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Using evolution of bacteria against themselves

Using evolution of bacteria against themselves


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We know that mutations happen regularly in bacteria and also that one bacteria might get the mutation and become stronger than the others and thus survive, causing antibiotic resistance as well. Can we deliberately make mutations in bacteria that would harm other bacteria but not humans. This would not only make them stronger and thus let them survive but would reduce the very need of antibiotics as they would be less virulent to humans?


Mutating Bacteria is a very plausible idea. If you mutate a particular strain of 'helpful' bacteria to become extremely positively selected for in the current environment then it is possible that the rest of the bacteria interacting with your new mutated will face heavy competition and eventually die out.

The major hole in the idea however, is that bacteria regularly undergo horizontal gene transfer which makes this idea extremely, extremely dangerous for humans. (If your mutated bacteria accidentally passes on the mutated gene to, say, a bacteria that causes Tuberculosis, it would initiate a pandemic. It is also equally possible that a dangerous bacteria might transfer its genes to your mutated bacteria.) It is generally accepted that mutating bacteria or other pathogens(most of which mutate at high rates) is generally a bad idea, because once released into the environment, the possibilities of the mutation going haywire are high(other mutations might make them dangerous).

Horizontal Gene Transfer: Transfer of genes due to recombination processes like Transduction, Transformation and Conjugation which can occur between bacteria of same or different strains, species, domains. etc


Turning bacteria against themselves

Bacteria often attack with toxins designed to hijack or even kill host cells. To avoid self-destruction, bacteria have ways of protecting themselves from their own toxins.

Now, researchers at Washington University School of Medicine in St. Louis have described one of these protective mechanisms, potentially paving the way for new classes of antibiotics that cause the bacteria's toxins to turn on themselves.

Scientists determined the structures of a toxin and its antitoxin in Streptococcus pyogenes, common bacteria that cause infections ranging from strep throat to life-threatening conditions like rheumatic fever. In Strep, the antitoxin is bound to the toxin in a way that keeps the toxin inactive.

"Strep has to express this antidote, so to speak," says Craig L. Smith, PhD, a postdoctoral researcher and first author on the paper that appears Feb. 9 in the journal Structure. "If there were no antitoxin, the bacteria would kill itself."

With that in mind, Smith and colleagues may have found a way to make the antitoxin inactive. They discovered that when the antitoxin is not bound, it changes shape.

"That's the Achilles' heel that we would like to exploit," says Thomas E. Ellenberger, DVM, PhD, the Raymond H. Wittcoff Professor and head of the Department of Biochemistry and Molecular Biophysics at the School of Medicine. "A drug that would stabilize the inactive form of the immunity factor would liberate the toxin in the bacteria."

In this case, the toxin is known as Streptococcus pyogenes beta-NAD+ glycohydrolase, or SPN. Last year, coauthor Michael G. Caparon, PhD, professor of molecular microbiology, and his colleagues in the Center for Women's Infectious Disease Research showed that SPN's toxicity stems from its ability to use up all of a cell's stores of NAD+, an essential component in powering cell metabolism. The antitoxin, known as the immunity factor for SPN, or IFS, works by blocking SPN's access to NAD+, protecting the bacteria's energy supply system.

With the structures determined, researchers can now test possible drugs that might force the antitoxin to remain unbound to the toxin, thereby leaving the toxin free to attack its own bacteria.

"The most important aspect of the structure is that it tells us a lot about how the antitoxin blocks the toxin activity and spares the bacterium," says Ellenberger.

Understanding how these bacteria cause disease in humans is important in drug design.

"There is a war going on between bacteria and their hosts," Smith says. "Bacteria secrete toxins and we have ways to counterattack through our immune systems and with the help of antibiotics. But, as bacteria develop antibiotic resistance, we need to develop new generations of antibiotics."

Many types of bacteria have evolved this toxin-antitoxin method of attacking host cells while protecting themselves. But today, there are no classes of drugs that take aim at the protective action of the bacteria's antitoxin molecules.

"Obviously they could evolve resistance once you target the antitoxin," Ellenberger says. "But this would be a new target. Understanding structures is a keystone of drug design."

Story Source:

Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.


Antimicrobial interactions: mechanisms and implications for drug discovery and resistance evolution

Combinations of antibiotics lead to synergistic and antagonistic drug interactions.

The underlying mechanisms of drug interactions can be elucidated using novel techniques.

Drug interactions offer opportunities for drug discovery.

Multidrug treatments can exploit evolutionary tradeoffs to slow resistance evolution.

General principles may enable the prediction of cellular responses to drug combinations.

Combining antibiotics is a promising strategy for increasing treatment efficacy and for controlling resistance evolution. When drugs are combined, their effects on cells may be amplified or weakened, that is the drugs may show synergistic or antagonistic interactions. Recent work revealed the underlying mechanisms of such drug interactions by elucidating the drugs’ joint effects on cell physiology. Moreover, new treatment strategies that use drug combinations to exploit evolutionary tradeoffs were shown to affect the rate of resistance evolution in predictable ways. High throughput studies have further identified drug candidates based on their interactions with established antibiotics and general principles that enable the prediction of drug interactions were suggested. Overall, the conceptual and technical foundation for the rational design of potent drug combinations is rapidly developing.


The name Deinococcus radiodurans derives from the Ancient Greek δεινός (deinos) and κόκκος (kokkos) meaning "terrible grain/berry" and the Latin radius and durare, meaning "radiation surviving". The species was formerly called Micrococcus radiodurans. As a consequence of its hardiness, it has been nicknamed “Conan the Bacterium”, in reference to Conan the Barbarian. [2]

Initially, it was placed in the genus Micrococcus. After evaluation of ribosomal RNA sequences and other evidence, it was placed in its own genus Deinococcus, which is closely related to the genus Thermus. The term "Deinococcus-Thermus group" is sometimes used to refer to members of Deinococcus and Thermus. [3]

Deinococcus is one genus of three in the order Deinococcales. D. radiodurans is the type species of this genus, and the best studied member. All known members of the genus are radioresistant: D. proteolyticus, D. radiopugnans, D. radiophilus, D. grandis, D. indicus, D. frigens, D. saxicola, D. marmoris, D. deserti, [4] D. geothermalis, and D. murrayi the latter two are also thermophilic. [5]

D. radiodurans was discovered in 1956 by Arthur Anderson at the Oregon Agricultural Experiment Station in Corvallis, Oregon. [6] Experiments were being performed to determine whether canned food could be sterilized using high doses of gamma radiation. A tin of meat was exposed to a dose of radiation that was thought to kill all known forms of life, but the meat subsequently spoiled, and D. radiodurans was isolated.

