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- Francisella tularensis subsp. tularensis Induces a Unique Pulmonary Inflammatory Response: Role of Bacterial Gene Expression in Temporal Regulation of Host Defense Responses. [Journal Article]
- PLoS One 2013; 8(5):e62412.
Pulmonary exposure to Francisella tularensis is associated with severe lung pathology and a high mortality rate. The lack of induction of classical inflammatory mediators, including IL1-β and TNF-α, during early infection has led to the suggestion that F. tularensis evades detection by host innate immune surveillance and/or actively suppresses inflammation. To gain more insight into the host response to Francisella infection during the acute stage, transcriptomic analysis was performed on lung tissue from mice exposed to virulent (Francisella tularensis ssp tularensis SchuS4). Despite an extensive transcriptional response in the lungs of animals as early as 4 hrs post-exposure, Francisella tularensis was associated with an almost complete lack of induction of immune-related genes during the initial 24 hrs post-exposure. This broad subversion of innate immune responses was particularly evident when compared to the pulmonary inflammatory response induced by other lethal (Yersinia pestis) and non-lethal (Legionella pneumophila, Pseudomonas aeruginosa) pulmonary infections. However, the unique induction of a subset of inflammation-related genes suggests a role for dysregulation of lymphocyte function and anti-inflammatory pathways in the extreme virulence of Francisella. Subsequent activation of a classical inflammatory response 48 hrs post-exposure was associated with altered abundance of Francisella-specific transcripts, including those associated with bacterial surface components. In summary, virulent Francisella induces a unique pulmonary inflammatory response characterized by temporal regulation of innate immune pathways correlating with altered bacterial gene expression patterns. This study represents the first simultaneous measurement of both host and Francisella transcriptome changes that occur during in vivo infection and identifies potential bacterial virulence factors responsible for regulation of host inflammatory pathways.
- Comparative evaluation of administration methods for a vaccine protecting rainbow trout against Yersinia ruckeri O1 biotype 2 infections. [JOURNAL ARTICLE]
- Vet Immunol Immunopathol 2013 Apr 8.
Numerous outbreaks of enteric red mouth disease (ERM) caused by Yersinia ruckeri O1 biotype 2 in rainbow trout farms are currently being recorded despite established vaccination procedures against this disease. This could indicate that the currently used application of single immersion vaccination (using a commercial vaccine AquaVac(®) RELERA™) does not provide full protection. We elucidated by a controlled duplicated experiment if different vaccine administration methods can improve level and extent of protection. Rainbow trout, Oncorhynchus mykiss were vaccinated by: (1) a single immersion in bacterin diluted 1:10 for 30s (only primary vaccination); (2) two times 30s immersion (primary immersion vaccination followed by booster immersion vaccination 1 month later); (3) a single i.p. injection (only primary vaccination); (4) immersion vaccination followed by injection booster 1 month later; (5) a single 1h bath in bacterin diluted 1:2000; and (6) immersion (30s, 1:10) plus booster (1h in diluted 1:2000 vaccine) 5 months later). Injection challenge experiments were performed 3, 5 and 7 months post primary vaccination with 8.5×10(6)CFU/fish, 10.6×10(6)CFU/fish and 1×10(8)CFU/fish, respectively. In the first challenge trial, control fish exhibited a mortality of 76%, one time immersion vaccination had a mortality of 37%, two times immersion vaccinated fish had a 4% mortality, the one-time injection vaccinated group showed a mortality of 2% and the immersion plus injection boostered fish showed no mortality at all. When rainbow trout were challenged 5 months post primary vaccination, 26% mortality occurred in control fish, 21% in one time immersion group, 12% in two times immersion group, 5% in the one-time injection vaccinated group whereas immersion plus injection boostered fish again showed no mortality at all. When challenged 7 months post vaccination, one-time immersion vaccinated were not protected at all compared to the control group whereas injection vaccinated fish showed lower mortality (17%) compared to booster immersed fish (32% mortality) which was still better than un-vaccinated controls (44% mortality). It was noteworthy that a diluted bacterin (1:2000 for 1h after 5 months post primary vaccination) booster showed the same effect as a booster with 1:10 bacterin dilution for 30s applied 1 month after primary vaccination. Antibody levels showing significant elevations 28 days post challenge in vaccinated fish point to this immune parameter as a protective element. The superior and extended protection offered by booster vaccination or simply injection is noteworthy and may be applied in future vaccination strategies at farm level.
