Kaposi’s sarcoma (KS) is a multifocal tumour only found in a few groups of people, including elderly Mediterranean men, individuals in Africa and patients with immune disorders. The tumours arise from the formation of new blood or lymphatic vessels (angiogenesis or lymphangiogenesis) due to the proliferation of endothelial cells. In 1994 Chang and Moore identified a new virus, Kaposi’s sarcoma-associated herpesvirus (KSHV) as the cause of these tumours.
Unlike other herpesviruses, the seroprevalence of KSHV is not ubiquitous, perhaps only 5% in those countries with low KSHV rates such as the USA and Northern Europe). Like all herpesviruses, KSHV infection persists for the life of the host and can enter either of two states: latency or lytic reactivation. In latency, the minimum number of viral genes is expressed to maintain the virus genome in dividing cells, evading immune detection. Lytic reactivation occurs when the virus re-enters productive replication to generate new progeny, lysing the host cell in the process. And like all herpesviruses KSHV likes to mess with the immune system of its host. The KSHV genome contains 86 genes, almost a quarter of which encode proteins with immunoregulatory activities such as T- and B-cell function, complement activation, the innate antiviral interferon response and natural killer cell activity. Many of these gene are homologues of cellular proteins.
The KSHV proteins MIR1 and MIR2 ubiquitinate the cytoplasmic tail of MHC-I which triggers endocytosis and proteasomal degradation. This protects KSHV-infected cells from NK-mediated lysis. MIR2 can also down-regulate other components of the immune synapse, ICAM (CD54) and PECAM (CD31) by the same mechanism.
The KSHV vOX2 protein causes the cellular CD200 receptor to deliver an inhibitory signal to granulocytes, although the mechanism by which this acts is not yet well defined.
The KCP protein is present on the surface of KSHV virions and infected cells and protects them from complement attack by accelerating the decay of the classical pathway C3 convertase enzyme complex.
The K15 protein activates MAP kinases and this affects immune function.
KSHV encodes a family of 12 miRNAs. These regulate both B- and T-cell function.
The K1 protein reduces the presence of B cell receptors on the surface of B cells and interferes with the production of cytokines, and inhibits apoptosis.
The MIR2 protein down-regulates tetherin, which is involved in normal B-cell differentiation.
Three KSHV chemokine homologues (vCCL1–3) have affinity for chemokine receptors (CCRs) and this affects T-cell responses.
KSHV proteins inhibit interferon pathways.
Since KSHV infection results in lifelong persistence of the virus, these immunomodulation activities are clearly successful in preventing its elimination by the immune system. Many questions about KSHV infection remain unanswered, but we have learned valuable lessons about the normal function of the immune system through studying this virus.
Obesity is an enormous public health problem, arising as a consequence of alterations in eating behavior and how the body regulates energy intake, expenditure, and storage. Although an increased intake of energy-dense foods, especially when combined with reduced physical activity, contributes to the high prevalence of obesity, the existence of complex systems that regulate energy balance requires that this paradigm be considered in a larger context. In particular, recent evidence suggests that the gut microbiota may play a role in obesity by increasing the host’s energy-harvesting efficiency.
The treatment of obesity is challenging. Various surgical procedures designed to interfere with the ingestion and/or absorption of foods have been developed over the last 60 years. The Roux-en-Y gastric bypass (RYGB), currently the most commonly performed operation, involves creating a small gastric pouch from the stomach. This surgery leads to changes in acid exposure to the gastric remnant and proximal small bowel, restricts the amount and types of food that can be comfortably ingested, promotes a modest degree of nutrient malabsorption by shortening the length of the small bowel, and may result in intestinal dysmotility, all of which might be expected to alter the gut microbiota. Presently, very little is known about the changes in the gut microbiota that occur after RYGB, and no information has been published on changes in microbial diversity after RYGB in humans.
A recent study used the traditional Sanger and high-throughput 454 pyrosequencing methods to analyze the human gut microbiota in 9 individuals, 3 in each of the categories of normal weight, morbidly obese, and post-gastric bypass surgery. The goals were to identify specific microbial lineages that may play important roles in the development of obesity and also to determine whether the presence or abundance of these microorganisms changes after RYGB.