The complete DNA sequence of D. radiodurans was published in 1999 by The Institute for Genomic Research. A detailed annotation and analysis of the genome appeared in 2001. [3] The sequenced strain was ATCC BAA-816.

Deinococcus radiodurans has a unique quality in which it can repair both single- and double-stranded DNA. When damage is apparent to the cell, it brings the damaged DNA into a compartmental ring-like structure where the DNA is repaired, and then is able to fuse the nucleoids from the outside of the compartment with the damaged DNA. [7]

In August 2020, scientists reported that bacteria from Earth, particularly Deinococcus radiodurans bacteria, were found to survive for three years in outer space, based on studies conducted on the International Space Station (ISS). These findings support the notion of panspermia, the hypothesis that life exists throughout the Universe, distributed in various ways, including space dust, meteoroids, asteroids, comets, planetoids, or contaminated spacecraft. [8] [9] In October 2020, related studies after one year of exposure outside the ISS were reported. [10]

D. radiodurans is a rather large, spherical bacterium, with a diameter of 1.5 to 3.5 μm. [11] Four cells normally stick together, forming a tetrad. The bacteria are easily cultured and do not appear to cause disease. [3] Under controlled growth conditions, cells of dimer, tetramer, and even multimer morphologies can be obtained. [11] Colonies are smooth, convex, and pink to red in color. The cells stain Gram positive, although its cell envelope is unusual and is reminiscent of the cell walls of Gram negative bacteria. [12]

D. radiodurans does not form endospores and is nonmotile. It is an obligate aerobic chemoorganoheterotroph, i.e., it uses oxygen to derive energy from organic compounds in its environment. It is often found in habitats rich in organic materials, such as sewage, meat, feces, or, soil, but has also been isolated from medical instruments, room dust, textiles, and dried foods. [12]

It is extremely resistant to ionizing radiation, ultraviolet light, desiccation, and oxidizing and electrophilic agents. [13]

Its genome consists of two circular chromosomes, one 2.65 million base pairs long and the other 412,000 base pairs long, as well as a megaplasmid of 177,000 base pairs and a plasmid of 46,000 base pairs. It has approximately 3,195 genes. In its stationary phase, each bacterial cell contains four copies of this genome when rapidly multiplying, each bacterium contains 8-10 copies of the genome.

D. radiodurans is capable of withstanding an acute dose of 5,000 grays (Gy), or 500,000 rad, of ionizing radiation with almost no loss of viability, and an acute dose of 15,000 Gy with 37% viability. [14] [15] [16] A dose of 5,000 Gy is estimated to introduce several hundred double-strand breaks (DSBs) into the organism's DNA (

0.005 DSB/Gy/Mbp (haploid genome)). For comparison, a chest X-ray or Apollo mission involves about 1 mGy, 5 Gy can kill a human, 200-800 Gy will kill E. coli, and more than 4,000 Gy will kill the radiation-resistant tardigrade.

Several bacteria of comparable radioresistance are now known, including some species of the genus Chroococcidiopsis (phylum cyanobacteria) and some species of Rubrobacter (phylum actinobacteria) among the archaea, the species Thermococcus gammatolerans shows comparable radioresistance. [5] Deinococcus radiodurans also has a unique ability to repair damaged DNA. It isolates the damaged segments in a controlled area and repairs it. These bacteria can also repair many small fragments from an entire chromosome. [17]

Deinococcus accomplishes its resistance to radiation by having multiple copies of its genome and rapid DNA repair mechanisms. It usually repairs breaks in its chromosomes within 12–24 hours by a 2-step process. First, D. radiodurans reconnects some chromosome fragments by a process called single-stranded annealing. In the second step, multiple proteins mend double-strand breaks through homologous recombination. This process does not introduce any more mutations than a normal round of replication would.

Scanning electron microscopy analysis has shown that DNA in D. radiodurans is organized into tightly packed toroids, which may facilitate DNA repair. [18]

A team of Croatian and French researchers led by Miroslav Radman have bombarded D. radiodurans to study the mechanism of DNA repair. At least two copies of the genome, with random DNA breaks, can form DNA fragments through annealing. Partially overlapping fragments are then used for synthesis of homologous regions through a moving D-loop that can continue extension until the fragments find complementary partner strands. In the final step, there is crossover by means of RecA-dependent homologous recombination. [19]

D. radiodurans is capable of genetic transformation, a process by which DNA derived from one cell can be taken up by another cell and integrated into the recipient genome by homologous recombination. [20] When DNA damages (e.g. pyrimidine dimers) are introduced into donor DNA by UV irradiation, the recipient cells efficiently repair the damages in the transforming DNA, as they do in cellular DNA, when the cells themselves are irradiated.

Michael Daly has suggested the bacterium uses manganese complexes as antioxidants to protect itself against radiation damage. [21] In 2007 his team showed that high intracellular levels of manganese(II) in D. radiodurans protect proteins from being oxidized by radiation, and they proposed the idea that "protein, rather than DNA, is the principal target of the biological action of [ionizing radiation] in sensitive bacteria, and extreme resistance in Mn-accumulating bacteria is based on protein protection". [22] In 2016, Massimiliano Peana et al. reported a spectroscopic study through NMR, EPR, and ESI-MS techniques on the Mn(II) interaction with two peptides, DP1 (DEHGTAVMLK) and DP2 (THMVLAKGED), whose amino acid composition was selected to include the majority of the most prevalent amino acids present in a Deinococcus radiodurans bacterium cell-free extract that contains components capable of conferring extreme resistance to ionizing radiation. [23] In 2018, M. Peana and C. Chasapis reported by a combined approach of bioinformatic strategies based on structural data and annotation, the Mn(II)-binding proteins encoded by the genome of DR and proposed a model for Manganese interaction with DR proteome network involved in ROS response and defense. [24]

A team of Russian and American scientists proposed that the radioresistance of D. radiodurans had a Martian origin. They suggested that evolution of the microorganism could have taken place on the Martian surface until it was delivered to Earth on a meteorite. [25] However, apart from its resistance to radiation, Deinococcus is genetically and biochemically very similar to other terrestrial life forms, arguing against an extraterrestrial origin not common to them.

