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Infection and Immunity

Lauren E Hartley-Tassell, Milena M Awad, Kate L Seib, Maria Scarselli, Silvana Savino, Joe Tiralongo, Dena Lyras, Christopher J Day, Michael P Jennings
Clostridium difficile is a major cause of hospital-acquired antibiotic-associated diarrhoea. C. difficile produces two cytotoxins, TcdA and TcdB, both toxins are multi-domain proteins that lead to cytotoxicity through the modification and inactivation of small GTPases of the Rho/Rac family. Previous studies have indicated that host glycans are targets for TcdA and TcdB, with interactions thought to be with both α- and β-linked galactose. In the current study, screening of glycan arrays with different domains of TcdA and TcdB revealed that the binding regions of both toxins interact with a wider range of host glycoconjugates than just terminal α- and β-linked galactose, including blood groups, Lewis antigens, N-Acetylglucosamine, mannose and glycosaminoglycans...
December 10, 2018: Infection and Immunity
Win-Yan Chan, Claire Entwisle, Giuseppe Ercoli, Elise Ramos-Sevillano, Ann McIlgorm, Paola Cecchini, Christopher Bailey, Oliver Lam, Gail Whiting, Nicola Green, David Goldblatt, Jun X Wheeler, Jeremy S Brown
Current vaccination against Streptococcus pneumoniae uses vaccines based on capsular polysaccharides from selected serotypes, and has led to non-vaccine serotype replacement disease. We have investigated an alternative serotype-independent approach, using multiple-antigen vaccines (MAV) prepared from S. pneumoniae TIGR4 lysates enriched for surface proteins by a chromatography step after culture under conditions that induce expression of heat shock proteins (Hsp, thought to be immune adjuvants). Proteomics and immunoblots demonstrated that compared to standard bacterial lysates, MAV was enriched with Hsps and contained several recognised protective protein antigens, including pneumococcal surface protein A (PspA) and pneumolysin (Ply)...
December 10, 2018: Infection and Immunity
Amanda N Samuels, Manuela Roggiani, Jun Zhu, Mark Goulian, Rahul M Kohli
Bacteria have a remarkable ability to survive, persist, and ultimately adapt to environmental challenges. A ubiquitous environmental hazard is DNA damage and most bacteria have evolved a network of genes known as the SOS response to combat genotoxic stress. The SOS response aids in bacterial survival by regulating genes involved in DNA repair and damage tolerance. Recently, the SOS response has been shown to play an important role in bacterial pathogenesis, yet the role of the SOS response in non-pathogenic organisms and in physiological settings remains underexplored...
December 3, 2018: Infection and Immunity
Sarah E Macdonald, Pauline M van Diemen, Henny Martineau, Mark P Stevens, Fiona M Tomley, Richard A Stabler, Damer P Blake
Eimeria tenella can cause the disease coccidiosis in chickens. The direct and often detrimental impact of this parasite on chicken health, welfare and productivity is well recognised, however less is known about the secondary effects infection may have on other gut pathogens. Campylobacter jejuni is the leading cause of human bacterial food-borne disease in many countries and has been demonstrated to exert negative effects on poultry welfare and production in some broiler lines. Previous studies have shown that concurrent Eimeria infection can influence colonisation and replication of bacteria such as Clostridium perfringens and Salmonella Typhimurium...
December 3, 2018: Infection and Immunity
Lilit Aslanyan, Hiu H Lee, Vaibhav V Ekhar, Raddy L Ramos, Luis R Martinez
The prevalence of methamphetamine (METH) use is estimated at ∼35 million people worldwide, with over 10 million users in the United States. Chronic METH abuse and dependence expose the users to participate in risky behaviors that may result in the acquisition of HIV and AIDS-related infections. Cryptococcus neoformans is an encapsulated fungus that causes cryptococcosis, an opportunistic infection that has recently been associated with drug users. METH enhances C. neoformans pulmonary infection, facilitating its dissemination and penetration to the central nervous system in mice...
December 3, 2018: Infection and Immunity
Lisa A Lewis, Peter A Rice, Sanjay Ram
Neisseria gonorrhoeae (Ng), the causative agent of gonorrhea, has evolved several mechanisms to subvert complement, including binding of the complement inhibitor factor H (FH). We previously reported FH binding to Ng independently of lipooligosaccharide (LOS) sialylation. Here we report that Factor H-like protein 1 (FHL-1), which contains FH domains 1 through 7 and possesses complement inhibitory activity, also binds to Ng The ligand for both FH and FHL-1 was identified as Neisserial surface protein A (NspA), which has previously been identified as a ligand for these molecules on N...