Human gut microbiota in obesity and after gastric bypass. PNAS USA January 21, 2009
Recent evidence suggests that the microbial community in the human intestine may play an important role in the pathogenesis of obesity. We examined 184,094 sequences of microbial 16S rRNA genes from PCR amplicons by using the 454 pyrosequencing technology to compare the microbial community structures of 9 individuals, 3 in each of the categories of normal weight, morbidly obese, and post-gastric-bypass surgery. Phylogenetic analysis demonstrated that although the Bacteria in the human intestinal community were highly diverse, they fell mainly into 6 bacterial divisions that had distinct differences in the 3 study groups. Specifically, Firmicutes were dominant in normal-weight and obese individuals but significantly decreased in post-gastric-bypass individuals, who had a proportional increase of Gammaproteobacteria. Numbers of the H2-producing Prevotellaceae were highly enriched in the obese individuals. Unlike the highly diverse Bacteria, the Archaea comprised mainly members of the order Methanobacteriales, which are H2-oxidizing methanogens. Using real-time PCR, we detected significantly higher numbers of H2-utilizing methanogenic Archaea in obese individuals than in normal-weight or post-gastric-bypass individuals. The coexistence of H2-producing bacteria with relatively high numbers of H2-utilizing methanogenic Archaea in the gastrointestinal tract of obese individuals leads to the hypothesis that interspecies H2 transfer between bacterial and archaeal species is an important mechanism for increasing energy uptake by the human large intestine in obese persons. The large bacterial population shift seen in the post-gastric-bypass individuals may reflect the double impact of the gut alteration caused by the surgical procedure and the consequent changes in food ingestion and digestion.
Burkitt’s lymphoma (BL) was first described 50 years ago, and the first human tumour virus Epstein–Barr virus (EBV) was discovered in BL tumours soon after. Since then, the role of EBV in the development of BL has become more and more enigmatic. Only recently have we finally begun to understand, at the cellular and molecular levels, the complex and interesting interaction of EBV with B cells that creates a predisposition for the development of BL. This review discusses the intertwined histories of EBV and BL and their relationship to the cofactors in BL pathogenesis: malaria and the MYC translocation.
There are many options still available for new antibiotics. While the search for new drugs seems to be declining, in this article in Microbiology Today, Flavia Marinelli takes a look at the need for new antimicrobials:
Novel classes of antibiotics are constantly required due to the expanding population of patients at risk and the growing prevalence of resistant pathogens in hospital- or community-acquired infections. Despite this need, major pharmaceutical players seem to be reducing their efforts to discover new antibiotics. This is due to a combination of factors such as the maturity, great competition and increased genericization of the antibiotic market. Unrealized expectations from high-throughput screening, combinatorial chemistry and pathogen-genome-derived targets have also had a negative effect. The perception prevails that the discovery of novel antibiotics is a very rare event. On the other hand, past and present successes speak for a return to microbial product screening.
Places to study at the University of Leicester are filling up fast:
Student application figures at the University of Leicester – named University of the Year for 2008-9 by the Times Higher – have rocketed. While applications nationally increased by over 7% – at Leicester applications are 16% higher than last year. That means that almost 20,000 students will chase 2,500 places at the University. Leicester has seen one of the largest increases in applications in the UK. In fact, over the past three years (2006-9) our applications have increased 49% – the 3rd biggest amongst traditional pre-1992 universities. This success is attributable to the strong research and teaching record Leicester enjoys and our very high student satisfaction record. Applications from Home and EU students for undergraduate study are up by 14% and overseas by 48%. Post graduate taught applications are also strong with an increase of 14% from home / EU students and 77% from overseas, an increase of 69% overall. Applications for postgraduate research are 37% higher than at the same point last year. In total, over 20,000 students study at the University of Leicester.
The good news is that in response to this, from 2010, you have not one but TWO choices to study microbiology at Leicester:
A recent paper in Trends in Microbiology examined the possibilities for using bacteriophages in controlling biofilms which might result in healthcare-associated infections (Preventing biofilms of clinically relevant organisms using bacteriophage. 2009 Trends in Microbiology 17: 66-72). Biofilms are firmly attached microbial communities in which the organisms produce an extracellular polymeric matrix. Biofilm organisms might cause disease by detachment of individual cells or clumps of cells, by production of endotoxin, or by providing a niche for the development of antibiotic-resistant organisms. Biofilm organisms are usually tolerant to antimicrobial agents and the treatment of indwelling medical device-associated infections with systemic antimicrobial agents is usually ineffective.
Bacteriophages have been used for the treatment of infectious diseases in plants and animals, although few clinical trials with stringent negative controls have been carried out. There is a renewed interest in phage therapy in light of growing concerns with antimicrobial resistance in healthcare institutions worldwide. The use of phages for the treatment of device-associated infections could reduce the use of antibiotics and might limit the spread of resistant organisms.
There is some evidence for the potential of phages in biofilm control. Bacteriophage T4 phage was effective against E. coli biofilms in a glucose-limited chemostat, although the rate of phage synthesis and assembly were directly proportional to the amount of protein synthesis in the host cell. Some phages produce polysaccharide depolymerases that have the potential to degrade the biofilm matrix.
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However, there are several important characteristics of phage that should be considered when evaluating the potential of phages to control clinically relevant biofilms. The specificity of receptors for a single phage strain will determine its host range; some phage have specificity at the strain level, such as strain typing phages, whereas some are more broad-spectrum and can infect multiple strains or related species. This high degree of specificity could be a drawback, especially in the case of polymicrobial biofilms.
