Chemical biology approaches have been used to reveal that cell cycle progression through mitosis is critical for HPV infection. Using infectious HPV16 particles containing the intact viral genome, G1-synchronized human keratinocytes as hosts, and early viral gene expression as a readout for infection, researchers learned that the recipient cell must enter M phase (mitosis) for HPV infection to take place. Late M phase inhibitors had no effect on infection, whereas G1, S, G2, and early M phase cell cycle inhibitors efficiently prevented infection. They concluded that host cells need to pass through early prophase for successful onset of transcription of the HPV encapsidated genes. These findings provide one reason why HPVs initially establish infections in the basal compartment of stratified epithelia. Only this compartment of the epithelium contains cells progressing through the cell cycle, and therefore it is only in these cells that HPVs can establish their infection. By defining a major condition for cell susceptibility to HPV infection, these results also have potentially important implications for HPV control.

Establishment of Human Papillomavirus Infection Requires Cell Cycle Progression. 2009 PLoS Pathog 5(2): e1000318
Human papillomaviruses (HPV), which comprise more than 100 genotypes, are the most prevalent sexually transmitted infection and are associated with multiple human cancers including all cervical cancers, many other anogenital cancers, and 25% of head and neck cancers. The HPV life cycle is closely linked to epithelial differentiation of skin keratinocytes, with initial infection occurring only in the undifferentiated proliferating basal compartment of the epithelium and progeny virus production only in the terminally differentiated suprabasal compartment. So far, little is known about how host cells restrict the HPV life cycle to specific stages of skin cell development. Here, by identifying small molecule inhibitors of HPV infection, we discovered that cell cycle progression through mitosis is critical for the establishment of HPV infection. In addition, our further chemical genetic dissection of this process showed that early steps of mitosis are required for HPV infection and early gene expression. Our findings provide one reason why HPV only infects undifferentiated proliferating cells and provide new leads for the development of preventive and therapeutic strategies against HPV infection.

Related:

• Should we cure cancer?
• Viruses and Human Cancer
• Transplacental transmission of Human Papillomavirus
• HPV vaccines: prospects for eliminating ano-genital cancer

The world is on the verge of making major inroads against malaria – a deadly disease that still claims the lives of more than 1 million people annually, mostly children less than 5 years of age. Over the past decade, scientists, large pharmaceutical companies and small biotechnology firms, governments and philanthropic organizations have come together to mount a full frontal attack on malaria, and there is now even talk of the ‘E word’ – that is, eradication. This collection highlights advances in the deployment of existing tools, and in the basic science of malaria – particularly those flowing from sequencing of the malaria parasite genomes – that will underpin the next generation of malaria-control tools, which will be needed if the scourge of malaria is to be eradicated.

Contents:

• Malaria: The end of the beginning – After decades of work, a pioneering malaria vaccine may soon reach the final phase of clinical trials. A vaccine that is far from perfect – but which may provide new direction and save thousands of lives.
• Malaria vaccine gets shot in the arm from tests – Promising results pave the way for a vaccine candidate to undergo full-blown trials across Africa.
• Malaria: The big push – Zambia, with help from partners around the world, is stepping up its battle against malaria.
• The billion-dollar malaria moment – For years the global malaria effort has been asking for more resources. Now the field needs to figure out a systematic strategy for spending the money effectively.
• Review: Malaria research in the post-genomic era

Articles:

• Comparative genomics of the neglected human malaria parasite Plasmodium vivax
• Genome sequence of the human malaria parasite Plasmodium falciparum
• Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii
• The genome of the simian and human malaria parasite Plasmodium knowlesi

Related:

• MicrobiologyBytes: Malaria

In 1998, the World Health Organization and several other international agencies launched Roll Back Malaria, a global partnership that aims to reduce the human and socioeconomic costs of malaria. Targets have been continually raised since this time and have culminated in the Roll Back Malaria Global Malaria Action Plan of 2008, where universal coverage of locally appropriate interventions is called for by 2010 and the long-term goal of malaria eradication again tabled for the international community. For malaria control and elimination initiatives to be effective, financial resources must be concentrated in regions where they will have the most impact, so it is essential to have up-to-date and accurate maps to guide effort and expenditure. In 2008, researchers of the Malaria Atlas Project constructed a map that stratified the world into three levels of malaria risk: no risk, unstable transmission risk (occasional focal outbreaks), and stable transmission risk (endemic areas where the disease is always present). Now, researchers extend this work by describing a new evidence-based method for generating continuous maps of P. falciparum endemicity within the area of stable malaria risk over the entire world’s surface. They then use this method to produce a P. falciparum endemicity map for 2007. Endemicity is important as it is a guide to the level of morbidity and mortality a population will suffer, as well as the intensity of the interventions that that will be required to bring the disease under control or additionally to interrupt transmission.

