Marine mimivirus relatives are large algal viruses

Acanthamoeba polyphaga mimivirus is the largest known ds-DNA virus and its 1.2 Mb-genome sequence has revealed many unique features. Mimivirus occupies an independent lineage among eukaryotic viruses and its known hosts include only species from the Acanthamoeba genus. The existence of Mimivirus relatives was first suggested by the analysis of the Sargasso Sea metagenomic data. We now further demonstrate the presence of numerous “mimivirus-like” sequences using a larger marine metagenomic data set. We also show that the DNA polymerase sequences from three algal viruses (CeV01, PpV01, PoV01) infecting different marine algal species (Chrysochromulina ericina, Phaeocystis pouchetii, Pyramimonas orientalis) are very closely related to their homolog in Mimivirus. The results suggest that the numerous mimivirus-related sequences identified in marine environments are likely to originate from diverse large DNA viruses infecting phytoplankton. Micro-algae thus constitute a new category of potential hosts in which to look for new species of Mimiviridae.

Marine mimivirus relatives are probably large algal viruses
Virol J. 2008 5:12

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• Marvellous mimivirus
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Genetic and environmental factors affect gene expression in yeast

Individuals frequently encounter different environmental conditions, and the physiological and behavioral responses to these conditions can depend on an individual’s genetic makeup. This phenomenon is known as gene–environment interaction. For example, individuals who are infected with the Plasmodium falciparum parasite are susceptible to malaria, but not if they carry the sickle-cell allele of hemoglobin. The general properties of gene–environment interaction are poorly understood, and a better understanding is essential if individuals are to make informed health choices guided by their genomic information. A new paper just published in the open-access journal PLoS Biology shows that there is a balance between inherited genes and the environment in determining thousands of traits in yeast.

The authors investigated gene–environment interaction on a genomic level, characterizing its role in over 4,000 traits at once by investigating natural variation in yeast gene expression. They compared lab and vineyard strains of yeast growing in two conditions (glucose and ethanol as carbon sources) in which they adopt two different metabolic states: fermentation and aerobic respiration, respectively. This showed that gene–environment interaction is a common phenomenon, and provides detailed molecular examples of these interactions.

As we approach the age of personal genomics, in which each of us knows something about the genetic variations we carry, it is important to understand how genes and the environment interact in order to draw medically sound conclusions from the information available e.g. whether exercise can reduce risks that are increased because of a genetic predisposition towards a certain illness. The phenomenon of gene/environment interaction has been documented before, that the environment affects the ways it genes are expressed so that genes that are on in one condition may be downregulated or switched off in other environments. What the new research adds is the ability to study thousands of gene expression patterns simultaneously, to understand the general properties of these previously poorly understood interactions. The expression of many genes is under the control of other genes. This paper shows that the environment often has a bigger effect on these regulated genes than on ones that are switched on and off by other, more direct mechanisms. Intriguingly, sometimes a control gene that positively affects another gene in one environment may have the opposite effect in another environment.

Gene environment interaction in yeast gene expression. PLoS Biol 6(4): e83

Pathogens and Proteins

Many pathogens, such as viruses and bacteria, cause disease in humans. Pathogen infections result in illness and death for millions of people each year. Pathogens communicate with human cells through physical interactions with various human proteins on the surface of the cell and within the interior of the cell. These interactions allow the pathogen to enter the host cell, manipulate important cellular processes, multiply, and invade other cells. A recent paper compares the interactions between human and pathogen proteins from 190 different pathogens to provide important insights into strategies used by pathogens to infect human cells. This shows that both viral and bacterial proteins interact with human proteins that themselves interact with many human proteins or with human proteins that lie on many communication channels between other human proteins. Pathogens may have evolved to interact with these human proteins since they may control critical human cellular process. We also demonstrate that many viruses share common infection strategies, e.g. lengthening particular stages of the cell cycle, controlling programmed cell death, and interacting with the nuclear membrane to transfer viral genetic material into and out of the nucleus. Such studies may help us better understand the process of infection and identify better strategies to prevent or cure infection.

