Tuberculosis, an ancient disease of mankind, remains one of the major infectious causes of human death. We examine newly discovered facets of tuberculosis pathogenesis and explore the evolution of ...its causative organism Mycobacterium tuberculosis from soil dweller to human pathogen. M. tuberculosis has coevolved with the human host to evade and exploit host macrophages and other immune cells in multiple ways. Though the host can often clear infection, the organism can cause transmissible disease in enough individuals to sustain itself. Tuberculosis is a near-perfect paradigm of a host-pathogen relationship, and that may be the challenge to the development of new therapies for its eradication.
Tuberculosis is an ancient disease that remains a medical challenge to date. Learn more about how its causative organism, Mycobacterium tuberculosis, has evolved unique strategies to infect, persist, and evade human immune defenses.
Persistent bacterial infections involving Mycobacterium tuberculosis, Salmonella enterica serovar Typhi (S. typhi) and Helicobacter pylori pose significant public-health problems. Multidrug-resistant ...strains of M. tuberculosis and S. typhi are on the increase, and M. tuberculosis and S. typhi infections are often associated with HIV infection. This review discusses the strategies used by these bacteria during persistent infections that allow them to colonize specific sites in the host and evade immune surveillance. The nature of the host immune response to this type of infection and the balance between clearance of the pathogen and avoidance of damage to host tissues are also discussed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In mid-1974, soon after the first recombinant DNA molecules were replicated in Escherichia coli, scientists called for, and observed, a voluntary moratorium on certain experiments. One goal of the ...moratorium was to hold a conference (Asilomar) to evaluate the risks, if any, of this new technology. The Asilomar conference concluded that recombinant DNA research should proceed but under strict guidelines. The furor surrounding the recent genetic manipulation of the transmissibility of avian influenza virus H5N1 led to a short-term moratorium that has been extended indefinitely. The question is how long should the moratorium remain in place, or should it be permanent? Voltaire observed, "History never repeats itself; man always does." I believe the parallels of Asilomar can be applied to the problem facing biomedical science today. We should move forward to establish standardized guidelines, using common sense and scientific creativity. The onus of responsibility falls on the individual scientist and involves the education of a new generation of scientists into the social and ethical implications of genetic engineering in a new age of genomics and synthetic biology. In addition, scientists who work with infectious agents must deal not only with biosafety but also, alas, with bioterrorism. The H5N1 "affair" is not a question of freedom of inquiry or the dissemination of scientific research; it is a question of the social responsibility of science and scientists to ensure that the public understands why this work is beneficial and worthwhile.
Interactions between microbes and human hosts can range from a benign, even symbiotic collaboration to a competition that may turn fatal--resulting in death of the host, the microbe or both. Despite ...advances that have been made over the past decades in understanding microbial pathogens, more people worldwide still die every year from infectious disease than from any other cause. This highlights the relevance of continuing to probe the mechanisms used by microorganisms to cause disease, and emphasizes the need for new model systems to advance our understanding of host-pathogen interactions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We employed DNA microarray technology to investigate the host response to Streptococcus pneumoniae in a mouse model of asymptomatic carriage. Over a period of six weeks, we profiled transcript ...abundance and complexity in the Nasal Associated Lymphoid Tissue (NALT) to identify genes whose expression differed between pneumococcal-colonized and uncolonized states.
Colonization with S. pneumoniae altered the expression of hundreds of genes over the course of the study, demonstrating that carriage is a dynamic process characterized by increased expression of a set of early inflammatory responses, including induction of a Type I Interferon response, and the production of several antimicrobial factors. Subsequent to this initial inflammatory response, we observed increases in transcripts associated with T cell development and activation, as well as wounding, basement membrane remodeling, and cell proliferation. Our analysis suggests that microbial colonization induced expression of genes encoding components critical for controlling JAK/STAT signaling, including stat1, stat2, socs3, and mapk1, as well as induction of several Type I Interferon-inducible genes and other antimicrobial factors at the earliest stages of colonization.
Examining multiple time points over six weeks of colonization demonstrated that asymptomatic carriage stimulates a dynamic host response characterized by temporal waves with distinct biological programs. Our data suggest that the usual response to the presence of the pneumocccus is an initial controlled inflammatory response followed by activation of host physiological processes such as response to wounding, basement membrane remodeling, and increasing cellular numbers that ultimately allow the host to maintain an intact epithelium and eventually mount a preventive adaptive immune response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Helicobacter pylori colonizes the stomach of half of the world's population, causing a wide spectrum of disease ranging from asymptomatic gastritis to ulcers to gastric cancer. Although the basis for ...these diverse clinical outcomes is not understood, more severe disease is associated with strains harboring a pathogenicity island. To characterize the genetic diversity of more and less virulent strains, we examined the genomic content of 15 H. pylori clinical isolates by using a whole genome H. pylori DNA microarray. We found that a full 22% of H. pylori genes are dispensable in one or more strains, thus defining a minimal functional core of 1281 H. pylori genes. While the core genes encode most metabolic and cellular processes, the strain-specific genes include genes unique to H. pylori, restriction modification genes, transposases, and genes encoding cell surface proteins, which may aid the bacteria under specific circumstances during their long-term infection of genetically diverse hosts. We observed distinct patterns of the strain-specific gene distribution along the chromosome, which may result from different mechanisms of gene acquisition and loss. Among the strain-specific genes, we have found a class of candidate virulence genes identified by their coinheritance with the pathogenicity island.
A selection strategy was devised to identify bacterial genes preferentially expressed when a bacterium associates with its host cell. Fourteen Salmonella typhimurium genes, which were under the ...control of at least four independent regulatory circuits, were identified to be selectively induced in host macrophages. Four genes encode virulence factors, including a component of a type III secretory apparatus. This selection methodology should be generally applicable to the identification of genes from pathogenic organisms that are induced upon association with host cells or tissues.
DNA microarrays provide an opportunity to combine the principles of signature-tagged mutagenesis (STM) with microarray technology to identify potentially important bacterial virulence genes. The ...scope of DNA microarrays allows for less laborious screening on a much larger scale than possible by STM alone. We have adapted a microarray-based transposon tracking strategy for use with a Salmonella enterica serovar Typhimurium cDNA microarray in order to identify genes important for survival and replication in RAW 264.7 mouse macrophage-like cells or in the spleens of BALB/cJ mice. A 50,000-CFU transposon library of S. enterica serovar Typhimurium strain SL1344 was serially passaged in cultured macrophages or intraperitoneally inoculated into BALB/cJ mice. The bacterial genomic DNA was isolated and processed for analysis on the microarray. The novel application of this approach to identify mutants unable to survive in cultured cells resulted in the identification of components of Salmonella pathogenicity island 2 (SPI2), which is known to be critical for intracellular survival and replication. In addition, array results indicated that a number of SPI1-associated genes, currently not associated with intracellular survival, are negatively selected. However, of the SPI1-associated mutants individually tested for intracellular survival, only a sirA mutant exhibited reduced numbers relative to those of wild-type bacteria. Of the mutants unable to survive in mice, significant proportions are either components of the SPI2 pathogenicity island or involved in lipopolysaccharide synthesis. This observation is in agreement with results obtained in the original S. enterica serovar Typhimurium STM screen, illustrating the utility of this approach for the high-throughput identification of virulence factors important for survival in the host.
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