Few studies have explored the role of biofilms in the development of phage-resistance. Phage cocktails developed via the isolation of host range mutants and broad spectrum phage could be advantageous. Another important question is how a patient’s immune system will respond to the therapeutic introduction of phage. Phages are antigenic and elicit a response by serum antibodies and the cellular immune system. Repeated exposure to the phage results in increasing antibody titers and studies in animal models have shown that phage is cleared from the bloodstream by the cellular immune system. In a short-lived treatment, the antibody response to phage is weak except in cases were serum antibody titers are present before phage treatment. It is possible, although unproven, that phage might associate with biofilms and thereby be protected from inactivation. It might also be possible to design mutant phages with enhanced ability to resist clearance by the cellular immune system.
“More researchers should engage with the blogosphere”
The blogosphere differs from mass media and specialized media in many respects, but the same considerations apply in disseminating new scientific results there. Authors of papers in press have the right to correct misrepresentations and to point to results that will appear in a paper. But a full discussion should await the paper’s publication.
Indeed, researchers would do well to blog more than they do. The experience of journals such as Cell and PLoS ONE, which allow people to comment on papers online, suggests that researchers are very reluctant to engage in such forums. But the blogosphere tends to be less inhibited, and technical discussions there seem likely to increase.
Moreover, there are societal debates that have much to gain from the uncensored voices of researchers. A good blogging website consumes much of the spare time of the one or several fully committed scientists that write and moderate it. But it can make a difference to the quality and integrity of public discussion.
HIV is evolving rapidly to escape the human immune system. Researchers have shown HIV is able to adapt rapidly to counter human genes controlling immune system molecules that can target it for destruction. Progression to AIDS is tied to genes which control production of key immune system molecules called human leucocyte antigens (HLAs). Humans differ in the HLA genes they have, and even small differences can have a big impact on how quickly AIDS develops. Researchers found mutations that enabled HIV effectively to neutralise the effect of a particular HLA gene were more frequent in populations with a high prevalence of that specific gene.
Adaptation of HIV-1 to human leukocyte antigen class I. Nature, 25 February 2009
The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host–pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8+ T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection1. Mutation within these epitopes can allow viral escape from CD8+ T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128–135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8+ T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.
Prion diseases are a closely related group of fatal neurodegenerative disorders affecting the central nervous system of humans and animals. They include Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), and kuru in humans; bovine spongiform encephalopathy (BSE) in cattle; and scrapie in sheep. The identification of variant CJD (vCJD) in the U.K. in 1996 and the subsequent experimental confirmation that BSE in cattle and vCJD in humans are caused by the same prion strain has led to a variety of concerns relating to public health. Iatrogenic transmission of classical (sporadic) CJD by a contaminated neurosurgical instrument has been reported, and epidemiological evidence suggests a fraction of apparently sporadic CJD may be caused by unrecognized iatrogenic infection during general surgery. The unknown but potentially substantial prevalence of clinically silent infection with vCJD prions in populations exposed to dietary BSE prions, together with the much wider tissue distribution of infectivity in vCJD, highlights the concerns of risk of infection through contact with surgical instruments. Secondary vCJD arising from blood transfusion has now been documented, indicating significant prionemia in asymptomatic donors during the incubation period. This wide distribution of infectivity makes common surgical and endoscopic procedures, in addition to neurosurgery and eye surgery, a potential risk factor for iatrogenic transmission of vCJD. Further, it is established that tissue prions withstand many forms of sterilization techniques and that the metal-adsorbed agent is even more resistant to both thermal and chemical treatments.
Highly sensitive, quantitative cell-based assay for prions adsorbed to solid surfaces. PNAS USA February 9, 2009
Prions are comprised principally of aggregates of a misfolded host protein and cause fatal transmissible neurodegenerative disorders of humans and animals, such as variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Prions pose significant public health concerns, including contamination of blood products and surgical instruments; require laborious and often insensitive animal bioassay to detect; and resist conventional hospital sterilization methods. A major experimental advance was the cell culture-based scrapie cell assay, allowing prion titres to be estimated more precisely and an order of magnitude faster than by animal bioassays. Here we describe a bioassay method that exploits the marked binding affinity of prions to steel surfaces. Using steel wires as a concentrating and sensitization tool and combining with an adapted scrapie cell endpoint assay we can achieve, for mouse prions, a sensitivity 100X higher than that achieved in standard mouse bioassays. The rapidity and sensitivity of this assay offers a major advance over small animal bioassay in many aspects of prion research. In addition, its specific application in assay of metal-bound prions allows evaluation of novel prion decontamination methods.
Kaposi’s sarcoma (KS) is a multifocal tumour only found in a few groups of people, including elderly Mediterranean men, individuals in Africa and patients with immune disorders. The tumours arise from the formation of new blood or lymphatic vessels (angiogenesis or lymphangiogenesis) due to the proliferation of endothelial cells. In 1994 Chang and Moore identified a new virus, Kaposi’s sarcoma-associated herpesvirus (KSHV) as the cause of these tumours.