The Landscape of Human Proteins Interacting with Viruses and Other Pathogens. 2008 PLoS Pathog 4(2): e32

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• Toll-Like Receptors

The continuing evolution of E. coli O157:H7

First recognized a quarter of a century ago, E. coli O157:H7 causes bloody and non-bloody diarrhoea, hemorrhagic colitis, and hemolytic uremic syndrome (HUS), which is the leading cause of acute renal failure in children. One of the most potent toxins ever described, Shiga toxin, is a critical virulence factor in HUS, and different variants of this bacteriophage-encoded toxin, e.g., Stx1, Stx2, Stx2c, are found in this pathogen. The mechanism of Shiga toxin is similar to that of ricin and involves inhibition of protein synthesis in renal endothelial and other cells. Toxin produced in the intestine enters the circulation, resulting in direct and indirect effects on the kidney. Other important virulence factors include the type III secretion system encoded on the locus of enterocyte effacement (LEE) pathogenicity island and a variety of secreted effector proteins encoded in the LEE and elsewhere in the genome.

The work of Manning et al (Variation in virulence among clades of Escherichia coli O157:H7 associated with disease outbreaks. 2008 PNAS USA 105:4868–4873) reminds us that evolution of microbial agents is an ongoing process. E. coli O157:H7 is the most notorious of several different types of pathogenic E. coli that are “relentlessly evolving” (7). This study demonstrates the power of current molecular techniques, where the entire genome sequence of a bacterial pathogen can be determined to investigate a specific disease outbreak, but it also demonstrates the limitations of such techniques in relating the sequence information to the complex interaction of host and pathogen.

The continuing evolution of a bacterial pathogen
PNAS Early Edition, March 19, 2008

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• E. coli O157:H7 - getting to the bottom of the burger bug
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Bacteria hedge their bets

On nutritional limitation, the bacterium Bacillus subtilis has the capability to enter the irreversible process of sporulation. This developmental process is bistable, and only a subpopulation of cells actually differentiates into endospores. Why a cell decides to sporulate or not to do so is poorly understood. Through the use of time-lapse microscopy, new research follows the growth, division, and differentiation of individual cells to identify elements of cell history and ancestry that could affect this decision process. These analyses show that during microcolony development, B. subtilis uses a bet-hedging strategy whereby some cells sporulate while others use alternative metabolites to continue growth, providing the latter subpopulation with a reproductive advantage.
B. subtilis is subject to aging. Nevertheless, the age of the cell plays no role in the decision of its fate. However, the physiological state of the cell’s ancestor (more than two generations removed) does affect the outcome of cellular differentiation. This epigenetic inheritance is based on positive feedback within the sporulation phosphorelay. The extended intergenerational “memory” caused by this autostimulatory network may be important for the development of multicellular structures such as fruiting bodies and biofilms.
The importance of epigenetic inheritance of cell fates on the population level may be based on the effect it has on neighboring cells. In bacterial colonies, which are sessile communities of cells, epigenetic inheritance affects those cells that are spatially grouped, in contrast to cells within planktonic cultures. The formation of biofilms requires systematic cell differentiation, and in B. subtilis, multicellular structure formation and sporulation are coordinated and intertwined by the action of Spo0A, suggesting that that epigenetic inheritance plays an important role in the formation of socially organized structures such as biofilms and fruiting bodies.

Bet-hedging and epigenetic inheritance in bacterial cell development
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0700463105

E. coli O157:H7 - getting to the bottom of the burger bug

The Zoonotic and Animal Pathogens Research Laboratory at the University of Edinburgh has worked with a UK-based animation company to produce a full-length animation representing the key stages of E. coli O157:H7 interaction within the gastrointestinal tract. This movie was featured in the August 2004 issue of Microbiology Today, published by the Society for General Microbiology.

Human Cytomegalovirus-encoded microRNA regulates expression of multiple genes involved in replication

Our ability to understand the biology of viruses depends not only on functional analysis of genes they encode but also on specific regulation of those genes during viral infection. In herpesviruses, virus gene regulation is highly complex and plays a significant role in determining the virus replication cycle during acute, latent, or persistent infection. The discovery that many herpesviruses express small regulatory RNAs, known as microRNAs (miRNAs), has opened up a whole new area of research in regulation of gene expression. A recent paper demonstrates that a microRNA expressed by human cytomegalovirus is able to regulate multiple virus genes, including one gene thought to be crucial for both acute and latent stages of viral infection in the host. Expression of this microRNA results in a significant reduction in viral replication. This work therefore demonstrates that viral microRNAs can regulate multiple viral genes and can have significant effects on the replication of a virus.