December 3, 2018: Infection and Immunity
John T Loh, Aung Soe Lin, Amber C Beckett, Mark S McClain, Timothy L Cover
Helicobacter pylori CagA is a secreted effector protein that contributes to gastric carcinogenesis. Previous studies showed that there is variation among H. pylori strains in steady-state levels of CagA, and that a strain-specific motif downstream of the cagA transcriptional start site (+59 motif) was associated with both high levels of CagA and premalignant gastric histology. The cagA 5' untranslated region contains a predicted stem-loop-forming structure adjacent to the +59 motif. In the current study, we investigated the effect of the +59 motif and the adjacent stem-loop on cagA transcript levels and cagA mRNA stability...
December 3, 2018: Infection and Immunity
Ciaran Skerry, William E Goldman, Nicholas H Carbonetti
Incidence of whooping cough (pertussis), a bacterial infection of the respiratory tract caused by the bacterium Bordetella pertussis , has reached levels not seen since the 1950s. Antibiotics fail to improve the course of disease unless administered early in infection. Therefore, there is an urgent need for the development of anti-pertussis therapeutics. Sphingosine-1-phosphate receptor (S1PR) agonists have been shown to reduce pulmonary inflammation during Bordetella pertussis infection in mouse models. However, the mechanisms by which S1PR agonists attenuate pertussis disease are unknown...
December 3, 2018: Infection and Immunity
Julianne E Rollenhagen, Franca Jones, Eric Hall, Ryan Maves, Gladys Nunez, Nereyda Espinosa, Aisling O'Dowd, Michael G Prouty, Stephen J Savarino
The establishment of an animal model that closely approximates ETEC disease in humans is critical for the development and evaluation of vaccines against this enteropathogen. Here, we evaluated the susceptibility of Aotus nancymaae , a New World monkey species, to ETEC infection. Animals were challenged orogastrically with 109 -1011 colony forming units (CFU) of the human pathogenic CFA/I+ ETEC strain H10407 and examined for evidence of diarrhea and fecal shedding of bacteria. A clear dose range effect was obtained with diarrheal attack rates of 40%- 80%, validated in a follow on study demonstrating an attack rate of 80% with 1011 CFU of H10407 ETEC...
December 3, 2018: Infection and Immunity
Isra Alsaady, Ellen Tedford, Mohammad Alsaad, Greg Bristow, Shivali Kohli, Matthew Murray, Matthew Reeves, M S Vijayabaskar, Steven J Clapcote, Jonathan Wastling, Glenn A McConkey
Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous system has previously been observed in chronically-infected animals. In the study described here, the noradrenergic system was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro The mechanism responsible for the NE suppression was found to be down-regulation of dopamine β-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine with down-regulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region...
December 3, 2018: Infection and Immunity
Ryan E Schaub, Krizia M Perez-Medina, Kathleen T Hackett, Daniel L Garcia, Joseph P Dillard
Neisseria gonorrhoeae releases peptidoglycan fragments during growth, and these molecules induce an inflammatory response in the human host. The proinflammatory molecules include peptidoglycan monomers, peptidoglycan dimers, and free peptides. These molecules can be released by the actions of lytic transglycosylases or an amidase. However, over 40% of the gonococcal cell wall is crosslinked, where the peptide stem on one peptidoglycan strand is linked to the peptide stem on a neighboring strand, suggesting that endopeptidases may be required for release of many peptidoglycan fragments...
December 3, 2018: Infection and Immunity
Michael V Tullius, Susana Nava, Marcus A Horwitz
Mycobacterium tuberculosis (Mtb), one of the world's leading causes of death, must acquire nutrients, such as iron, from the host to multiply and cause disease. Iron is an essential metal and Mtb possesses two different systems to acquire iron from its environment: Siderophore-Mediated Iron Acquisition (SMIA) and Heme-Iron Acquisition (HIA), involving uptake and degradation of heme to release ferrous iron. We have discovered that Mycobacterium bovis BCG, the tuberculosis vaccine strain, is severely deficient in HIA, and exploited this phenotypic difference between BCG and Mtb to identify genes involved in HIA by complementing BCG's defect with a fosmid library...
November 19, 2018: Infection and Immunity
Rebecca E McHugh, Nicky O'Boyle, James P R Connolly, Paul A Hoskisson, Andrew J Roe
Recent work has demonstrated that the polyketide natural product Aurodox, from Streptomyces goldiniensis is able to block the pathogenesis of the murine pathogen Citrobacter rodentium In this work we aimed to aimed gain a better understanding of the mechanism of action of the compound. We show that Aurodox downregulates the expression of the Type Three Secretion Systems of enteropathogenic and enterohaemorhagic Escherichia coli Furthermore, we have used transcriptomic analysis to show that Aurodox inhibits the expression at the transcriptional level by repressing the master regulator, ler Our data support a model in which Aurodox acts upstream of ler and not directly on the secretion system itself...