In 2009, nitric oxide was reported to play an important role in the bacteria's recovery from radiation exposure: the gas is required for division and proliferation after DNA damage has been repaired. A gene was described that increases nitric oxide production after UV radiation, and in the absence of this gene, the bacteria were still able to repair DNA damage, but would not grow. [26]

A persistent question regarding D. radiodurans is how such a high degree of radioresistance could evolve. Natural background radiation levels are very low—in most places, on the order of 0.4 mGy per year, and the highest known background radiation, near Ramsar, Iran is only 260 mGy per year. With naturally occurring background radiation levels so low, organisms evolving mechanisms specifically to ward off the effects of high radiation are unlikely.

Valerie Mattimore of Louisiana State University has suggested the radioresistance of D. radiodurans is simply a side effect of a mechanism for dealing with prolonged cellular desiccation (dryness). To support this hypothesis, she performed an experiment in which she demonstrated that mutant strains of D. radiodurans that are highly susceptible to damage from ionizing radiation are also highly susceptible to damage from prolonged desiccation, while the wild-type strain is resistant to both. [27] In addition to DNA repair, D. radiodurans use LEA proteins (Late Embryogenesis Abundant proteins) [28] expression to protect against desiccation. [29]

In this context, also the robust S-layer of D. radiodurans through its main protein complex, the S-layer Deinoxanthin Binding Complex (SDBC), strongly contributes to its extreme radioresistance. In fact, this S-layer acts as a shield against electromagnetic stress, as in the case of ionizing radiation exposure, but also stabilize the cell wall against possible consequent high temperatures and desiccation. [30] [31]


Suicidal bacteria: Biologists study unicellular organisms that occasionally poison themselves with a toxin

A typical liquid culture of the cyanobacterium Synechocystis.

The cyanobacterium Synechocystis produces toxins that often lead to its own demise. The biologists Stefan Kopfmann and Prof. Dr. Wolfgang Hess from the University of Freiburg have determined the logic governing this mechanism.. Their findings have been published in the renowned periodicals Journal of Biological Chemistry (JBC) and Public Library of Science (PLoS ONE).

The cyanobacterium Synechocystis produces several toxins. However, most of the time they cannot become active because the unicellular organism usually only produces them together with an antitoxin that neutralizes their poisonous effect. This is a trick of nature: The genes for the toxin and the antitoxin are located together on a plasmid, i.e. a fragment of DNA that exists independently of the actual bacterial chromosome. In contrast to the toxin, the antitoxin is not very stable. When a cell loses the plasmid during cell division, both of the genes are lost. Since the toxin is more stable than the antitoxin and is thus effective for a longer period of time, these cells eventually die off. Hence, the toxin-antitoxin pairs constitute a natural selection mechanism that sees to it that only cells which retain the plasmid survive.

The plasmid pSYSA of the cyanobacterium Synechocystis has not one but seven different systems of this kind and is thus well protected. The reason for this is because in addition to the genes for the seven toxin-antitoxin pairs, the plasmid pSYSA possesses the genetic information for a bacterial immune system. If the plasmid with this system gets lost in cell division, several toxins thus see to it that the bacterium is killed. The fact that the genes responsible for it are combined with a high amount of toxin-antitoxin pairs indicates that this system has special significance for the cyanobacterial cell.


Bacteria 'shuffle' their genetics around to develop antibiotic resistance on demand

To stop antibiotic resistance, scientists need to know how bacteria become resistant. Credit: Jarun Ontakrai/ Shutterstock

Antibiotic resistance—the ability of harmful bacteria to survive treatment by antibiotics—is a growing threat. It is making it harder to treat life-threatening infections, including tuberculosis, MRSA, and gonorrhea—and increasing the risks of even minor surgery.

In order to solve antibiotic resistance, one thing researchers first need to understand is how to stop resistance from happening to begin with. A recent study I conducted with colleagues at the University of Oxford has helped increase that understanding by showing bacteria can cleverly rearrange their genetics in order to evade the effects of an antibiotic.

Bacteria have multiple ways of evolving resistance. They can mutate to prevent antibiotics from targeting them, which can be done by modifying the proteins within the cell where antibiotics act. They can also acquire genes that help them produce antibiotic-destroying molecules, called enzymes.

However, all these strategies carry a cost for resistant bacteria. Producing resistance enzymes requires a lot of energy. Modified proteins also cannot perform as effectively as before. Both these factors severely hamper bacteria, and make them replicate slower when antibiotics aren't present. This leads resistant bacteria to lose the competition against other bacteria for precious nutrients and resources, threatening their survival.

The cost of antibiotic resistance. Credit: Célia Souque

But resistant bacteria have found a way to become resistant to antibiotics while limiting the costs associated with it. My recent study showed how one such mechanism, involving something known as an integron, provides bacteria with an incredible potential to acquire high levels of resistance while reducing its energy cost. This makes it easier for antibiotic resistant bacteria to survive—and thrive.

Integrons are bits of DNA, unique to bacteria, that allow bacteria to stockpile genes they acquire from other resistant bacteria. These resistance genes are lined up in the bacteria genome one after the other forming "arrays". The position of the genes in the array has a big impact on the bacteria's resistance levels.

Genes that are present toward the start of the array are heavily expressed (meaning they're actively being used) and provide high levels of resistance. Genes at the back are kept silent and can be conserved at low cost, reducing their impact on the bacteria.

