as elicitors. Plants exposed to infection can increase the effectiveness of their immune system by increasing the speed and strength of their defence mechanisms. However, pathogens that have the ability to evade recognition can spread rapidly through plant populations. The instability of receptor-dependent resistance in the face of rapid microbial evolution creates one of the most fundamental challenges in plant breeding. In this article we discuss why receptordependent resistance breaks down in the face of pathogen evolution and consider whether knowledge of pathogen evolution can provide insights to improve disease control.

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How do marine microbial ecosystems respond to climate change and pollution? In this article in Microbiology Today, Jack Gilbert explains how treating microbial marine communities as single cells in a metatranscriptomics approach could shed light on this fundamental question:

If the number of known stars in the Milky Way is multiplied by the number of known galaxies in the universe the result is a huge number, a septillion (1×10²⁴). Yet, large as this is, it pales in comparison to the number of microbial cells found in the world oceans, estimated to be 1 nonillion (1×10³⁰). When we start to include soil, air and organism-associated environments, this number becomes unimaginable. Traditional microbiology is our gold standard for understanding how these trillions and trillions of bacteria function. Basically, we grow the bugs in a laboratory, one species at a time, and test how they respond to chemical stimuli. Ultimately, we sequence their genome and try to map their genes to particular functions. To help make this link we can observe the expression of these genes in response to certain stimuli, so called transcriptomics.

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Inflammatory bowel disease (IBD) in humans, such as Crohn’s disease and ulcerative colitis, is a complex chronic inflammatory disorder of largely unknown cause in a genetically predisposed host. The incidence of these diseases varies widely between different countries, but overall has increased greatly in recent years, and IBD is now a major public health problem. The gastrointestinal tract of mammals is colonized by a vast range of microorganisms, and this intestinal microbiota is required for intestinal homeostasis and function. Tolerance towards commensal or symbiotic organisms must be maintained to benefit from this colonization. In contrast, colonization with specific pathogenic bacteria can be detrimental to the host, leading to infectious diseases. Thus the host has evolved numerous homeostatic responses towards microbial infections or harmless colonization on the one hand and host defence mechanisms on the other. The multifactorial mechanisms underlying IBD are emphasized by the number of host IBD susceptibility genes that have been identified in recent years. The contributions of the host immune system and the genetic factors that predispose to IBD have been extensively researched and reviewed. This review focuses on the role of bacteria in IBD.

The impact of the microbiota on the pathogenesis of IBD: lessons from mouse infection models. (2010) Nature Reviews Microbiology 8, 564-577 doi:10.1038/nrmicro2403
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a major human health problem. The bacteria that live in the gut play an important part in the pathogenesis of IBD. However, owing to the complexity of the gut microbiota, our understanding of the roles of commensal and pathogenic bacteria in establishing a healthy intestinal barrier and in its disruption is evolving only slowly. In recent years, mouse models of intestinal inflammatory disorders based on defined bacterial infections have been used intensively to dissect the roles of individual bacterial species and specific bacterial components in the pathogenesis of IBD. In this Review, we focus on the impact of pathogenic and commensal bacteria on IBD-like pathogenesis in mouse infection models and summarize important recent developments.

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