MicrobiologyBytes

The urinary tract is among the most common sites of bacterial infection. Over half (53%) of all women and 14% of men experience at least one urinary tract infection (UTI) in their lifetime, leading to an average of 6.8 million physician office visits, 1.3 million emergency room visits, and 245,000 hospitalizations per year, with an annual cost of over US$2.4 billion in the United States alone. Escherichia coli is the infectious agent in more than 80% of uncomplicated UTIs, which occur in patients with a normal urinary tract devoid of structural abnormalities or inflammatory lesions.

In light of the recent E. coli outbreak in the UK, the news that scientists have made an important step toward what could become the first vaccine to prevent urinary tract infections is interesting. To help combat this common health issue, the scientists used a novel systematic approach combining bioinformatics, genomics and proteomics to look for key parts of the E. coli bacterium that could be used in a vaccine to elicit an effective immune response. The team screened 5,379 possible bacterial proteins and identified three strong candidates to use in a vaccine to prime the body to fight E. coli, the cause of most uncomplicated urinary tract infections. The vaccine produced prevented infection and produced key types of immunity when tested in mice.

Scientists have attempted to develop a vaccine for UTIs over the past two decades. This latest potential vaccine has features that may better its chances of success. It alerts the immune system to iron receptors on the surface of bacteria that perform a critical function allowing infection to spread. Administered via the nose rather than injected, it induces an immune response in the body’s mucosa, a first line of defense against invading pathogens. The protective immune response, which also produced in mucosal tissue in the urinary tract, should help the body fight infection where it starts. The research team is currently testing more strains of E. coli. Most of the strains produce the same iron-related proteins that the vaccine targets, an encouraging sign that the vaccine could work against many urinary tract infections.

Iron acquisition is a critical function required by bacteria in order to cause infections. In uropathogenic E. coli, this function is mediated by a repertoire of systems that scavenge iron from the host during infection. Vaccination with certain iron receptors from these systems is sufficient to elicit protective immunity from experimental urinary tract infection. Induction of an antibody response played a key role in protection from infection because antibody class-switching and the production of antibodies in urine correlated with reduced numbers of bacteria in the bladder. By targeting an entire class of molecules involved in iron acquisition instead of a single protein, it was possible to successfully identify components of a protective UTI vaccine. This strategy could be a useful approach in the development of vaccines to prevent infections caused by other pathogenic bacteria.

However, this is still early clinical research and this candidate vaccine has not yet undegone even a phase 1 safety trial in humans. And even if that were successful, the vaccine would take several more years to reach the market, even if manufacturers decided they could make a profit from producing it. So the next time you’re down on the farm, wash your hands – and make sure that burger is properly cooked through.

Mucosal Immunization with Iron Receptor Antigens Protects against Urinary Tract Infection. 2009PLoS Pathog 5(9): e1000586 doi:10.1371/journal.ppat.1000586
Uncomplicated infections of the urinary tract, caused by uropathogenic Escherichia coli, are among the most common diseases requiring medical intervention. A preventive vaccine to reduce the morbidity and fiscal burden these infections have upon the healthcare system would be beneficial. Here, we describe the results of a large-scale selection process that incorporates bioinformatic, genomic, transcriptomic, and proteomic screens to identify six vaccine candidates from the 5379 predicted proteins encoded by uropathogenic E. coli strain CFT073. The vaccine candidates, ChuA, Hma, Iha, IreA, IroN, and IutA, all belong to a functional class of molecules that is involved in iron acquisition, a process critical for pathogenesis in all microbes. Intranasal immunization of CBA/J mice with these outer membrane iron receptors elicited a systemic and mucosal immune response that included the production of antigen-specific IgM, IgG, and IgA antibodies. The cellular response to vaccination was characterized by the induction and secretion of IFN-c and IL-17. Of the six potential vaccine candidates, IreA, Hma, and IutA provided significant protection from experimental infection. In immunized animals, class-switching from IgM to IgG and production of antigen-specific IgA in the urine represent immunological correlates of protection from E. coli bladder colonization. These findings are an important first step toward the development of a subunit vaccine to prevent urinary tract infections and demonstrate how targeting an entire class of molecules that are collectively required for pathogenesis may represent a fundamental strategy to combat infections.