On top of this, integrons come with a fantastic trick: an enzyme, called integrase, that allows bacteria to cut off and move genes in the array when the bacteria are in danger. The integrase is thought to provide bacteria with the ability to "shuffle" the order of their genes, letting bacteria modulate their resistance levels on demand. Our study was the first to test this hypothesis.

To see how useful integrons can be for bacteria, we built custom integrons in the lab which contained a relevant resistance gene in last position. Some were made to have a dysfunctioning integrase enzyme, which would prevent them from being able to move their genes around. This allowed us to measure the impact of gene shuffling on antibiotic resistance.

We then used an approach called experimental evolution where we challenged bacteria with increasing doses of antibiotics and observed how long they survived. This technique allowed us to directly measure how good bacteria are at evolving resistance.

We showed that the bacteria that could shuffle their genes survived longer and evolved resistance more frequently than the ones that couldn't. This shows how integrons can help bacteria evolve high levels of antibiotic resistance in response to treatment with antibiotics.

Interestingly, this shuffling was often linked with loss of the other resistance genes present in the bacteria. By shuffling genes around to become resistant against our chosen antibiotic, bacteria lost some of their other resistance genes in the process—again becoming susceptible to these other antibiotics.

The results from our study provide potential strategies to counteract integrons and their role in evolving resistance. For example, antibiotics could be combined with drugs that can inhibit the enzyme integrase to reduce gene shuffling. Drugs that stop the bacteria's "SOS response"—the bacteria's last resort reaction to antibiotics—would also limit integron shuffling as well. So called "anti-evolution" drugs, which do not kill bacteria directly but help prevent the evolution of resistance, are currently an active area of research.

Another alternative would be to exploit the integron shuffling to promote the loss of resistance genes by cycling through different antibiotics. This would steer the evolution of bacteria in a way that makes them sensitive to previously unusable antibiotics.

Integrons first evolved millions of years ago. But now they've found themselves to be a uniquely suited mechanism for bacteria to adapt to the use of antibiotics by humans, and evolve resistance to them.

Though antibiotics save countless lives every year, they must also be used carefully to avoid the further spread of antibiotic resistant bacteria and diseases. Better understanding how bacteria evolve resistance will allow us to improve how we use our current antibiotics, as well as the ones we will develop in the future.

This article is republished from The Conversation under a Creative Commons license. Read the original article.


Contents

All plants and animals, from simple life forms to humans, live in close association with microbial organisms. [12] Several advances have driven the perception of microbiomes, including:

  • the ability to perform genomic and gene expression analyses of single cells and of entire microbial communities in the disciplines of metagenomics and metatranscriptomics[13]
  • databases accessible to researchers across multiple disciplines [13]
  • methods of mathematical analysis suitable for complex data sets [13]

Biologists have come to appreciate that microbes make up an important part of an organism's phenotype, far beyond the occasional symbiotic case study. [13]

Types of microbe-host relationships Edit

Commensalism, a concept developed by Pierre-Joseph van Beneden (1809–1894), a Belgian professor at the University of Louvain during the nineteenth century [14] is central to the microbiome, where microbiota colonize a host in a non-harmful coexistence. The relationship with their host is called mutualistic when organisms perform tasks that are known to be useful for the host, [15] : 700 [16] parasitic, when disadvantageous to the host. Other authors define a situation as mutualistic where both benefit, and commensal, where the unaffected host benefits the symbiont. [17] A nutrient exchange may be bidirectional or unidirectional, may be context dependent and may occur in diverse ways. [17] Microbiota that are expected to be present, and that under normal circumstances do not cause disease, are deemed normal flora or normal microbiota [15] normal flora can not only be harmless, but can be protective of the host. [18]

Acquisition and change Edit

The initial acquisition of microbiota in animals from mammalians to marine sponges is at birth, and may even occur through the germ cell line. In plants, the colonizing process can be initiated below ground in the root zone, around the germinating seed, the spermosphere, or originate from the above ground parts, the phyllosphere and the flower zone or anthosphere. [19] The stability of the rhizosphere microbiota over generations depends upon the plant type but even more on the soil composition, i.e. living and non living environment. [20] Clinically, new microbiota can be acquired through fecal microbiota transplant to treat infections such as chronic C. difficile infection. [21]

Humans Edit

The human microbiota includes bacteria, fungi, archaea and viruses. Micro-animals which live on the human body are excluded. The human microbiome refers to their genomes. [15]

Humans are colonized by many microorganisms the traditional estimate was that humans live with ten times more non-human cells than human cells more recent estimates have lowered this to 3:1 and even to about 1:1. [22] [23] [24] [25]

In fact, these are so small that there are around 100 trillion microbiota on the human body, which is higher than the amount of people on Earth. [26]

The Human Microbiome Project sequenced the genome of the human microbiota, focusing particularly on the microbiota that normally inhabit the skin, mouth, nose, digestive tract, and vagina. [15] It reached a milestone in 2012 when it published initial results. [27]

