Monthly Archives: March 2010

Pandemic norovirus rapidly evolves to make you vomit

Pandemic noroviruses have a faster rate of evolution than non-pandemic strains, which could explain why they are better adapted to cause worldwide outbreaks of viral gastroenteritis, according to research published free in PLoS Pathogens this week.

...probably not as clean as this if you have a norovirus infection!!

Norovirus is an RNA virus that is responsible for the majority of viral gastroenteritis outbreaks worldwide. Norovirus infection—dubbed ‘winter vomiting disease’—is notoriously associated with cruiseships and can cause havoc in hospitals. Symptoms of norovirus infection include diarrhoea and projectile vomiting, which can spread viral particles easily from person-to-person, on contaminated surfaces or in contaminated food and water. Moreover, the virus is incredibly contagious—only 10 or so viral particles are needed to cause infection—and able to survive for several days in a contaminated area.

Despite the fact that over 40 genotypes of norovirus circulate within a population at the same time, only one, known as genogroup II genotype 4 (GII.4), causes winter vomiting disease pandemics. 62% of worldwide norovirus outbreaks are caused by GII.4 and very little is known about why this particular norovirus genotype causes mass disease outbreaks.

Bull et al. investigated how quickly different norovirus genotypes replicated and mutated, and how this could contribute to the ‘fitness’ of the virus during infection. The researchers used in vitro RNA dependent RNA polymerase assays and bioinformatics data to measure the rates of replication, mutation and evolution for the GII.4 pandemic norovirus compared with rates for the less frequently detected non-pandemic norovirus genotypes (recombinant GII.b/G.III, GII.3 and GII.7), and hepatitis C virus as a control. They found that GII.4 strains of norovirus had much higher rates of mutation, replication and evolution than the other norovirus strains tested. Evolution rates were measured within the viral capsid (the outer protein coat of the virus) and GII.4 strains had more mutations that made changes to the capsid’s amino acid sequence than the other noroviruses.

Bull and colleagues argue that the rapid mutations seen in the GII.4 norovirus make it similar to influenza, in which “an increase in antigenic drift has been associated with increased outbreaks.” The research will help scientists better understand how norovirus causes winter vomiting disease pandemics and could prove useful during development of a vaccine or treatment for norovirus. So just remember this when you’re quarantined in your cruise cabin and upchucking into your toilet—the norovirus has mutated fast to make it ‘fit’ to infect you.

ResearchBlogging.orgBull, R., Eden, J., Rawlinson, W., & White, P. (2010). Rapid Evolution of Pandemic Noroviruses of the GII.4 Lineage PLoS Pathogens, 6 (3) DOI: 10.1371/journal.ppat.1000831

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Weak link in TB bacteria cell wall

The Mycobacterium tuberculosis protein LdtM2, involved in making “nonclassical” crosslinks in the bacterial cell wall, is required for virulence and antibiotic resistance. The study results, published online in Nature Medicine, could help identify new treatment combinations to tackle chronic tuberculosis infections.

Tuberculosis is a major global health threat. Drug resistance in TB is becoming a monumental problem and the very nature of the treatment schedule—usually a combination of four anti-TB drugs taken daily for six months—directly contributes to this problem. The majority of the TB bacteria are killed within the first two weeks of treatment but the remaining “persisters” need six months or more of treatment to effectively kill them. If this drug regime is misused or mismanaged then multidrug resistant and extensively drug resistant (XDR) strains of M. tuberculosis can develop …you only have to watch this slideshow of James Nachtwey’s photographs for XDRTB.org to see for yourself the devastating effects of XDR-TB.

Gupta and colleagues investigated the role of the M. tuberculosis cell wall in chronic TB infection—the physiology of which is poorly understood in the persistent stationary phase of bacterial growth. They examined the M. tuberculosis gene MT2594 (renamed in this paper ldtM2), which is a L,D-transpeptidase that helps create the “nonclassical” 3→3 crosslinks in the bacterial cell wall—a process which helps give the cell wall strength.