The researchers identified nearly 8,000 surveys of P. falciparum parasite rates (Pf PR; the percentage of a population with parasites detectable in their blood) completed since 1985 that met predefined criteria for inclusion into a global database of PfPR data. They then used ‘‘model-based geostatistics’’ to build a world map of P. falciparum endemicity for 2007 that took into account where and, importantly, when and all these surveys were done. Predictions were comprehensive (for every area of stable transmission globally) and continuous (predicted as a endemicity value between 0% and 100%). The population at risk of three levels of malaria endemicity were identified to help summarize these findings: low endemicity, where PfPR is below 5% and where it should be technically feasible to eliminate malaria; intermediate endemicity where PfPR is between 5% and 40% and it should be theoretically possible to interrupt transmission with the universal coverage of bed nets; high endemicity is where PfPR is above 40% and suites of locally appropriate intervention will be needed to bring malaria under control. The global level of malaria endemicity is much reduced when compared with historical maps. Nevertheless, the resulting map indicates that in 2007 almost 60% of the 2.4 billion people at malaria risk were living in areas with a stable risk of P. falciparum transmission – 0.69 billion people in Central and South East Asia (CSE Asia), 0.66 billion in Africa, Yemen, and Saudi Arabia (Africaþ), and 0.04 billion in the Americas. The people of the Americas were all in the low endemicity class. Although most people exposed to stable risk in CSE Asia were also in the low endemicity class (88%), 11% were in the intermediate class, and 1% were in the high endemicity class. By contrast, high endemicity was most common and widespread in the Africaþ region (53%), but with significant numbers in the intermediate (30%), and low (17%) endemicity classes.

The accuracy of this new world map of P. falciparum endemicity depends on the assumptions made in its construction and critically on the accuracy of the data fed into it, but because of the statistical methods used to construct this map, it is possible to quantify the uncertainty in the results for all users. Thus, this map (which, together with the data used in its construction, will be freely available) represents an important new resource that clearly indicates areas where malaria control can be improved (for example, Africa) and other areas where malaria elimination may be technically possible. In addition, planned annual updates of the global P. falciparum endemicity map and the PfPR database by the Malaria Atlas Project will help public health experts to monitor the progress of the malaria control community towards international control and elimination targets.

A world malaria map: Plasmodium falciparum endemicity in 2007. 2009 PLoS Med 6(3): e1000048
Efficient allocation of resources to intervene against malaria requires a detailed understanding of the contemporary spatial distribution of malaria risk. It is exactly 40 y since the last global map of malaria endemicity was published. This paper describes the generation of a new world map of Plasmodium falciparum malaria endemicity for the year 2007. A total of 8,938 P. falciparum parasite rate (PfPR) surveys were identified using a variety of exhaustive search strategies. Of these, 7,953 passed strict data fidelity tests for inclusion into a global database of PfPR data, age-standardized to 2–10 y for endemicity mapping. A model based geostatistical procedure was used to create a continuous surface of malaria endemicity within previously defined stable spatial limits of P. falciparum transmission. These procedures were implemented within a Bayesian statistical framework so that the uncertainty of these predictions could be evaluated robustly. The uncertainty was expressed as the probability of predicting correctly one of three endemicity classes; previously stratified to be an informative guide for malaria control. Population at risk estimates, adjusted for the transmission modifying effects of urbanization in Africa, were then derived with reference to human population surfaces in 2007. Of the 1.38 billion people at risk of stable P. falciparum malaria, 0.69 billion were found in Central and South East Asia (CSE Asia), 0.66 billion in Africa, Yemen, and Saudi Arabia (Africaþ), and 0.04 billion in the Americas. All those exposed to stable risk in the Americas were in the lowest endemicity class. The vast majority (88%) of those living under stable risk in CSE Asia were also in this low endemicity class; a small remainder(11%) were in the intermediate endemicity class; and the remaining fraction (1%) in high endemicity areas. High endemicity was widespread in the Africaþ region, where 0.35 billion people are at this level of risk. Most of the rest live at intermediate risk (0.20 billion), with a smaller number (0.11 billion) at low stable risk. High levels of P. falciparum malaria endemicity are common in Africa. Uniformly low endemic levels are found in the Americas. Low endemicity is also widespread in CSE Asia, but pockets of intermediate and very rarely high transmission remain. There are therefore significant opportunities for malaria control in Africa and for malaria elimination elsewhere. This 2007 global P. falciparum malaria endemicity map is the first of a series with which it will be possible to monitor and evaluate the progress of this intervention process.

