Archive for April, 2011

Tuberculosis: forgotten but not gone

Friday, April 29th, 2011

Microbiology Today UK scientists had an important role to play in the development of the first antibiotics for the treatment of tuberculosis in the mid-20th century. As we enter the second decade of the 21st century, the world is now confronted with the appearance of extremely drug-resistant strains. In this article in Microbiology Today (pdf) Stephen Gillespie asks what are UK scientists doing this time to help combat this serious threat?

It was not until the mid-1940s that specific antibiotic therapy became available when Selman Waks- man and Albert Schatz extracted a substance named streptomycin from a Streptomyces bacterium isolated from the soil. Shortly after this, a number of other antibiotics with activity against M. tuberculosis were described. The UK played an important role in developing effective treatment regimens. When streptomycin was first available, there was not enough for all of the patients who needed it, so the Medical Research Council team who had been asked to investigate the new drug decided that it was fair and ethical to develop a randomized placebo control trial of the new treatment. This was the first trial of this type ever performed, and the importance of its results made it the standard way of testing new drugs throughout the world. What the study revealed was that the patients receiving streptomycin fared much better initially, but at the end of 5 years the same number of patients had died. This was because the organisms infecting the streptomycin-treated patients had developed resistance. Fortunately, other drugs had been developed and could be combined with streptomycin; of these the most important was isoniazid. As new drugs became available, the Medical Research Council tuberculosis unit and their counterparts in the US Public Health Service trialled new agents in various combinations, incorporating rifampicin in the 1960s and, in the 1970s, rediscovering the value of pyrazinamide, which had previously been rejected due to toxicity. Each of the new regimens was shorter so that, by the time that the regimen that remains the international standard was finalized, treatment duration had reduced from 2 years to 6 months. In most European and North American countries, the combination of effective treatment, rising living standards and BCG vaccination resulted in the number of cases of tuberculosis falling to very low levels. In resource-poor countries, however, the number of cases did not fall in the same way. Also, for many countries in sub-Saharan Africa, the emergence of human immunodeficiency virus (HIV) was a catastrophe as the virus rendered the patients especially susceptible to TB. From the mid-1980s, the number of cases of TB increased rapidly across the continent.

 

 

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Proof, if proof were needed

Thursday, April 28th, 2011

Proofs … that the page proofs for the fifth edition of Principles of Molecular Virology have been approved, the book is currently being printed, and you can order your copy now from Amazon or Amazon.co.uk!

Regulation of Listeria virulence

Wednesday, April 27th, 2011

Listeria monocytogenes Listeria monocytogenes is the causative agent of listeriosis, a severe foodborne infection. These bacteria live as soil saprotrophs on decaying plant matter but also as intracellular parasites, using the cell cytosol as a replication niche. PrfA, a regulatory protein, integrates a number of environmental cues that signal the transition between these two contrasting lifestyles, activating a set of key virulence factors during host infection. While a number of details concerning the general mode of action of this virulence master switch have been elucidated, others remain unsolved. Recent work has revealed additional mechanisms that contribute to L. monocytogenes virulence modulation, often via cross-talk with PrfA, or by regulating new genes involved in host colonization.

Regulation of Listeria virulence: PrfA master and commander. Curr Opin Microbiol. Mar 7 2011

Mosquitoes and malaria (nice video)

Tuesday, April 26th, 2011

Clinical Management of HIV Drug Resistance

Monday, April 25th, 2011

HIV Drug Resistance Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy.

Clinical Management of HIV Drug Resistance. Viruses 2011, 3(4), 347-378; doi:10.3390/v3040347

The proportional lack of archaeal pathogens – do phages hold the key?

Friday, April 22nd, 2011

Tree of life Although Archaea inhabit the human body and possess some characteristics of pathogens, there is a notable lack of pathogenic archaeal species identified to date. This paper proposes that the scarcity of disease-causing Archaea is due, in part, to mutually-exclusive phage and virus populations infecting Bacteria and Archaea, coupled with an association of bacterial virulence factors with phages or mobile elements. The ability of bacterial phages to infect Bacteria and then use them as a vehicle to infect eukaryotes may be difficult for archaeal viruses to evolve independently. Differences in extracellular structures between Bacteria and Archaea would make adsorption of bacterial phage particles onto Archaea (i.e. horizontal transfer of virulence) exceedingly hard. If phage and virus populations are indeed exclusive to their respective host Domains, this has important implications for both the evolution of pathogens and approaches to infectious disease control.

The proportional lack of archaeal pathogens: Do viruses/phages hold the key? (2011) BioEssays 1521-1878 doi: 10.1002/bies.201000091

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Routine rotavirus vaccination in Brazil has reduced diarrheoa deaths in children

Wednesday, April 20th, 2011

Rotavirus Diarrhoeal disease, usually caused by infectious agents, is the second major cause of death in children aged under five years. Access to clean water and improved sanitation is the key to the primary prevention of diarrheal illnesses. Yet despite the targets of Millennium Development Goal 7 to half the number of people without access to clean water or improved sanitation by 2015, over one billion people worldwide do not currently have access to clean water and over two billion do not currently have access to improved sanitation. Since enteric viruses are primarily transmitted directly from one person to another, they cannot be controlled completely by improvements in sanitation. Therefore, although not replacing the urgent need to provide access to clean water and improved sanitation for all, vaccination programs that protect young children against some infections that cause diarrhea, such as rotavirus, which accounts for one-third of all child deaths caused by diarrhoea, are a pragmatic way forward. As large clinical trials have shown the safety and efficacy of rotavirus vaccines in population settings, in July 2009, the World Health Organization recommended including rotavirus vaccines into every country’s national immunization programs.

