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Doubts have been raised about the reliability of a trial suggesting success for a vaccine against HIV. In the large-scale trial in Thailand, a combination of vaccines seemed to give volunteers a protective effect of 31%. The US military and Thai government, who co-sponsored the trial, said the effect was not caused by random chance but was statistically significant. Allegedly, if one more person had been infected in the trial, the result would not have been statistically significant.

Related:

• HIV – new vaccine, new hope?
• Can you have confidence in the news?
• Media coverage affects how people perceive the threat of disease

MicroRNAs regulate fundamental cellular processes in all metazoans The first discovered microRNA (miRNA), lin-4 of Caenorhabditis elegans, was found because of its role in a developmental timing defect. To date, more than 900 human miRNAs have been identified. MicroRNAs have been isolated from every metazoan and plant species examined thus far, and around 30% of all metazoan miRNAs are conserved between species. A hallmark of herpesvirus biology is the ability of the viruses to establish and maintain latent infections wherein the virus genome circularizes and persists as an episome, and where only very limited virus gene expression takes place. Herpesviruses establish infections that persist for the life of the host; an intricate balance therefore exists between host immune surveillance and virus immune evasion.

MicroRNAs (miRNAs) are short RNAs of about 22 nucleotides in length that post-transcriptionally regulate gene expression by binding to 3′ untranslated regions of mRNAs, thereby inducing translational silencing. Recently, more than 140 miRNAs have been identified in the genomes of herpesviruses. Deciphering their role in viral biology requires the identification of target genes, a challenging task because miRNAs require only limited complementarity. The subject of this review will be the herpesvirus miRNAs and their respective target genes that have been determined experimentally to date. These miRNAs regulate fundamental cellular processes including immunity, angiogenesis, apoptosis, and key steps in the herpesvirus life cycle, latency and the switch from latent to lytic replication.

Role of virus-encoded microRNAs in herpesvirus biology. Trends Microbiol. Oct 12 2009

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• Human Cytomegalovirus-encoded microRNA regulates expression of multiple genes involved in replication
• Cellular Genes Targeted by KSHV MicroRNAs
• RNAi and Cold Sores

A 21-year Michigan State University experiment that distills the essence of evolution in laboratory flasks not only demonstrates natural selection at work, but could lead to biotechnology and medical research advances. Researchers at Michigan State University started a culture of Escherichia coli bacteria in 1988. The results are in.

Genome evolution and adaptation in a long-term experiment with Escherichia coli. Nature 18 October 2009 doi:10.1038/nature08480
The relationship between rates of genomic evolution and organismal adaptation remains uncertain, despite considerable interest. The feasibility of obtaining genome sequences from experimentally evolving populations offers the opportunity to investigate this relationship with new precision. Here we sequence genomes sampled through 40,000 generations from a laboratory population of Escherichia coli. Although adaptation decelerated sharply, genomic evolution was nearly constant for 20,000 generations. Such clock-like regularity is usually viewed as the signature of neutral evolution, but several lines of evidence indicate that almost all of these mutations were beneficial. This same population later evolved an elevated mutation rate and accumulated hundreds of additional mutations dominated by a neutral signature. Thus, the coupling between genomic and adaptive evolution is complex and can be counterintuitive even in a constant environment. In particular, beneficial substitutions were surprisingly uniform over time, whereas neutral substitutions were highly variable.

Related:

• The continuing evolution of E. coli O157:H7
• Global functional atlas of Escherichia coli proteins

Non-typhoidal Salmonella serotypes (NTS) are a leading cause of acute food borne disease worldwide. The most common human clinical isolates are Salmonella enterica serotypes Typhimurium (S. Typhimurium) and Enteritidis (S. Enteritidis). In immunocompetent individuals, NTS are associated with gastroenteritis, a localized infection of the terminal ileum and colon that manifests as fever, diarrhea and intestinal cramping. However, a breach of mucosal barrier functions in immunocompromised individuals can result in the development of a life-threatening bacteremia. Current research on S. Typhimurium pathogenesis is beginning to paint a novel picture of the unique challenges and opportunities encountered during life in the inflamed intestine. Recent studies have identified host factors that are crucial for activating mucosal barrier functions in the inflamed intestine of immunocompetent hosts. In turn, these findings provide clues about the identity of mucosal barrier defects that put immunocompromised hosts at risk of developing bacteremia. New insights into the consequences consequences of inflammation on the growth conditions encountered by microbes residing in the intestinal lumen reveal how the pathogen might benefit from inducing antimicrobial host responses.