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Influenza viruses contain segmented, negative-strand RNA genomes. Genome segmentation facilitates reassortment between different influenza virus strains infecting the same cell. This phenomenon results in the rapid exchange of RNA segments. In this study, we have developed a method to prevent the free reassortment of influenza A virus RNAs by rewiring their packaging signals. Specific packaging signals for individual influenza virus RNA segments are located in the 5′ and 3′ noncoding regions as well as in the terminal regions of the ORF of an RNA segment. By putting the nonstructural protein (NS)-specific packaging sequences onto the ORF of the hemagglutinin (HA) gene and mutating the packaging regions in the ORF of the HA, we created a chimeric HA segment with the packaging identity of an NS gene. By the same strategy, we made an NS gene with the packaging identity of an HA segment. This rewired virus had the packaging signals for all eight influenza virus RNAs, but it lost the ability to independently reassort its HA or NS gene. A similar approach can be applied to the other influenza A virus segments to diminish their ability to form reassortant viruses.

Rewiring the RNAs of influenza virus to prevent reassortment. PNAS USA September 8 2009 doi:10.1073/pnas.0908897106

For a nice discussion of why this isn’t the answer to influenza pandemics, read What if influenza virus did not reassort? at the Virology Blog.

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Prostate cancer is the most common form of nonskin cancer in U.S. men. The lifetime risk for developing prostate cancer is
1 in 6 in the United States, and globally, 3% of men die of prostate cancer. Morbidity and mortality from prostate cancer are likely to grow further, given increasing longevity. Epidemiologic studies indicate that infection and inflammation may play a role in the development of prostate cancer.

XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. PNAS USA September 8 2009 doi:10.1073/pnas.0906922106
Xenotropic murine leukemia virus–related virus (XMRV) was recently discovered in human prostate cancers and is the first gammaretrovirus known to infect humans. While gammaretroviruses have well-characterized oncogenic effects in animals, they have not been shown to cause human cancers. We provide experimental evidence that XMRV is indeed a gammaretrovirus with protein composition and particle ultrastructure highly similar to Moloney murine leukemia virus (MoMLV), another gammaretrovirus. We analyzed 334 consecutive prostate resection specimens, using a quantitative PCR assay and immunohistochemistry with an anti-XMRV specific antiserum. We found XMRV DNA in 6% and XMRV protein expression in 23% of prostate cancers. XMRV proteins were expressed primarily in malignant epithelial cells, suggesting that retroviral infection may be directly linked to tumorigenesis. XMRV infection was associated with prostate cancer, especially higher-grade cancers. We found XMRV infection to be independent of a common polymorphism in the RNASEL gene, unlike results previously reported. This finding increases the population at risk for XMRV infection from only those homozygous for the RNASEL variant to all individuals. Our observations provide evidence for an association of XMRV with malignant cells and with more aggressive tumors.

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Colors are vital to the sensing of the environment and have evolved in higher living organisms to guide their interactions with others. For example, it is well appreciated that many birds exhibit brightly colored plumage to attract members of the opposite sex, that a chameleon’s adaptation to surrounding color is an important means of camouflage, and that the bright coloration of the poison dart frog warn potential predators to stay away. But such explanations cannot be offered to explain why certain microorganisms are pigmented. Because they lack color perception, one must assume evolutionary selective pressures behind the acquisition of pigments that promotes survival independent of their light absorbance, reflection or emission spectral properties.