Rotavirus vaccination in all areas of Brazil is associated with reduced diarrheoa-related deaths and hospital admissions in children aged under five years. New research has shown that these real-world impact data – what actually happens in reality rather than in strictly controlled clinical trial settings – are consistent with the clinical trials and conclude that their study strengthens the evidence base for use of rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrheoa.

Brazil has a high incidence of diarrhea-related deaths and hospital admissions in young children and, in July 2006, the Brazilian Ministry of Health introduced rotavirus vaccination simultaneously in all 27 states, allowing the authors to conduct a ‘‘before’’ and ‘‘after’’ intervention analysis. Using routinely collected national data, the authors found that in 2007 an estimated 80% of infants received two doses of rotavirus vaccine, and by 2009 that this proportion rose to 84% of children younger than one year of age. In the three years following the introduction of rotavirus vaccination, diarrhea-related mortality rates and admissions among children aged under five years were, respectively, 22% and 17% lower than expected, with a cumulative total of 1,500 fewer diarrheoa deaths and 130,000 fewer hospital admissions. Furthermore, the largest reductions in deaths and admissions were among children who had the highest rates of vaccination (less than two years of age), and the lowest reductions were among children who were not age-eligible for vaccination during the study period (aged 2–4 years).

This time-series analysis provides evidence of substantial reductions following the introduction of rotavirus vaccination of both diarrheoa-related deaths and diarrheoa-related hospital admissions from a large middle-income country in the Americas with both developing and developed regions. In middle-income countries that are not eligible for financial support from donors, the potential reductions in diarrheoa-related hospital admissions and other health-care costs will be important for cost-effectiveness considerations to justify the purchase of these relatively expensive vaccines.

Decline in Diarrhea Mortality and Admissions after Routine Childhood Rotavirus Immunization in Brazil: A Time-Series Analysis. 2011 PLoS Med 8(4): e1001024. doi:10.1371/journal.pmed.1001024
Background: In 2006, Brazil began routine immunization of infants ,15 wk of age with a single-strain rotavirus vaccine. We evaluated whether the rotavirus vaccination program was associated with declines in childhood diarrhea deaths and hospital admissions by monitoring disease trends before and after vaccine introduction in all five regions of Brazil with varying disease burden and distinct socioeconomic and health indicators.
Methods and Findings: National data were analyzed with an interrupted time-series analysis that used diarrhea-related mortality or hospitalization rates as the main outcomes. Monthly mortality and admission rates estimated for the years after rotavirus vaccination (2007–2009) were compared with expected rates calculated from pre-vaccine years (2002–2005), adjusting for secular and seasonal trends. During the three years following rotavirus vaccination in Brazil, rates for diarrhea- related mortality and admissions among children ,5 y of age were 22% (95% confidence interval 6%–44%) and 17% (95% confidence interval 5%–27%) lower than expected, respectively. A cumulative total of ,1,500 fewer diarrhea deaths and 130,000 fewer admissions were observed among children ,5 y during the three years after rotavirus vaccination. The largest reductions in deaths (22%–28%) and admissions (21%–25%) were among children younger than 2 y, who had the highest rates of vaccination. In contrast, lower reductions in deaths (4%) and admissions (7%) were noted among children two years of age and older, who were not age-eligible for vaccination during the study period.
Conclusions: After the introduction of rotavirus vaccination for infants, significant declines for three full years were observed in under-5-y diarrhea-related mortality and hospital admissions for diarrhea in Brazil. The largest reductions in diarrhea-related mortality and hospital admissions for diarrhea were among children younger than 2 y, who were eligible for vaccination as infants, which suggests that the reduced diarrhea burden in this age group was associated with introduction of the rotavirus vaccine. These real-world data are consistent with evidence obtained from clinical trials and strengthen the evidence base for the introduction of rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.

Bacteriophage therapy of Pseudomonas aeruginosa in Cystic Fibrosis

Monday, April 18th, 2011

Pseudomonas aeruginosa Pseudomonas aeruginosa is the second most common pathogen responsible for hospital-acquired bacterial pneumonia as well as ventilator-associated pneumonia, and the first causative agent of morbidity and mortality in cystic fibrosis (CF) patients. Although antibiotics are still an effective means of treating bacterial lung infections, the alarming rise of multidrug-resistant bacteria in hospitals has highlighted the need for new therapies. Bacteriophages – viruses infecting bacteria – have been proposed to treat human bacterial infections since their discovery in the early 20th century. However, after a short period of development, the advent of antibiotics led to this therapeutic approach being abandoned, except in Eastern Europe where bacteriophages are still used today to treat patients. During the past 20 years, studies in animal models have demonstrated the potential of bacteriophages. Recently the first phase II clinical trial on bacteriophage treatments of chronic otitis was published, and demonstrated the interest of using bacteriophages on multidrug resistant infections.