The lower gastrointestinal tract is densely populated with resident microbial communities (microbiota), which do not elicit overt host responses but rather provide benefit to the host, including niche protection from pathogens. However, introduction of bacteria into the underlying tissue evokes acute inflammation. Non-typhoidal Salmonella serotypes (NTS) elicit this stereotypic host response by actively penetrating the intestinal epithelium and surviving in tissue macrophages. Initial responses generated by bacterial host cell interaction are amplified in tissue through the interleukin (IL)-18/interferon-gamma and IL-23/IL-17 axes, resulting in the activation of mucosal barrier functions against NTS dissemination. However, the pathogen is adapted to survive antimicrobial defenses encountered in the lumen of the inflamed intestine. This strategy enables NTS to exploit inflammation to outcompete the intestinal microbiota, and promotes the Salmonella transmission by the fecal/oral route.

Life in the inflamed intestine, Salmonella style. Trends Microbiol. Oct 9 2009

Related:

• Novel genetic tools for studying food-borne Salmonella
• Sept. 23, 1869: Here Comes Typhoid Mary

Multiple species of Chlamydia exist, which have a diverse range of tissue tropisms and are involved in various diseases. Chlamydia trachomatis and Chlamydia pneumoniae are human pathogens causing ocular and urogenital tract infections, and respiratory infection, respectively. Despite profound differences in host range, different species of Chlamydia display a remarkable similarity in their genome sequences and possess a conserved intracellular growth cycle with distinct biphasic stages. The infectious particle (also called elementary body or EB) can invade non-phagocytic epithelial cells via induced phagocytosis. The EB-laden cytoplasmic vacuole (also called inclusion) migrates to the peri-Golgi region as the EB starts to differentiate into a noninfectious but metabolically active reticulate body (RB) that can undergo rapid replication. The progeny RBs eventually differentiate back to EBs for spreading to other cells. The entire intracellular growth cycle occurs within the initial inclusion that expands to occupy a large proportion of the host cytoplasmic space as the parasites replicate. It takes several days for most human chlamydiae to complete a productive infection cycle in cell culture. However, infection in humans can become persistent, during which the RBs, instead of undergoing rapid replication and differentiating into infectious EBs, are limited in numbers and each becomes the so-called aberrant or persistent body with enlarged size and multiple nucleoids. The aberrant body-laden inclusions can persist in the infected hosts for long periods of time. Intracellular survival and growth are considered major contributors to chlamydial pathogenesis. Some infected women, if untreated, can develop inflammatory pathologies, including pelvic inflammatory diseases, ectopic pregnancy and infertility.

Killing me softly: chlamydial use of proteolysis for evading host defenses. Trends Microbiol. Sep 16 2009
Chlamydial infections in humans cause severe health problems, including blinding trachoma and sexually transmitted diseases. Although the involved pathogenic mechanisms remain unclear, the ability to replicate and maintain long-term residence in the infected cells seems to significantly contribute to chlamydial pathogenicity. These obligate intracellular parasites maintain a delicate balance between exploiting and protecting their host: they occupy intracellular space and acquire nutrients from the infected cells, but at the same time they have to maintain the integrity of the host cells for the completion of their intracellular growth. For this purpose, chlamydiae hijack certain signaling pathways that prevent the host cells from undergoing apoptosis induced by intracellular stress and protect the infected cells from recognition and attack by host defenses. Interestingly, one of the strategies that chlamydiae use for these purposes is the induction of limited proteolysis of host proteins, which is the main focus of this article.