Related:

• MicrobiologyBytes: Malaria
• Malaria, mosquitoes and the legacy of Ronald Ross
• New ways to beat malaria
• Researchers characterize potential protein targets for malaria vaccine
• Researchers Find Essential Proteins for Critical Stage of Malaria Transmission

Larval therapy for leg ulcers (VenUS II): randomised controlled trial. BMJ 2009;338:b773
Objective: To compare the clinical effectiveness of larval therapy with a standard debridement technique (hydrogel) for sloughy or necrotic leg ulcers.
Design: Pragmatic, three armed randomised controlled trial.
Setting: Community nurse led services, hospital wards, and hospital outpatient leg ulcer clinics in urban and rural settings, United Kingdom.
Participants: 267 patients with at least one venous or mixed venous and arterial ulcer with at least 25% coverage of slough or necrotic tissue, and an ankle brachial pressure index of 0.6 or more.
Interventions: Loose larvae, bagged larvae, and hydrogel.
Main outcome measures: The primary outcome was time to healing of the largest eligible ulcer. Secondary outcomes were time to debridement, health related quality of life (SF-12), bacterial load, presence of meticillin resistant Staphylococcus aureus, adverse events, and ulcer related pain (visual analogue scale, from 0 mm for no pain to 150 mm for worst pain imaginable).
Results: Time to healing was not significantly different between the loose or bagged larvae group and the hydrogel group (hazard ratio for healing using larvae v hydrogel 1.13, 95% confidence interval 0.76 to 1.68; P=0.54). Larval therapy significantly reduced the time to debridement (2.31, 1.65 to 3.2; P<0.001). Health related quality of life and change in bacterial load over time were not significantly different between the groups. 6.7% of participants had MRSA at baseline. No difference was found between larval therapy and hydrogel in their ability to eradicate MRSA by the end of the debridement phase (75% (9/12) v 50% (3/6); P=0.34), although this comparison was underpowered. Mean ulcer related pain scores were higher in either larvae group compared with hydrogel (mean difference in pain score: loose larvae v hydrogel 46.74 (95% confidence interval 32.44 to 61.04), P<0.001; bagged larvae v hydrogel 38.58 (23.46 to 53.70), P<0.001).
Conclusions: Larval therapy did not improve the rate of healing of sloughy or necrotic leg ulcers or reduce bacterial load compared with hydrogel but did significantly reduce the time to debridement and increase ulcer pain.

Related:

• MRSA: Methicillin-resistant Staphylococcus aureus
• Novel treatments for MRSA
• Evolution and pathogenesis of Staphylococcus aureus

The press was buzzing with speculation about the chances of a vaccine to prevent diabates. Very good news for diabetics? Well not so fast. Before we look at the science, let me tell you two things about myself. First, I have two close relatives who are affected by diabetes, so this is a disease I care a lot about. Second, I’ve been in the virology business a long time – and we’ve been here before.

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The new paper claimed to have detected “enterovirus capsid protein vp1″ in 44 out of 72 pancreases from children who had died of type-1 diabetes shortly after becoming ill, but in only three out of 50 neonatal and paediatric normal control specimens. Statistically there is a strong correlation in this study between diabetes and the presence of the virus protein, but a correlation does not indicate a cause. Are diabetics more susceptible to enterovirus infection? We don’t know. While it’s not ethically possible to satisfy Koch’s postulates in humans, we need to be very careful in inferring from small scale studies such as this one:

1. The microorganism must be found in abundance in all organisms suffering from the disease.
2. The microorganism must be isolated from a diseased organism and grown in pure culture.
3. The cultured microorganism should cause disease when introduced into a healthy organism.
4. The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.