- Comparison of the cytokine immune response to pathogenic Yersinia enterocolitica bioserotype 1B/O:8 and 2/O:9 in susceptible BALB/C and resistant C57BL/6 mice. [Journal Article]
- Mol Immunol 2013 Oct; 55(3-4):365-71.
We investigated the lethality of pathogenic Yersinia enterocolitica bioserotypes 1B/O:8 and 2/O:9 in susceptible BALB/C and resistant C57BL/6 mice; the cytokine alterations and histopathological changes were observed comparing the two strains in BALB/C mice. The data showed the 50% lethal dose (LD50) for the pathogenic Y. enterocolitica bioserotype 1B/O:8 was 10(3)cfu in both BALB/C and C57BL/6 mice; while the LD50 for the 2/O:9 was 10(8)cfu in BALB/C mice and 10(9)cfu in C57BL/6 mice, a large difference. After infection with the two strains in BALB/C mice, GM-CSF (granulocyte-macrophage colony stimulating factor), IFN-γ (interferon-γ), IL-1β (interleukin-1β), IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and TNF-α (tumor necrosis factor-α) appeared as a cytokine storm in a short period, reached peak values, and then quickly decreased. This appeared important for the immune response and cytokine immunopathogenesis in pathogenic Y. enterocolitica infections. In the initial infection stage, GM-CSF, IL-6, and TNF-α of 2/O:9 were higher than 1B/O:8; and subsequently the status was reversed. However, levels of IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12 following infection with 1B/O:8 were always higher than with 2/O:9. The histopathological changes in the liver and spleen in BALB/C mice infected with the two strains were similar at different times and doses. These observations show the different immunological effects and changes for pathogenic Y. enterocolitica 1B/O:8 and 2/O:9 infections using the mouse model.
- Prevalence of Yersinia enterocolitica in raw cow's milk collected from stables of Mexico City. [Journal Article]
- J Food Prot 2013 Apr; 76(4):694-8.
Yersinia enterocolitica has been isolated from a batch of pork-derived products, from healthy and diseased animals, and from different types of milk and dairy products, among others. We studied the prevalence and diversity of Y. enterocolitica isolated from raw cow's milk collected from stables in Mexico City. Of the 1,300 samples analyzed, Y. enterocolitica was isolated in 454, with an average of 25% positive samples for each stable. Of the total isolated bacteria of the Yersinia genus, 44.25% were Y. enterocolitica, 18.28% were Y. kristensenii, 13.65% were Y. intermedia, 14.85% were Y. frederiksenii, and 9.14% were Y. aldovae. Among the different strains of Y. enterocolitica, biotype 1A was present in 70%, biotype 2 in 13.2%, biotype 3 in 8.54%, and biotype 4 in 8.15% of samples. Serotypes O:5, O:3, O:2, and O:9 were found in all biotypes identified. There were no statistically significant differences in the isolation of this bacterium with respect to the stables where they were found, although there was significant difference regarding the time of year. The data obtained in this work show the need to protect public health in Mexico against infections transmitted by raw cow's milk.
- What's in that pork? We found antibiotic-resistant bacteria--and traces of a veterinary drug. [Journal Article]
- Consum Rep 2013 Jan; 78(1):44-6.
- Increased detection of invasive enteropathogenic bacteria in pre-incubated blood culture materials by real-time PCR in comparison with automated incubation in Sub-Saharan Africa. [JOURNAL ARTICLE]
- Scand J Infect Dis 2013 Apr 3.