The researchers found that mutants lacking ldtM2 had an altered colony morphology compared with the wild-type strain—small, smooth, tower block-like colonies growing up from the agar surface into the air compared with the larger, rougher and flatter colonies of the wild-type. By making the mutants express ldtM2 again, they successfully restored the wild-type growth phenotype. They then infected mice with these mutant TB bacteria to see whether LdtM2 was important for bacterial virulence. After four weeks, mice were heavily infected with the wild-type and complemented bacterial strains and subsequently died, however, mice infected with ldtM2 mutant did not die nor were they significantly ill despite having bacteria present in their lungs. Moreover, during chronic TB infection in mice, ldtM2 mutants were more susceptible than wild-type bacteria to the antibiotic amoxicillin, in combination with clavulanate—added to inhibit the natural β-lactamases produced by TB bacteria, which normally allow the bacteria to resist the effects of β-lactam antibiotics like amoxicillin.

The authors suggest that the unusual 3→3 crosslinks made by the LdtM2 L,D-transpeptidase are “vital to the physiology of the peptidoglycan layer” and that these linkages, along with the classical 4→3 crosslinks, are involved in “maintaining and remodelling” the cell wall of the TB bacteria. Interestingly, this new data indicates that a combination of drugs to inhibit the L,D-transpeptidases and β-lactamases produced by TB bacteria could effectively kill the persistent bacteria that contribute  to chronic TB infection—something that would be most welcome on World TB day today.

ResearchBlogging.orgGupta, R., Lavollay, M., Mainardi, J., Arthur, M., Bishai, W., & Lamichhane, G. (2010). The Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin Nature Medicine DOI: 10.1038/nm.2120

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Vaccinate the kids to protect the “herd”

Vaccinating young children and adolescents against influenza protects unvaccinated individuals in the wider community (the herd immunity), show results from a clinical trial conducted in rural communities in Canada and published free in the journal JAMA. “Our findings … support selective influenza immunisation of school aged children with inactivated influenza vaccine to interrupt influenza transmission,” writes Mark Loeb and colleagues.

Influenza is an infectious disease which causes significant morbidity and mortality; in the United States around 36,000 people die, and 200,000 people are hospitalised, each year from influenza. Vaccination against seasonal and pandemic flu is fundamental to prevent the spread of disease. Current immunisation policy targets individuals who have a greater risk of flu complications, but flu vaccines can also be used to interrupt the spread of influenza across an entire population. Previous work has shown that children and adolescents play an important role in the transmission of influenza but it is still unclear whether vaccinating these children benefits the community as a whole and protects those that have not been immunised.

Loeb et al. recruited individuals from 46 Hutterite colonies in western Canada to test the community-wide benefits of flu vaccination programmes in children and young adolescents. Their cluster trial included 947 healthy children and adolescents, ranging from 3 to 15 years old, who they randomly assigned according to community to receive either a trivalent seasonal influenza vaccine or a hepatitis A vaccine as a control. They also recruited 2,326 members from the Hutterite communities who were not vaccinated during the study. All participants in the study were followed up for signs and symptoms of influenza over a six month period.

The investigators observed that the uptake of both vaccines in eligible healthy children was similar; 83% for the influenza vaccine and 79% for the hepatitis A vaccine. 119 unvaccinated individuals had laboratory-confirmed influenza; twice as many people in the communities assigned to the control vaccine had the disease compared to those communities assigned to influenza vaccine. Loeb et al. found that this pattern of disease incidence remained even when taking into account all study participants, including those who did and did not receive a vaccine. The researchers concluded that immunising children aged 3–15 years old against seasonal flu conferred 61% indirect protection in unvaccinated people.

“Our data suggest that a significant herd immunity effect can be achieved when the uptake of vaccine is approximately 80%,” write the investigators. Their study suggests that selectively immunising children during flu epidemics may help to prevent spread of the disease in the rest of the population.