There are over a hundred different enteroviruses and the antibody used for detection of virus protein in this study (yes, that’s right, just one non-specific antibody) does not identify the virus involved. Vaccine against diabetes? I don’t think so.

But as I said, we’ve been here before. There are reports of viruses associated with diabetes dating from the 1960s, and a very well known model of Coxsackie virus B4 causing diabetes in mice dating from the 1970s (Coxsackie Viruses and Diabetes Mellitus. BMJ 1973 November 3; 4(5887): 260–262). So does the latest work add anything new, and is a vaccine against diabetes just around the corner? No. I wish it was.

Related:

• Can you have confidence in the news?
• Media coverage affects how people perceive the threat of disease

Related:

• Vaccination does not cause autism
• MMR: our children, our choice?

With life-cycles measured in minutes as opposed to years, bacteria have an extraordinary ability to evolve and adapt rapidly to changes in their environment. Thus, in a world where only the fittest survive, those bacteria which have developed resistance to antibiotics will predominate. This is particularly apparent in hospital environments where bacteria are in constant contact with many different antibiotics; such repeated exposure has facilitated the development of resistance to multiple antibiotics and what we now refer to as hospital acquired or nosocomial infections.

Read more

Related:

• Probiotics – friendly bacteria?
• Probiotics – weapons in the war against gut pathogens
• Antibiotics, your gut, and you
• Gut Feeling

In prion diseases, what transforms the normal PrP protein into a life-threatening substance is the abnormal alteration of its chemical structure. Moreover, prions have the treacherous ability to replicate by imprinting their abnormal structure into healthy PrPs, thereby generating new pathogenic particles. While this conversion process explains how prions are disseminated, an abnormal function of the prion protein is considered to be one of the reasons for neuronal degeneration. However, the normal function of PrP has remained an unsolved mystery for many years. All previous experiments in genetically modified mice had failed to provide conclusive evidence, as these animals lacking PrP seemed perfectly healthy. The scientists were able to show that the lack of PrP can cause clear physiological abnormalities in a living animal by using the tiny zebrafish as a model.

When the researchers microinjected zebrafish eggs with morpholinos, DNA-like molecules that prevent the normal production of PrP, the treated zebrafish embryos were unable to develop normally and eventually died. The proteins in the fish embryos normally found at cell-to-cell contact sites disappeared, rendering these cells unable to communicate and carry out the differentiation program that shapes the major structures of the body, including the nervous system. PrP serves as a glue element, bringing cells together and keeping them in contact. When two neighboring cells make contact, they become able to exchange important signals that affect the function of a tissue in the body. Although this work does not offer an immediate cure for CJD or BSE, it widens our understanding of prion diseases and provides hope for effective treatments.

Regulation of embryonic cell adhesion by the prion protein. 2009 PLoS Biol 7(3): e1000055
Prion proteins (PrPs) are key players in fatal neurodegenerative disorders, yet their physiological functions remain unclear, as PrP knockout mice develop rather normally. We report a strong PrP loss-of-function phenotype in zebrafish embryos, characterized by the loss of embryonic cell adhesion and arrested gastrulation. Zebrafish and mouse PrP mRNAs can partially rescue this knockdown phenotype, indicating conserved PrP functions. Using zebrafish, mouse, and Drosophila cells, we show that PrP: (1) mediates Caþ2-independent homophilic cell adhesion and signaling; and (2) modulates Caþ2-dependent cell adhesion by regulating the delivery of E-cadherin to the plasma membrane. In vivo time-lapse analyses reveal that the arrested gastrulation in PrP knockdown embryos is due to deficient morphogenetic cell movements, which rely on E-cadherin–based adhesion. Cell-transplantation experiments indicate that the regulation of embryonic cell adhesion by PrP is cell-autonomous. Moreover, we find that the local accumulation of PrP at cell contact sites is concomitant with the activation of Src-related kinases, the recruitment of reggie/flotillin microdomains, and the reorganization of the actin cytoskeleton, consistent with a role of PrP in the modulation of cell adhesion via signaling. Altogether, our data uncover evolutionarily conserved roles of PrP in cell communication, which ultimately impinge on the stability of adherens cell junctions during embryonic development.

Related:

• The Origin of BSE
• A novel approach in the molecular differentiation of prion strains
• What the heck are prions for?
• Alzheimer’s Disease and Prions