Related:

• Chlamydia Infection
• Low uptake of Chlamydia screening in the UK

Normal functioning of virus host cells is altered by invading virus proteins to the benefit of the virus. Virus proteins are known to compete with host proteins, disrupting the normal host protein-protein interaction network. Molecular studies have revealed nearly 1500 interactions between HIV-1 and human proteins which are catalogued in the HIV-1. Efforts to understand the interactions between viral and cellular gene products that together determine the host’s susceptibility to infection and disease have led to significant new insights about HIV-1.

In addition to the structural genes (gag, pol and env), the HIV-1 genome contains 4 accessory (vif, vpr, vpu, nef) and 2 regulatory (tat, rev) genes, the products of which are responsible for establishing sophisticated interactions between the virus and human host. HIV-1 Tat is a multifunctional protein that contributes to several pathological symptoms of HIV-1 infection as well as playing a critical role in virus replication. Tat is a robust transactivating protein that induces a variety of effects by altering the expression levels of cell and virus genes. The functions of Tat are therefore primarily related to its role in modulation of gene expression. In this review the functions of HIV-1 Tat that have been well documented, as well as a number of novel functions that have been proposed for this protein, are discussed. Since some of the functions of Tat vary in different cell types in a concentration dependent manner and because Tat sometimes exerts the same activity through different pathways, study of this protein has at times yielded conflicting and controversial results. Due to its pivotal role in viral replication and in disease pathogenesis, Tat and the cellular pathways targeted by Tat are potential targets for new anti-HIV drugs.

Functions of Tat: the versatile protein of human immunodeficiency virus type 1. J Gen Virol. Oct 7 2009

Related:

• HIV Rev – beyond nuclear export
• Why is HIV a pathogen?
• How does HIV cause AIDS?
• Re-awakening old genes to help in the fight against viruses

The year 2008 marked the 25th year of human immunodeficiency virus (HIV) research. Such a milestone often prompts an assessment of what has been accomplished and where gaps remain in our knowledge. As with most things in their mid-twenties, HIV research has achieved a great deal, but there is still a lot to learn. This dichotomy is exemplified by the viral regulatory protein Rev. Most reviews specifically addressing Rev function date from the 1990s; this is surprising, given the diversity of roles attributed to it since then.

Rev is best known to stimulate nucleocytoplasmic transport of incompletely spliced viral RNAs. Rev binds to RNAs containing the Rev-response element (RRE), which is contained within all incompletely spliced RNAs. The amino-terminal domain of Rev contains the RNA-binding activity of the protein and is an arginine-rich sequence that also serves as the nuclear-localization signal. Regions surrounding the amino-terminal domain are proposed to be important in the multimerization of the protein onto the RNA. The carboxy-terminal domain, originally referred to as the activation domain, contains the nuclear-export signal. The combined effects of the nuclear-localization and nuclear-export signals allow Rev to shuttle in and out of the host cell nucleus. This allows incompletely spliced RNAs access to the translation machinery and makes full-length genomic RNA available for encapsidation into virus particles.

The HIV Rev protein remains a hot topic. This review revisits the insights that have been gained into the control of gene expression by Rev and speculates on where current research is leading. It outlines what is known about the role of Rev in translation and encapsidation and how these are linked to its more traditional role of nuclear export, underlining the multifaceted nature of this small viral protein. It also discusses what more is to be learned in these fields and why continuing research on these 116 amino acids and understanding their function is still important in devising methods to combat AIDS.