Non-human animals Edit

  • Amphibians have microbiota on their skin. [28] Some species are able to carry a fungus named Batrachochytrium dendrobatidis, which in others can cause a deadly infection Chytridiomycosis depending on their microbiome, resisting pathogen colonization or inhibiting their growth with antimicrobial skin peptides. [29]
  • In mammals, herbivores such as cattle depend on their rumen microbiome to convert cellulose into proteins, short chain fatty acids, and gases. Culture methods cannot provide information on all microorganisms present. Comparative metagenomic studies yielded the surprising result that individual cattle possess markedly different community structures, predicted phenotype, and metabolic potentials, [30] even though they were fed identical diets, were housed together, and were apparently functionally identical in their utilization of plant cell wall resources. have become the most studied mammalian regarding their microbiomes. The gut microbiota have been studied in relation to allergic airway disease, obesity, gastrointestinal diseases and diabetes. Perinatal shifting of microbiota through low dose antibiotics can have long-lasting effects on future susceptibility to allergic airway disease. The frequency of certain subsets of microbes has been linked to disease severity. The presence of specific microbes early in postnatal life, instruct future immune responses. [31][32] In gnotobiotic mice certain gut bacteria were found to transmit a particular phenotype to recipient germ-free mice, that promoted accumulation of colonic regulatory T cells, and strains that modulated mouse adiposity and cecal metabolite concentrations. [33] This combinatorial approach enables a systems-level understanding of microbial contributions to human biology. [34] But also other mucoide tissues as lung and vagina have been studied in relation to diseases such as asthma, allergy and vaginosis. [35]
  • Insects have their own microbiomes. For example, leaf-cutter ants form huge underground colonies harvesting hundreds of kilograms of leaves each year and are unable to digest the cellulose in the leaves directly. They maintain fungus gardens as the colony's primary food source. While the fungus itself does not digest cellulose, a microbial community containing a diversity of bacteria is doing so. Analysis of the microbial population's genome revealed many genes with a role in cellulose digestion. This microbiome's predicted carbohydrate-degrading enzyme profile is similar to that of the bovine rumen, but the species composition is almost entirely different. [36] Gut microbiota of the fruit fly can affect the way its gut looks, by impacting epithelial renewal rate, cellular spacing, and the composition of different cell types in the epithelium. [37] When the moth Spodoptera exigua is infected with baculovirus immune-related genes are downregulated and the amount of its gut microbiota increases. [38] In the dipteran intestine, enteroendocrine cells sense the gut microbiota-derived metabolites and coordinate antibacterial, mechanical, and metabolic branches of the host intestinal innate immune response to the commensal microbiota. [39]
  • Fish have their own microbiomes, including the short-lived species Nothobranchius furzeri (turquoise killifish). Transferring the gut microbiota from young killfish into middle-aged killifish significantly extends the lifespans of the middle-aged killfish. [40]

Plants Edit

The plan microbiome was recently discovered to originate from the seed. [42] Microorganism which are transmitted via seed migrate into the developing seedling in a specific route in which certain community move to the leaves and others to the roots. [42] In the diagram on the right, microbiota colonizing the rhizosphere, entering the roots and colonizing the next tuber generation via the stolons, are visualized with a red color. Bacteria present in the mother tuber, passing through the stolons and migrating into the plant as well as into the next generation of tubers are shown in blue. [41]

  • The soil is the main reservoir for bacteria that colonize potato tubers
  • Bacteria are recruited from the soil more or less independent of the potato variety
  • Bacteria might colonize the tubers predominantly from the inside of plants via the stolon
  • The bacterial microbiota of potato tubers consists of bacteria transmitted from one tuber generation to the next and bacteria recruited from the soil colonize potato plants via the root. [41]

Plants are attractive hosts for microorganisms since they provide a variety of nutrients. Microorganisms on plants can be epiphytes (found on the plants) or endophytes (found inside plant tissue). [43] [44] Oomycetes and fungi have, through convergent evolution, developed similar morphology and occupy similar ecological niches. They develop hyphae, threadlike structures that penetrate the host cell. In mutualistic situations the plant often exchanges hexose sugars for inorganic phosphate from the fungal symbiont. It is speculated that such very ancient associations have aided plants when they first colonized land. [17] [45] Plant-growth promoting bacteria (PGPB) provide the plant with essential services such as nitrogen fixation, solubilization of minerals such as phosphorus, synthesis of plant hormones, direct enhancement of mineral uptake, and protection from pathogens. [46] [47] PGPBs may protect plants from pathogens by competing with the pathogen for an ecological niche or a substrate, producing inhibitory allelochemicals, or inducing systemic resistance in host plants to the pathogen [19]

The symbiotic relationship between a host and its microbiota is under laboratory research for how it may shape the immune system of mammals. [48] [49] In many animals, the immune system and microbiota may engage in "cross-talk" by exchanging chemical signals, which may enable the microbiota to influence immune reactivity and targeting. [50] Bacteria can be transferred from mother to child through direct contact and after birth. [51] As the infant microbiome is established, commensal bacteria quickly populate the gut, prompting a range of immune responses and "programming" the immune system with long-lasting effects. [50] The bacteria are able to stimulate lymphoid tissue associated with the gut mucosa, which enables the tissue to produce antibodies for pathogens that may enter the gut. [50]

The human microbiome may play a role in the activation of toll-like receptors in the intestines, a type of pattern recognition receptor host cells use to recognize dangers and repair damage. Pathogens can influence this coexistence leading to immune dysregulation including and susceptibility to diseases, mechanisms of inflammation, immune tolerance, and autoimmune diseases. [52] [53]

Organisms evolve within ecosystems so that the change of one organism affects the change of others. The hologenome theory of evolution proposes that an object of natural selection is not the individual organism, but the organism together with its associated organisms, including its microbial communities.

Coral reefs. The hologenome theory originated in studies on coral reefs. [54] Coral reefs are the largest structures created by living organisms, and contain abundant and highly complex microbial communities. Over the past several decades, major declines in coral populations have occurred. Climate change, water pollution and over-fishing are three stress factors that have been described as leading to disease susceptibility. Over twenty different coral diseases have been described, but of these, only a handful have had their causative agents isolated and characterized. Coral bleaching is the most serious of these diseases. In the Mediterranean Sea, the bleaching of Oculina patagonica was first described in 1994 and shortly determined to be due to infection by Vibrio shiloi. From 1994 to 2002, bacterial bleaching of O. patagonica occurred every summer in the eastern Mediterranean. Surprisingly, however, after 2003, O. patagonica in the eastern Mediterranean has been resistant to V. shiloi infection, although other diseases still cause bleaching. The surprise stems from the knowledge that corals are long lived, with lifespans on the order of decades, [55] and do not have adaptive immune systems. [ citation needed ] Their innate immune systems do not produce antibodies, and they should seemingly not be able to respond to new challenges except over evolutionary time scales. [ citation needed ]