A hallmark feature of several pathogenic microbes is the distinctive color of their colonies when propagated in the clinical laboratory. Such pigmentation comes in a variety of hues, and has often proven useful in presumptive clinical diagnosis. Recent advances in microbial pigment biochemistry and the genetic basis of pigment production have sometimes revealed a more sinister aspect to these curious materials that change the color of reflected light by selective light absorbance. In many cases, the microbial pigment contributes to disease pathogenesis by interfering with host immune clearance mechanisms or by exhibiting pro-inflammatory or cytotoxic properties. We review several examples of pigments that promote microbial virulence, including the golden staphyloxanthin of Staphylococcus aureus, the blue-green pyocyanin of Pseudomonas spp., and the dark brown or black melanin pigments of Cryptococcus neoformans and Aspergillus spp. Targeted pigment neutralisation might represent a viable concept to enhance treatment of certain difficult infectious disease conditions.

Color me bad: microbial pigments as virulence factors. Trends in Microbiology Aug 31 2009

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The ability of fungal pathogens to cause disease is dependent on the ability to grow within the human host environment. In general, the human host environment can be considered a slightly alkaline environment, and the ability of fungi to grow at this pH is essential for pathogenesis. The Rim101 signal transduction pathway is the primary pH sensing pathway described in the pathogenic fungi, and in Candida albicans, it is required for a variety of diseases. As more detailed analyses have been conducted studying pathogenesis at the molecular level, it has become clear that the Rim101 pathway, and pH responses in general, play an intimate role in pathogenesis beyond simply allowing the organism to grow.

The mammalian host environment can generally be considered to be at a pH slightly greater than neutral. The pH of human blood and tissues is 7.4 ± 0.1; the pH of murine blood and tissues is 7.2 ± 0.1. However, this represents a rather limited view of the host environment from a standpoint of pH, when mucosal and other sites exposed to the outside world are considered, dramatic variations from this slightly alkaline pH are found. One obvious example is the digestive track, which shows spatial variations in pH from extremely acidic (pH < 2.0) to more alkaline (pH > 8.0). Further, temporal changes in pH within a single site have been well documented, such as within the oral cavity following the fermentation of dietary sugar by endogenous microbes. The vaginal cavity is an acidic environment, pH 4; however, increases in vaginal pH occur in conjunction with menses. Thus, while fungi must be able to adapt to changes in pH within the host, most if not all pathogenic fungi must be able to thrive at neutral-alkaline pH within host tissues in order to cause disease. This paper discusses the signaling pathways required for growth and adaptation to host pH and the contributions these pathways make to pathogenesis.

Recent studies have found that the pathways responsible for sensing and responding to environmental pH have been co-opted for adaptation to the mammalian host. The pathogenic fungi, including C. albicans, C. neoformans, and A. nidulans, face physical and chemical stresses due to neutral-alkaline pH similarly to environmental fungi, such as S. cerevisiae, such as iron starvation. What has been somewhat surprising is that these pH sensing pathways also control expression of virulence traits not necessarily predicted to be associated with pH, including adhesion to host cells, tissue invasion, as well as other virulence attributes. This highlights the importance of continuing studies of these fundamental pH response pathways in pathogenic fungi in order to understand how these pathogens are adapted to the mammalian host and potentially identify new approaches for preventing or treating infections.

How human pathogenic fungi sense and adapt to pH: the link to virulence. Curr Opin Microbiol. 23 July 2009. doi:10.1016/j.mib.2009.05.006

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Exactly 25 years ago today, Alec Jeffreys, Professor of Genetics at the University of Leicester discovered a technique that has subsequently had an incalculable effect on society, helping to solve criminal cases, resolve immigration arguments and clarify questions of paternity, not to mention creating one of the biggest civil liberties issues of our times. Working in the laboratory, Sir Alec recalls, he and his technician were simply following their noses. They had “absolutely no idea” of the applications that would result from the discovery they stumbled upon.

“I have never approached an experiment with a desire to solve a practical problem,” he observes, pinning down his moment of discovery to precisely 9.05am on Monday 10 September 1984. “My forensic thoughts at 8.55 on that morning were precisely zero; they simply were not there. The technology comes first and then suggests the applications, not the other way around, and you see this over and over again.”

But just as he has spoken out about the ethical and moral issues concerning the use of the technology he made possible, Sir Alec is a staunch defender of Britain’s curiosity-driven research. And the 25th anniversary of his discovery is, he believes, the right time to be discussing its future.