Background:Invasive enteropathogenic bacteria can cause systemic infections. Data from studies with PCR detection suggest, at least for Salmonella enterica, that blood culture may lead to underestimation in the tropics. Corresponding data are lacking for other invasive enteropathogenic bacteria. We compared classical blood culture and molecular methods for the diagnosis of blood infections.
Methods:A real-time multiplex PCR for Salmonella spp., Shigella spp./entero- invasive Escherichia coli (EIEC), Yersinia spp., and Campylobacter jejuni was applied to 2321 retained blood culture samples from Ghanaian patients, after enrichment by automated culture.
Results:PCR detected Salmonella DNA in 56 out of 58 pre-incubated Ghanaian blood cultures with growth of S. enterica. In 2 samples molecular diagnosis was only possible after 1:10 dilution. Twenty-two samples negative by blood culture and 1 positive with Micrococcus spp. were PCR-positive for Salmonella spp. In addition, 3 Shigella spp./EIEC, 2 Yersinia spp., and 1 C. jejuni were detected by PCR but not by culture growth.
Conclusions:Real-time PCR was more sensitive in identifying invasive enteropathogenic bacteria than automated blood culture, which is hampered by a lack of evidence-based standardization of pre-analytic conditions in the tropics. Primary agar culture and Gram-staining prior to automated blood culture is advisable in cases where transportation times are long.
- Pathogen-specific Risk of Reactive Arthritis from Bacterial Causes of Foodborne Illness. [Journal Article]
- J Rheumatol 2013 May; 40(5):712-4.
Reactive arthritis (ReA) is a sequelae of common bacterial infections of acute gastroenteritis. We assessed incidence of ReA following Campylobacter, Salmonella, Shigella, or Yersinia infection utilizing a US Department of Defense medical database.Subjects with acute gastroenteritis attributed to these pathogens were matched with ≥ 4 unexposed subjects. Medical history was analyzed for 6 months postinfection to assess for incident ReA.A total of 1753 cases of gastroenteritis were identified. ReA incidence ranged from 0 to 4 per 100,000 person-years.These data are consistent with prior studies and highlight the need for continued primary prevention efforts.
- Structure and Biophysics of Type III Secretion in Bacteria. [Journal Article]
- Biochemistry 2013 Apr 16; 52(15):2508-17.
Many plant and animal bacterial pathogens assemble a needle-like nanomachine, the type III secretion system (T3SS), to inject virulence proteins directly into eukaryotic cells to initiate infection. The ability of bacteria to inject effectors into host cells is essential for infection, survival, and pathogenesis for many Gram-negative bacteria, including Salmonella, Escherichia, Shigella, Yersinia, Pseudomonas, and Chlamydia spp. These pathogens are responsible for a wide variety of diseases, such as typhoid fever, large-scale food-borne illnesses, dysentery, bubonic plague, secondary hospital infections, and sexually transmitted diseases. The T3SS consists of structural and nonstructural proteins. The structural proteins assemble the needle apparatus, which consists of a membrane-embedded basal structure, an external needle that protrudes from the bacterial surface, and a tip complex that caps the needle. Upon host cell contact, a translocon is assembled between the needle tip complex and the host cell, serving as a gateway for translocation of effector proteins by creating a pore in the host cell membrane. Following delivery into the host cytoplasm, effectors initiate and maintain infection by manipulating host cell biology, such as cell signaling, secretory trafficking, cytoskeletal dynamics, and the inflammatory response. Finally, chaperones serve as regulators of secretion by sequestering effectors and some structural proteins within the bacterial cytoplasm. This review will focus on the latest developments and future challenges concerning the structure and biophysics of the needle apparatus.
- The landscape of host transcriptional response programs commonly perturbed by bacterial pathogens: towards host-oriented broad-spectrum drug targets. [Journal Article, Research Support, Non-U.S. Gov't]
- PLoS One 2013; 8(3):e58553.