Although multiple studies have documented the expression of over 70 novel virus-encoded miRNAs, the targets and functions of most of these regulatory RNA species are unknown. In this study a comparative bioinformatics approach was employed to identify potential human cytomegalovirus (HCMV) mRNA targets of a virus-encoded miRNA. Bioinformatics analysis of the known HCMV mRNA 3 untranslated regions revealed 14 potential virus transcripts that were predicted to contain functional target sites for the miRNA. Three of the 14 HCMV miRNA targets were validated, including the major immediate early gene encoding IE72. Further analysis of IE72 regulation by the miRNA with clones encoding the complete major immediate early region revealed that the IE72 3 UTR target site is necessary and sufficient to direct miRNA-specific inhibition of expression in transfected cells. In addition, miRNA regulation is mediated through translational inhibition rather than RNA degradation. Premature expression of the miRNA during HCMV infection resulted in a significant decrease in genomic viral DNA levels, suggesting a functional role in regulating the expression of genes involved in virus replication.

A Human Cytomegalovirus-Encoded microRNA Regulates Expression of Multiple Viral Genes Involved in Replication. PLoS Pathog 2007 3(11): e163

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• Hepatitis B virus integration and hepatocarcinogenesis
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Life on us

The human body provides a wonderful habitat for microbes. In this article in Microbiology Today (February 200 , SGM President Robin Weiss takes a look at some of the microbes who share our bodies and wonders just how human we are:

As an ecosystem, it has become clear that we are only part human, because a significant amount of our biomass is microbial. In demographic terms, microbes outnumber our own cells. While there are 10¹⁴ human cells in the average adult, there are probably approximately 10¹⁵ bacteria and more than 10¹⁷ viruses associated with the human body. In terms of genetic diversity and complexity, the microbial metagenome of humans may be greater than the 3×10⁹ base pairs of human DNA …

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Polyomavirus and Human Merkel Cell Carcinoma

It has been known for over 50 years that Polyomaviruses can cause cancers in animals, but until now, there has been no scientific evidence that these viruses cause human cancers. Merkel cell polyomavirus (MCV) was discovered by the husband-and-wife team who found the cause of Kaposi’s sarcoma using a new strategy to hunt for human viruses. The research team analyzed nearly 400,000 messenger RNA genetic sequences from four samples of tumor tissue using a technique called digital transcriptome subtraction. Comparing the sequences expressed by the tumor genome to gene sequences mapped by the Human Genome Project, the researchers systematically subtracted known human sequences, leaving a group of genetic transcripts that might be from a foreign organism. One sequence was similar to but distinct from all known viruses. The team went on to show that this sequence belonged to a new polyomavirus present in 80% of Merkel cell tumors they tested but in only 8% of control tissues from various body sites and 16% of control skin tissues. So although MCV is most commonly found in Merkel cell tumors, it also can be found in healthy people. The most important distinguishing feature is that MCV integrates into tumor cells in what is known as a monoclonal pattern, indicating that it infects the cell before the cell becomes cancerous. While the research team emphasizes that their work does not prove MCV to be the cause of Merkel cell carcinoma, if the findings are confirmed, they may lead to new cancer treatment and prevention options.

Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma. Science, January 17, 2008
Merkel cell carcinoma (MCC) is a rare but aggressive human skin cancer that typically affects elderly and immunosuppressed individuals, a feature suggestive of an infectious origin. We studied MCC samples by digital transcriptome subtraction (DTS) and detected a fusion transcript between a previously undescribed virus T antigen and a human receptor tyrosine phosphatase. Further investigation led to discovery and sequence analysis of the 5387-base-pair genome of a new polyomavirus that we call Merkel cell polyomavirus (MCV or MCPyV). MCV sequences were detected in 8 of 10 (80%) MCC tumors but in only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues. In 6 of 8 MCV-positive MCCs, viral DNA was integrated within the tumor genome in a pattern suggesting that MCV infection/integration preceded clonal expansion of the tumor cells. Thus, MCV may be a contributing factor in the pathogenesis of MCC.

Human endogenous retroviruses: from ancestral pathogens to bona fide genes

Humans and their endogenous retroviruses (HERVs) are in the most intimate host-pathogen relationship. In this article in Microbiology Today (February 200 , David Griffiths and Cecile Voisset look at the role of HERVs and question their future:

Over the course of evolution, retroviruses have invaded the germ-line of our ancestors on numerous occasions such that human ERVs (HERVs) now comprise ~8 % of our genome. These can be divided into around 30 different families, each representing a different ancestral infection event. The timing of their introduction into the genome ranges from over 30 million years ago up to less than 1 million years ago, depending on the family. Since HERVs represent ancient infections, they are not closely related to retroviruses currently circulating in humans, such as HIV. Instead, they have greater sequence similarity with ERVs of animals …

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• Viruses and Cancer: XMRV and Prostate Cancer
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