“As scientists, we have to be accountable to the public purse for the money we are spending, but if you take it too far – and in my view it has gone far too far now – it actually stifles the creativity of the very thing you are trying to promote.”

His warning is simple: applied science can be managed from the top down, but we apply the same approach to pure science “at our peril”. “It is blue-skies research that is the ultimate driver – delivering the new techniques, concepts and tools that we need to progress”.

Read more

Study at the University of Leicester

Slightly more than 20% of the global cancer burden can presently be linked to infectious agents, including viruses, bacteria and parasites. This manuscript analyzes reasons for their relatively late discovery and highlights epidemiological observations that may point to an involvement of additional infectious agents in specific human cancers. A number of infectious agents have been identified which either cause or contribute to specific human cancers. They include two members of the herpes virus family, Epstein–Barr virus and human herpesvirus type 8, high risk and low risk human papillomaviruses (HPV), Hepatitis B and C viruses, a recently identified human polyomavirus, Merkel cell polyomavirus, the human T-lymphotropic retrovirus type 1 (HTLV-1), and human immunodeficiency viruses (HIV) types 1 and 2. In addition, human endogenous retroviruses have been suspected to play a role in human cancers. Besides viruses, other pathogens have also been identified. They include the bacterium Helicobacter pylori, a major contributor to gastric cancer, and parasitic infections, here in particular Schistosoma hematobium, a major cause of bladder cancer in Egypt, and liver flukes.

Although we know that presently slightly more than 20% of the global cancer incidence is linked to infectious events, some epidemiological observations suggest that this percentage will increase in the future. The recognition that no cancer linked to infections develops without additional modifications within the host cell genome permits the speculation that even cancers with well established chromosomal modifications deserve a careful analysis for an additional involvement of infectious agents. Prime malignancies suggested here as candidates for potential links with infections are hematopoietic malignancies, particularly childhood lymphoblastic leukemias, Epstein–Barr virus-negative Hodgkin’s lymphomas, basal cell carcinomas of the skin, and breast, colorectal and a subgroup of lung cancers. Although still hypothetical, this proposal is accessible to experimental verification. Even if only one of these speculations turns out to be correct, this would have profound implications for the prevention, diagnosis and hopefully also for therapy of the respective malignancy.

The search for infectious causes of human cancers: where and why. 2009 Virology 392(1): 1-10

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The continued evolution of antimicrobial resistance in the hospital and more recently in the community threatens to seriously compromise our ability to treat serious infections. The major success of the seven-valent Streptococcus pneumoniae vaccine at reducing both infection and resistance has been followed by the emergence of previously minor serotypes that express multiresistance. The almost universal activity of cephalosporins and fluoroquinolones against community Escherichia coli strains has been compromised by the spread of CTX-M beta-lactamase-producing, fluoroquinolone-resistant strains, and the emergence of community-onset methicillin-resistant Staphylococcus aureus, particularly in the United States, has forced us to re-think our empirical treatment guidelines for skin and soft-tissue infections. Finally, our most potent and reliable class of antibiotics, the carbapenems, is compromised by the growth, primarily in intensive care units, of multiresistant Klebsiella pneumoniae, Acinetobacter baumanni, and Pseudomonas aeruginosa. The lack of a robust pipeline of new agents, particularly against resistant Gram-negative bacteria, emphasizes the importance of optimizing our use of current antimicrobials and promoting strict adherence to established infection control practices.

While talk of reaching the “post-antibiotic era” is largely over blown, there is little question that we are now entering an era in which future gains in antimicrobial therapy will come in modest increments at best. It has therefore never been more important for us to understand in detail the mechanisms of and routes to resistance in pathogenic bacteria, so that we can adjust our clinical behavior in ways that minimize the future growth of resistance. By minimizing selective pressure through more judicious use of antibiotics, we may well be able to maintain antimicrobial susceptibility patterns at a level we can all live with.

The clinical consequences of antimicrobial resistance. Curr Opin Microbiol. Aug 27 2009

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