The puzzle of how corals managed to acquire resistance to a specific pathogen led to a 2007 proposal, that a dynamic relationship exists between corals and their symbiotic microbial communities. It is thought that by altering its composition, the holobiont can adapt to changing environmental conditions far more rapidly than by genetic mutation and selection alone. Extrapolating this hypothesis to other organisms, including higher plants and animals, led to the proposal of the hologenome theory of evolution. [54]

As of 2007 [update] the hologenome theory was still being debated. [56] A major criticism has been the claim that V. shiloi was misidentified as the causative agent of coral bleaching, and that its presence in bleached O. patagonica was simply that of opportunistic colonization. [57] If this is true, the basic observation leading to the theory would be invalid. The theory has gained significant popularity as a way of explaining rapid changes in adaptation that cannot otherwise be explained by traditional mechanisms of natural selection. Within the hologenome theory, the holobiont has not only become the principal unit of natural selection but also the result of other step of integration that it is also observed at the cell (symbiogenesis, endosymbiosis) and genomic levels. [8]

Targeted amplicon sequencing Edit

Targeted amplicon sequencing relies on having some expectations about the composition of the community that is being studied. In target amplicon sequencing a phylogenetically informative marker is targeted for sequencing. Such a marker should be present in ideally all the expected organisms. It should also evolve in such a way that it is conserved enough that primers can target genes from a wide range of organisms while evolving quickly enough to allow for finer resolution at the taxonomic level. A common marker for human microbiome studies is the gene for bacterial 16S rRNA (i.e. "16S rDNA", the sequence of DNA which encodes the ribosomal RNA molecule). [58] Since ribosomes are present in all living organisms, using 16S rDNA allows for DNA to be amplified from many more organisms than if another marker were used. The 16S rDNA gene contains both slowly evolving regions and fast evolving regions the former can be used to design broad primers while the latter allow for finer taxonomic distinction. However, species-level resolution is not typically possible using the 16S rDNA. Primer selection is an important step, as anything that cannot be targeted by the primer will not be amplified and thus will not be detected. Different sets of primers have been shown to amplify different taxonomic groups due to sequence variation.

Targeted studies of eukaryotic and viral communities are limited [59] and subject to the challenge of excluding host DNA from amplification and the reduced eukaryotic and viral biomass in the human microbiome. [60]

After the amplicons are sequenced, molecular phylogenetic methods are used to infer the composition of the microbial community. This is done by clustering the amplicons into operational taxonomic units (OTUs) and inferring phylogenetic relationships between the sequences. Due to the complexity of the data, distance measures such as UniFrac distances are usually defined between microbiome samples, and downstream multivariate methods are carried out on the distance matrices. An important point is that the scale of data is extensive, and further approaches must be taken to identify patterns from the available information. Tools used to analyze the data include VAMPS, [61] QIIME [62] and mothur. [63]

Metagenomic sequencing Edit

Metagenomics is also used extensively for studying microbial communities. [64] [65] [66] In metagenomic sequencing, DNA is recovered directly from environmental samples in an untargeted manner with the goal of obtaining an unbiased sample from all genes of all members of the community. Recent studies use shotgun Sanger sequencing or pyrosequencing to recover the sequences of the reads. [67] The reads can then be assembled into contigs. To determine the phylogenetic identity of a sequence, it is compared to available full genome sequences using methods such as BLAST. One drawback of this approach is that many members of microbial communities do not have a representative sequenced genome, but this applies to 16S rRNA amplicon sequencing as well and is a fundamental problem. [58] With shotgun sequencing, it can be resolved by having a high coverage (50-100x) of the unknown genome, effectively doing a de novo genome assembly. As soon as there is a complete genome of an unknown organism available it can be compared phylogenetically and the organism put into its place in the tree of life, by creating new taxa. An emerging approach is to combine shotgun sequencing with proximity-ligation data (Hi-C) to assemble complete microbial genomes without culturing. [68]

Despite the fact that metagenomics is limited by the availability of reference sequences, one significant advantage of metagenomics over targeted amplicon sequencing is that metagenomics data can elucidate the functional potential of the community DNA. [69] [70] Targeted gene surveys cannot do this as they only reveal the phylogenetic relationship between the same gene from different organisms. Functional analysis is done by comparing the recovered sequences to databases of metagenomic annotations such as KEGG. The metabolic pathways that these genes are involved in can then be predicted with tools such as MG-RAST, [71] CAMERA [72] and IMG/M. [73]

RNA and protein-based approaches Edit

Metatranscriptomics studies have been performed to study the gene expression of microbial communities through methods such as the pyrosequencing of extracted RNA. [74] Structure based studies have also identified non-coding RNAs (ncRNAs) such as ribozymes from microbiota. [75] Metaproteomics is an approach that studies the proteins expressed by microbiota, giving insight into its functional potential. [76]

The Human Microbiome Project launched in 2008 was a United States National Institutes of Health initiative to identify and characterize microorganisms found in both healthy and diseased humans. [77] The five-year project, best characterized as a feasibility study with a budget of $115 million, tested how changes in the human microbiome are associated with human health or disease. [77]

The Earth Microbiome Project (EMP) is an initiative to collect natural samples and analyze the microbial community around the globe. Microbes are highly abundant, diverse and have an important role in the ecological system. Yet as of 2010 [update] , it was estimated that the total global environmental DNA sequencing effort had produced less than 1 percent of the total DNA found in a liter of seawater or a gram of soil, [78] and the specific interactions between microbes are largely unknown. The EMP aims to process as many as 200,000 samples in different biomes, generating a complete database of microbes on earth to characterize environments and ecosystems by microbial composition and interaction. Using these data, new ecological and evolutionary theories can be proposed and tested. [79]

The gut microbiota is very important for the host health because it play role in degradation of non- digestible polysaccharides (fermentation of resistant starch, oligosaccharides, inulin) strengthening gut integrity or shaping the intestinal epithelium, harvesting energy, protecting against pathogens, and regulating host immunity. [80] [81]

Several studies showed that the gut bacterial composition in diabetic patients became altered with increased levels of Lactobacillus gasseri, Streptococcus mutans and Clostridiales members, with decrease in butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii [82] [83] . This alteration is due to many factors such as antibiotic abuse, diet, and age.