Rev: beyond nuclear export. 2009 J Gen Virol. 90: 1303-1318

Related:

• Tat – the versatile protein of HIV-1
• Why is HIV a pathogen?
• How does HIV cause AIDS?
• Re-awakening old genes to help in the fight against viruses
• HIV is evolving rapidly to escape the immune system

Chemoreceptors are key components of the high-performance signal transduction system that controls bacterial chemotaxis. Chemoreceptors are typically localized in a cluster at the cell pole, where interactions among the receptors in the cluster are thought to contribute to the high sensitivity, wide dynamic range, and precise adaptation of the signaling system. Previous structural and genomic studies have produced conflicting models, however, for the arrangement of the chemoreceptors in the clusters. Using whole-cell electron cryo-tomography, here we show that chemoreceptors of different classes and in many different species representing several major bacterial phyla are all arranged into a highly conserved, 12-nm hexagonal array consistent with the proposed “trimer of dimers” organization. The various observed lengths of the receptors confirm current models for the methylation, flexible bundle, signaling, and linker sub-domains in vivo. Our results suggest that the basic mechanism and function of receptor clustering is universal among bacterial species and was thus conserved during evolution.

Universal architecture of bacterial chemoreceptor arrays. PNAS USA September 23 2009 doi: 10.1073/pnas.0905181106

Related:

• Bacterial Motility
• Super-Resolution Light Microscopy of Escherichia coli

Scientists have found that the human liver fluke (Opisthorchis viverrini) contributes to the development of bile duct (liver) cancer by secreting granulin, a growth hormone that is known to cause uncontrolled growth of cells. It was known that O. viverrini secreted a protein that caused cell growth, but the identity of the protein was unknown. It was also known that the parasite secreted granulin but we did not know that it could affect the human cells around it. Scientists used E. coli bacteria to express the O. viverrini granulin, which was shown to induce proliferation in mouse fibroblast cells and human bile duct cancer cells in the absence of the parasite. Proliferation of the cells was halted by adding anti-granulin antibody, proving granulin’s role in producing a cancerous environment.

The International Agency for Research on Cancer classifies the human liver fluke as a Group I Carcinogen, meaning that O. viverrini is a proven cause of cancer. In northern Thailand, where the liver fluke is most common, more than 7 million people are infected at any given time. Previously, it was thought that the cancer was caused by the physical damage brought about by the fluke feeding on cells lining the bile ducts, as well as a diet high in nitrosamines from fermented fish (a native dish of Thailand). The paper suggests that the granulin secreted by the parasite is a major contributing factor to developing bile duct cancer. This discovery leads the way to a better understanding of how liver flukes cause such a devastating form of cancer.

A Granulin-Like Growth Factor Secreted by the Carcinogenic Liver Fluke, Opisthorchis viverrini, Promotes Proliferation of Host Cells. PLoS Pathog 5(10): e100061 doi:10.1371/journal.ppat.1000611
The human liver fluke, Opisthorchis viverrini, infects millions of people throughout south-east Asia and is a major cause of cholangiocarcinoma, or cancer of the bile ducts. The mechanisms by which chronic infection with O. viverrini results in cholangiocarcinogenesis are multi-factorial, but one such mechanism is the secretion of parasite proteins with mitogenic properties into the bile ducts, driving cell proliferation and creating a tumorigenic environment. Using a proteomic approach, we identified a homologue of human granulin, a potent growth factor involved in cell proliferation and wound healing, in the excretory/secretory (ES) products of the parasite. O. viverrini granulin, termed Ov-GRN-1, was expressed in most parasite tissues, particularly the gut and tegument. Furthermore, Ov-GRN-1 was detected in situ on the surface of biliary epithelial cells of hamsters experimentally infected with O. viverrini. Recombinant Ov-GRN-1 was expressed in E. coli and refolded from inclusion bodies. Refolded protein stimulated proliferation of murine fibroblasts at nanomolar concentrations, and proliferation was inhibited by the MAPK kinase inhibitor, U0126. Antibodies raised to recombinant Ov- GRN-1 inhibited the ability of O. viverrini ES products to induce proliferation of murine fibroblasts and a human cholangiocarcinoma cell line in vitro, indicating that Ov-GRN-1 is the major growth factor present in O. viverrini ES products. This is the first report of a secreted growth factor from a parasitic worm that induces proliferation of host cells, and supports a role for this fluke protein in establishment of a tumorigenic environment that may ultimately manifest as cholangiocarcinoma.