ResearchBlogging.orgLoeb, M., Russell, M., Moss, L., Fonseca, K., Fox, J., Earn, D., Aoki, F., Horsman, G., Van Caeseele, P., Chokani, K., Vooght, M., Babiuk, L., Webby, R., & Walter, S. (2010). Effect of Influenza Vaccination of Children on Infection Rates in Hutterite Communities: A Randomized Trial JAMA: The Journal of the American Medical Association, 303 (10), 943-950 DOI: 10.1001/jama.2010.250

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The MetaHIT catalogue 2010— your gut microbiome directory

An international team of scientists have produced a catalogue of genes from the micro-organisms that live in our gut (the gut microbiome), and it is the first published work from the MetaHIT (Metagenomics of the Human Intestinal Tract) project. “This gene catalogue contains virtually all of the prevalent gut microbial genes in our cohort, provides a broad view of the functions important for bacterial life in the gut and indicates that many bacterial species are shared by different individuals,” write Junjie Qin and colleagues.

The research, published last week in the journal Nature, pieces together a staggering 576.6 gigabases of gene sequence to assemble and characterise 3.3 million non-redundant microbial genes from faecal samples from124 European individuals. The results provide a vital clue to the microbial species which are prevalent, and surprisingly common between different individuals, in the human gut.

The human body hosts trillions of micro-organism, most of which live in our gut. These gut bacteria are hugely important for human life, not only do they help us to get vital energy from the food we eat but changes in the types of micro-organisms in the gut are thought to contribute to bowel disease and obesity.

The researchers used an Illumina Genome Analyser to deep sequence DNA from faecal samples from Danish and Spanish adults who were healthy, overweight and obese, or had inflammatory bowel disease. This approach is called metagenomics and directly analyses genetic material from environmental samples, which means that organisms can be studied in their natural habitat and allows otherwise difficult-to-culture micro-organisms to be studied.

Qin et al. generated almost 200 times more metagenomic sequence data from the gut than had been produced in previous studies. The scientists found that their gene set was 150 times bigger than the human gene complement and included most of the known human intestinal microbial genes. Furthermore, their analysis revealed that 99% of the genes they identified were bacterial and that a common core of bacterial species existed in each person— including members of the Bacteriodetes and the Firmicutes, which have already been shown to be abundant in the gut environment. Finally, they used their gene catalogue to uncover the bacterial functions which are important for life in this habitat, such as synthesis of short-chain fatty acids, vital amino acids and vitamins, and the breakdown of complex polysaccharides.

“We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively,” conclude the investigators who hope that their extensive catalogue of the human gut microbiome will enable future studies of the association between microbial genes and human phenotypes, disease and living habits from birth to old age.

ResearchBlogging.orgQin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., Yamada, T., Mende, D., Li, J., Xu, J., Li, S., Li, D., Cao, J., Wang, B., Liang, H., Zheng, H., Xie, Y., Tap, J., Lepage, P., Bertalan, M., Batto, J., Hansen, T., Le Paslier, D., Linneberg, A., Nielsen, H., Pelletier, E., Renault, P., Sicheritz-Ponten, T., Turner, K., Zhu, H., Yu, C., Li, S., Jian, M., Zhou, Y., Li, Y., Zhang, X., Li, S., Qin, N., Yang, H., Wang, J., Brunak, S., Doré, J., Guarner, F., Kristiansen, K., Pedersen, O., Parkhill, J., Weissenbach, J., Antolin, M., Artiguenave, F., Blottiere, H., Borruel, N., Bruls, T., Casellas, F., Chervaux, C., Cultrone, A., Delorme, C., Denariaz, G., Dervyn, R., Forte, M., Friss, C., van de Guchte, M., Guedon, E., Haimet, F., Jamet, A., Juste, C., Kaci, G., Kleerebezem, M., Knol, J., Kristensen, M., Layec, S., Le Roux, K., Leclerc, M., Maguin, E., Melo Minardi, R., Oozeer, R., Rescigno, M., Sanchez, N., Tims, S., Torrejon, T., Varela, E., de Vos, W., Winogradsky, Y., Zoetendal, E., Bork, P., Ehrlich, S., & Wang, J. (2010). A human gut microbial gene catalogue established by metagenomic sequencing Nature, 464 (7285), 59-65 DOI: 10.1038/nature08821

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