The decrease in butyrate production is associated with defect in intestinal permeability, this defect lead to the case of endotoxemia, which is the increased level of circulating Lipopolysaccharides from gram negative bacterial cells wall. It is found that endotoxemia has association with development of insulin resistance. [82]

In addition that butyrate production affects serotonin level. [82] Elevated serotonin level has contribution in obesity, which is known to be a risk factor for development of diabetes.

Microbiota can be transplanted in the human body for medical purposes. [84]

The colonization of the human gut microbiota may start already before birth. [85] There are multiple factors in the environment that affects the development of the microbiota with birthmode being one of the most impactful. [86]

Another factor that has been observed to cause huge changes in the gut microbiota, particularly in children, is the use of antibiotics, associating with health issues such as higher BMI, [87] [88] and further an increased risk towards metabolic diseases such as obesity. [89] In infants it was observed that amoxicillin and macrolides cause significant shifts in the gut microbiota characterized by a change in the bacterial classes Bifidobacteria, Enterobacteria and Clostridia. [90] A single course of antibiotics in adults causes changes in both the bacterial and fungal microbiota, with even more persistent changes in the fungal communities. [91] The bacteria and fungi live together in the gut and there is most likely a competition for nutrient sources present. [92] [93] Seelbinder et al. found that commensal bacteria in the gut regulate the growth and pathogenicity of Candida albicans by their metabolites, particularly by propionate, acetic acid and 5-dodecenoate. [94] Candida has previously been associated with IBD [95] and further it has been observed to be increased in non-responders to a biological drug, infliximab, given to IBD patients suffering from severe IBD. [96] Propionate and acetic acid are both short-chain fatty acids (SCFAs) that have been observed to be beneficial to gut microbiota health. [97] [98] [99] When antibiotics affect the growth of bacteria in the gut, there might be an overgrowth of certain fungi, which might be pathogenic when not regulated. [100]

Microbial DNA inhabiting a person's human body can uniquely identify the person. A person's privacy may be compromised if the person anonymously donated microbe DNA data. Their medical condition and identity could be revealed. [101] [102] [103]


Turning bacteria against themselves

IMAGE: The Streptococcus pyogenes toxin SPN (shown in purple) is inhibited by the antitoxin IFS (left, shown in orange). IFS blocks the active site of SPN and prevents NAD+ from binding. view more

Credit: Image provided by Craig L. Smith

Bacteria often attack with toxins designed to hijack or even kill host cells. To avoid self-destruction, bacteria have ways of protecting themselves from their own toxins.

Now, researchers at Washington University School of Medicine in St. Louis have described one of these protective mechanisms, potentially paving the way for new classes of antibiotics that cause the bacteria's toxins to turn on themselves.

Scientists determined the structures of a toxin and its antitoxin in Streptococcus pyogenes , common bacteria that cause infections ranging from strep throat to life-threatening conditions like rheumatic fever. In Strep, the antitoxin is bound to the toxin in a way that keeps the toxin inactive.

"Strep has to express this antidote, so to speak," says Craig L. Smith, PhD, a postdoctoral researcher and first author on the paper that appears Feb. 9 in the journal Structure . "If there were no antitoxin, the bacteria would kill itself."

With that in mind, Smith and colleagues may have found a way to make the antitoxin inactive. They discovered that when the antitoxin is not bound, it changes shape.

"That's the Achilles' heel that we would like to exploit," says Thomas E. Ellenberger, DVM, PhD, the Raymond H. Wittcoff Professor and head of the Department of Biochemistry and Molecular Biophysics at the School of Medicine. "A drug that would stabilize the inactive form of the immunity factor would liberate the toxin in the bacteria."

In this case, the toxin is known as Streptococcus pyogenes beta-NAD+ glycohydrolase, or SPN. Last year, coauthor Michael G. Caparon, PhD, professor of molecular microbiology, and his colleagues in the Center for Women's Infectious Disease Research showed that SPN's toxicity stems from its ability to use up all of a cell's stores of NAD+, an essential component in powering cell metabolism. The antitoxin, known as the immunity factor for SPN, or IFS, works by blocking SPN's access to NAD+, protecting the bacteria's energy supply system.

With the structures determined, researchers can now test possible drugs that might force the antitoxin to remain unbound to the toxin, thereby leaving the toxin free to attack its own bacteria.

"The most important aspect of the structure is that it tells us a lot about how the antitoxin blocks the toxin activity and spares the bacterium," says Ellenberger.

Understanding how these bacteria cause disease in humans is important in drug design.

"There is a war going on between bacteria and their hosts," Smith says. "Bacteria secrete toxins and we have ways to counterattack through our immune systems and with the help of antibiotics. But, as bacteria develop antibiotic resistance, we need to develop new generations of antibiotics."

Many types of bacteria have evolved this toxin-antitoxin method of attacking host cells while protecting themselves. But today, there are no classes of drugs that take aim at the protective action of the bacteria's antitoxin molecules.

"Obviously they could evolve resistance once you target the antitoxin," Ellenberger says. "But this would be a new target. Understanding structures is a keystone of drug design."

Smith CL, Ghosh J, Elam JS, Pinkner JS, Hultgren SJ, Caparon MG, Ellenberger T. Structural basis of Streptococcus pyogenes immunity to its NAD+ glycohydrolase toxin. Structure . Feb. 9, 2011.

This work was supported by grants from the National Institutes of Health and the UNCF/Merck Science Initiative Postdoctoral Fellowship awarded to Craig L. Smith.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Rooting the bacterial tree of life

Scientists now better understand early bacterial evolution, thanks to new research featuring University of Queensland researchers.

Bacteria comprise a very diverse domain of single-celled organisms that are thought to have evolved from a common ancestor that lived more than three billion years ago.

Professor Phil Hugenholtz, from the Australian Centre for Ecogenomics in UQ's School of Chemistry and Molecular Biosciences, said the root of the bacterial tree, which would reveal the nature of the last common ancestor, is not agreed upon.