November 19, 2018: Infection and Immunity
Faiza Basheer, Parisa Rasighaemi, Clifford Liongue, Alister C Ward
Granulocyte colony-stimulating factor receptor (G-CSFR), encoded by the CSF3R gene, represents a major regulator of neutrophil production and function in mammals, with inactivating extracellular mutations identified in a cohort of neutropenia patients unresponsive to G-CSF treatment. This study sought to elucidate the role of the zebrafish G-CSFR by generating mutants harboring these inactivating extracellular mutations using genome editing. Zebrafish csf3r mutants possessed significantly decreased numbers of neutrophils from embryonic to adult stages, which were also functionally compromised, did not respond to G-CSF and displayed enhanced susceptibility to bacterial infection...
November 19, 2018: Infection and Immunity
Sarah R Elliott, Dylan W White, Anna D Tischler
The Mycobacterium tuberculosis Type VII secretion system ESX-5, which has been implicated in virulence, is activated at the transcriptional level by the phosphate starvation responsive Pst/SenX3-RegX3 signal transduction system. Deletion of pstA1 , which encodes a Pst phosphate transporter component, causes constitutive activation of the response regulator RegX3, hyper-secretion of ESX-5 substrates and attenuation in the mouse infection model. We hypothesized that constitutive activation of ESX-5 secretion causes attenuation of the Δ pstA1 mutant...
November 19, 2018: Infection and Immunity
Telmo Graça, Pei-Shin Ku, Marta G Silva, Joshua E Turse, Kenitra G Hammac, Wendy C Brown, Guy H Palmer, Kelly A Brayton
Anaplasma marginale is a prototypical highly antigenically variant bacterial pathogen, dependent on sequential generation of Major Surface Protein-2 (Msp2) outer membrane variants to establish persistent infection. Msp2 is encoded by a single expression site and diversity is achieved by gene conversion of chromosomally encoded msp2 pseudogenes. Analysis of the full complement of msp2 pseudogenes in the St. Maries strain revealed identical sequences in different loci. The Florida strain shared the same locus structure but in the loci where the St...
November 19, 2018: Infection and Immunity
Jeroen D Langereis, Amelieke J H Cremers, Marloes Vissers, Josine van Beek, Jacques F Meis, Marien I de Jonge
Non-typeable Haemophilus influenzae (NTHi) bacteria express various molecules that contribute to their virulence. The presence of phosphocholine (PCho) on NTHi lipooligosaccharide increases adhesion to epithelial cells and is an advantage for the bacterium enabling nasopharyngeal colonization, as measured in humans and animal models. However, when PCho is expressed on the lipooligosaccharide, it is also recognized by acute phase protein C-reactive protein (CRP) and PCho-specific antibodies, both potent initiators of the classical pathway of complement activation...
November 19, 2018: Infection and Immunity
Morvarid Oveisi, Harold Shifman, Noah Fine, Chunxiang Sun, Naomi Glogauer, Dilani Senadheera, Michael Glogauer
Neutrophils, the most numerous leukocytes, play an important role in maintaining oral health through interactions with oral microbial biofilms. Both neutrophil hyperactivity and the bacterial subversion of neutrophil responses can cause inflammation-mediated tissue damage as seen in periodontal disease. We describe here an assay that assesses neutrophil activation responses to mono-species biofilms bacteria in vitro based on surface expression of cluster of differentiation (CD) markers associated with various neutrophil functions...
November 19, 2018: Infection and Immunity
Sirina Muntaka, Yasir Almuhanna, Darryl Jackson, Sonali Singh, Afrakoma Afryie-Asante, Miguel Cámara, Luisa Martínez-Pomares
Macrophages are important orchestrators of inflammation during bacterial infection acting both as effector cells and as regulators of neutrophil recruitment and life span. Differently activated macrophage populations with distinct inflammatory and microbicidal potential have been described. Our previous work unveiled a positive and a negative correlation between levels of IFN-γ and IL-17A, respectively, and lung function in cystic fibrosis, particularly in patients chronically infected with P. aeruginosa This study sought to define key parameters in human anti-bacterial immunity under Th1- and Th17-dominated inflammatory conditions; the final aim was to identify unique characteristics that could be fine-tuned therapeutically to minimise tissue damage while maximising bacterial clearance...
November 19, 2018: Infection and Immunity
Kimberly L James, Austin B Mogen, Jessica N Brandwein, Silvia S Orsini, Miranda J Ridder, Mary A Markiewicz, Jeffrey L Bose, Kelly C Rice
Staphylococcus aureus nitric oxide synthase (saNOS) is a major contributor to virulence, stress resistance, and physiology, yet the specific mechanism(s) by which saNOS intersects with other known regulatory circuits are largely unknown. The SrrAB two-component system, which modulates gene expression in response to the reduced state of respiratory menaquinones, is a positive regulator of nos expression. Several SrrAB-regulated genes were also previously-shown to be induced in an aerobically-respiring nos mutant, suggesting potential interplay between saNOS and SrrAB...
November 12, 2018: Infection and Immunity
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