The effects of bacteriophage therapy on lung infections has only very recently been addressed in animal models. On the one hand, a proof of concept with a bioluminescent strain of P. aeruginosa showed that bacteriophages administrated intranasally had a rapid efficacy with respect to preventing and curing deadly lung infections. On the other hand, a clinical strain of Burkholderia cenocepacia isolated from a CF patient was used to show that the intraperitoneal administration of bacteriophages was more effective than intranasal applications in a non-deadly infectious model. This paper reports an evaluation in an animal model of the efficacy of curative and preventive bacteriophage treatments of lung infections using a multidrug resistant mucoid P. aeruginosa strain isolated from a CF patient.

Pulmonary Bacteriophage Therapy on Pseudomonas aeruginosa Cystic Fibrosis Strains: First Steps Towards Treatment and Prevention. (2011) PLoS ONE 6(2): e16963. doi:10.1371/journal.pone.0016963
Multidrug-resistant bacteria are the cause of an increasing number of deadly pulmonary infections. Because there is currently a paucity of novel antibiotics, phage therapy – the use of specific viruses that infect bacteria – is now more frequently being considered as a potential treatment for bacterial infections. Using a mouse lung-infection model caused by a multidrug resistant Pseudomonas aeruginosa mucoid strain isolated from a cystic fibrosis patient, we evaluated bacteriophage treatments. New bacteriophages were isolated from environmental samples and characterized. Bacteria and bacteriophages were applied intranasally to the immunocompetent mice. Survival was monitored and bronchoalveolar fluids were analysed. Quantification of bacteria, bacteriophages, pro-inflammatory and cytotoxicity markers, as well as histology and immunohistochemistry analyses were performed. A curative treatment (one single dose) administrated 2 h after the onset of the infection allowed over 95% survival. A four-day preventive treatment (one single dose) resulted in a 100% survival. All of the parameters measured correlated with the efficacy of both curative and preventive bacteriophage treatments. We also showed that in vitro optimization of a bacteriophage towards a clinical strain improved both its efficacy on in vivo treatments and its host range on a panel of 20 P. aeruginosa cystic fibrosis strains. This work provides an incentive to develop clinical studies on pulmonary bacteriophage therapy to combat multidrug-resistant lung infections.

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Vaccine Potential of Nipah Virus-Like Particles

Friday, April 15th, 2011

Nipah VLP Since it was first recognized in 1998, Nipah virus (NiV) has caused several outbreaks in humans of encephalitic disease associated with high lethality. In the first outbreak, which was in Malaysia and Singapore, 265 humans became sick and some 40% of them died. Epidemiological links pointed to human contact with sick pigs in commercial piggeries, and the outbreak was brought under control through culling of approximately 1.1 million pigs. Since then, the virus has re-emerged in Bangladesh and neighboring India, starting in 2001, and between then and now, has caused several smaller but even deadlier disease outbreaks with case fatality rates ranging between 60 and 90%. Unlike the Malaysian outbreak, the route of transmission in these outbreaks was considered to be bat-to-human via food contaminated with bat saliva. In some cases, nosocomial transmissibility and person-to-person spread was also noted. An additional concern is that NiV is also potentially an agent of agro-terror since the rate of transmission of this virus in the pig population is close to 100%. Effective vaccine and therapies are needed to combat the threats posed by NiV.

2011 Vaccine Potential of Nipah Virus-Like Particles. 2011 PLoS ONE 6(4): e18437. doi:10.1371/journal.pone.0018437
Nipah virus (NiV) was first recognized in 1998 in a zoonotic disease outbreak associated with highly lethal febrile encephalitis in humans and a predominantly respiratory disease in pigs. Periodic deadly outbreaks, documentation of person-to-person transmission, and the potential of this virus as an agent of agroterror reinforce the need for effective means of therapy and prevention. In this report, we describe the vaccine potential of NiV virus-like particles (NiV VLPs) composed of three NiV proteins G, F and M. Co-expression of these proteins under optimized conditions resulted in quantifiable amounts of VLPs with many virus-like/vaccine desirable properties including some not previously described for VLPs of any paramyxovirus: The particles were fusogenic, inducing syncytia formation; PCR array analysis showed NiV VLP-induced activation of innate immune defense pathways; the surface structure of NiV VLPs imaged by cryoelectron microscopy was dense, ordered, and repetitive, and consistent with similarly derived structure of paramyxovirus measles virus. The VLPs were composed of all the three viral proteins as designed, and their intracellular processing also appeared similar to NiV virions. The size, morphology and surface composition of the VLPs were consistent with the parental virus, and importantly, they retained their antigenic potential. Finally, these particles, formulated without adjuvant, were able to induce neutralizing antibody response in Balb/c mice. These findings indicate vaccine potential of these particles and will be the basis for undertaking future protective efficacy studies in animal models of NiV disease.

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