"There's great debate about the root of this bacterial tree of life and indeed whether bacterial evolution should even be described as a tree has been contested," Professor Hugenholtz said.

"This is in large part because genes are not just shared 'vertically' from parents to offspring, but also 'horizontally' between distant family members.

"We've all inherited certain traits from our parents, but imagine going to a family BBQ and suddenly inheriting your third cousin's red hair.

"As baffling as it sounds, that's exactly what happens in the bacterial world, as bacteria can frequently transfer and reconfigure genes horizontally across populations quite easily.

"This might be useful for bacteria but makes it challenging to reconstruct bacterial evolution."

For the bacterial world, many researchers have suggested throwing the 'tree of life' concept out the window and replacing it with a network that reflects horizontal movement of genes.

"However, by integrating vertical and horizontal gene transmission, we found that bacterial genes travel vertically most of the time - on average two-thirds of the time - suggesting that a tree is still an apt representation of bacterial evolution," Professor Hugenholtz said.

"The analysis also revealed that the root of the tree lies between two supergroups of bacteria, those with one cell membrane and those with two.

"Their common ancestor was already complex, predicted to have two membranes, the ability to swim, sense its environment, and defend itself against viruses."

The University of Bristol's Dr Tom Williams said this fact led to another big question.

"Given the common ancestor of all living bacteria already had two membranes, we now need to understand how did single-membrane cells evolve from double-membraned cells, and whether this occurred once or on multiple occasions," Dr Williams said.

"We believe that our approach to integrating vertical and horizontal gene transmission will answer these and many other open questions in evolutionary biology."

The research was a collaboration between UQ, the University of Bristol in the UK, Eötvös Loránd University in Hungary, and NIOZ in the Netherlands, and has been published in Science (DOI: 10.1126/science.abe5011).

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Dover and beyond

Q: What was at stake in the Dover trial?

Miller: One of the things that the Dover trial brought to a head was the idea that the intelligent-design movement represented a genuine alternative, something very different from the creation-science movement that took hold in several states in the U.S. in the early 1980s. The advocates of intelligent design disavow any connection with creationism or creation science. They say their ideas are purely scientific and have nothing to do with religion.

In the trial, documents regarding the formation of the intelligent-design movement, the construction of the intelligent-design textbook that was recommended for use in the Dover schools, came to light. And it was very clear that intelligent design represented nothing more than an intentional effort to relabel creation science by taking all the same old arguments and putting a new label on them.

The second thing that was very much at stake in the trial was religious freedom. Religious freedom in this country is based on two great and essential principles. One is that the government shall not interfere with the free exercise of religion, and the other one is that the government shall not endorse or establish a religion. What the Dover board was doing very clearly, by their own statements, was trying to establish an official religion for the school district of Dover and trying to get science teachers to advance the Dover board's view of that religion.

Now, the members of the Dover board are perfectly entitled to hold all these religious views and to hold these views about intelligent design and evolution and everything else. But what they're not entitled to do, under our Constitution, is to use the force and power of the state to foist those ideas on young people. That would have been a very dangerous precedent if they'd been able to get away with it.

Q: Was it wrong, in your view, for the Dover school board to try to get their ideas into the science classroom?

Miller: No idea should be inserted into the science classroom by force of law unless that idea can first win a place for itself in the scientific community. The real problem that happened in Dover was not intelligent design being a bad idea or anything else. The real problem was the use of a government agency to pick up an idea that science itself had rejected and to say, "We're going to put this idea in the science classroom regardless of its inability to win any following within science itself."

They did this for religious reasons. That's why they lost the case. But the general idea of not allowing science to work was at the heart of what was wrong about Dover.

"Not a single scientific society has made a statement or claim in support of intelligent design. In fact, quite the contrary."

Q: So is this over? Are we beyond intelligent design yet?

Miller: I'd love to think that this battle is over. It's not. The war is going to go on. Intelligent design as anything resembling a scientific theory has been shown fundamentally to be intellectually bankrupt, and it's also been shown to be an idea that is religious in character, simply cloaked in the language of science. I think that came out of the trial at Dover. The evidence that was presented, and even the testimony from the other side, showed that beyond any shadow of a doubt.

But the people behind the intelligent-design movement will do what they've always done. They will move on, they'll change terms, they'll come up with a new label, and they'll continue to fight this fight against evolution and against scientific rationalism.

One of the legacies of the Dover trial is that the term intelligent design has almost become a kind of intellectual poison, and its advocates are running around saying, "No, no, no, no. We don't want to teach intelligent design in the schools." They'd better not, especially after the Dover trial. Instead, they say, "What we want to do is we want to teach critical analysis of evolution, or we want to teach the controversy surrounding evolution."

Ironically, when you look at what they actually would like to teach, it is simply the collection of anti-evolution arguments that were always part and parcel of intelligent design in the first place. So it is simply relabeling the intelligent design critique of evolution. And this idea of teaching the controversy is built upon a false premise, that there is a controversy within the scientific community on the issue of evolution. Well, there isn't. Evolution is, in fact, mainstream science.

Q: Critics of Darwinism often say that evolution is a theory in crisis. How do you see it?

Miller: Evolutionary theory has never been more active in terms of an area of inquiry and an area of scholarship than it is right now. Evolution as an idea has never been more useful than it is right now, because we use evolution everyday to interpret genomes, to develop drugs, to prolong the useful lifetime of antibiotics, to grow genetically modified crops—all these things have components of evolution in them.

If you look at the major scientific societies in the United States and around the world, not a single scientific society has made a statement or claim in support of intelligent design, in support of scientific creationism. In fact, quite the contrary. Every major scientific organization that I'm aware of that has taken a position on this issue has taken their position four-square in favor of evolution. So the notion that evolution is in some sort of crisis is just not true.

The intelligent-design movement, says Ken Miller, "is basically designed to bring the supernatural into science. And that kind of introduction would destroy both science and religion."

Interview conducted on April 19, 2007 by Joe McMaster, producer of "Judgment Day: Intelligent Design on Trial," and edited by Lauren Aguirre and Peter Tyson, executive editor and editor in chief of NOVA online


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