The emergence of drug-resistant pathogen strains and new infectious agents pose major challenges to public health. A promising approach to combat these problems is to target the host's genes or proteins, especially to discover targets that are effective against multiple pathogens, i.e., host-oriented broad-spectrum (HOBS) drug targets. An important first step in the discovery of such drug targets is the identification of host responses that are commonly perturbed by multiple pathogens.In this paper, we present a methodology to identify common host responses elicited by multiple pathogens. First, we identified host responses perturbed by each pathogen using a gene set enrichment analysis of publicly available genome-wide transcriptional datasets. Then, we used biclustering to identify groups of host pathways and biological processes that were perturbed only by a subset of the analyzed pathogens. Finally, we tested the enrichment of each bicluster in human genes that are known drug targets, on the basis of which we elicited putative HOBS targets for specific groups of bacterial pathogens. We identified 84 up-regulated and three down-regulated statistically significant biclusters. Each bicluster contained a group of pathogens that commonly dysregulated a group of biological processes. We validated our approach by checking whether these biclusters correspond to known hallmarks of bacterial infection. Indeed, these biclusters contained biological process such as inflammation, activation of dendritic cells, pro- and anti- apoptotic responses and other innate immune responses. Next, we identified biclusters containing pathogens that infected the same tissue. After a literature-based analysis of the drug targets contained in these biclusters, we suggested new uses of the drugs Anakinra, Etanercept, and Infliximab for gastrointestinal pathogens Yersinia enterocolitica, Helicobacter pylori kx2 strain, and enterohemorrhagic Escherichia coli and the drug Simvastatin for hematopoietic pathogen Ehrlichia chaffeensis.Using a combination of automated analysis of host-response gene expression data and manual study of the literature, we have been able to suggest host-oriented treatments for specific bacterial infections. The analyses and suggestions made in this study may be utilized to generate concrete hypothesis on which gene sets to probe further in the quest for HOBS drug targets for bacterial infections. All our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/ murali/supplements/2013-kidane-plos-one.
- Pathogen-specific risk of chronic gastrointestinal disorders following bacterial causes of foodborne illness. [Journal Article, Research Support, U.S. Gov't, Non-P.H.S.]
- BMC Gastroenterol 2013.:46.
The US CDC estimates over 2 million foodborne illnesses are annually caused by 4 major enteropathogens: non-typhoid Salmonella spp., Campylobacter spp., Shigella spp. and Yersinia enterocoltica. While data suggest a number of costly and morbid chronic sequelae associated with these infections, pathogen-specific risk estimates are lacking. We utilized a US Department of Defense medical encounter database to evaluate the risk of several gastrointestinal disorders following select foodborne infections.We identified subjects with acute gastroenteritis between 1998 to 2009 attributed to Salmonella (nontyphoidal) spp., Shigella spp., Campylobacter spp. or Yersinia enterocolitica and matched each with up to 4 unexposed subjects. Medical history was analyzed for the duration of military service time (or a minimum of 1 year) to assess for incident chronic gastrointestinal disorders. Relative risks were calculated using modified Poisson regression while controlling for the effect of covariates.A total of 1,753 pathogen-specific gastroenteritis cases (Campylobacter: 738, Salmonella: 624, Shigella: 376, Yersinia: 17) were identified and followed for a median of 3.8 years. The incidence (per 100,000 person-years) of PI sequelae among exposed was as follows: irritable bowel syndrome (IBS), 3.0; dyspepsia, 1.8; constipation, 3.9; gastroesophageal reflux disease (GERD), 9.7. In multivariate analyses, we found pathogen-specific increased risk of IBS, dyspepsia, constipation and GERD.These data confirm previous studies demonstrating risk of chronic gastrointestinal sequelae following bacterial enteric infections and highlight additional preventable burden of disease which may inform better food security policies and practices, and prompt further research into pathogenic mechanisms.