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Reynolds L.A.,Infection and Evolution and Institute of Immunology and Infection Research | Smith K.A.,Infection and Evolution and Institute of Immunology and Infection Research | Filbey K.J.,Infection and Evolution and Institute of Immunology and Infection Research | Harcus Y.,Infection and Evolution and Institute of Immunology and Infection Research | And 5 more authors.
Gut microbes | Year: 2014

The intestinal microbiota are pivotal in determining the developmental, metabolic and immunological status of the mammalian host. However, the intestinal tract may also accommodate pathogenic organisms, including helminth parasites which are highly prevalent in most tropical countries. Both microbes and helminths must evade or manipulate the host immune system to reside in the intestinal environment, yet whether they influence each other's persistence in the host remains unknown. We now show that abundance of Lactobacillus bacteria correlates positively with infection with the mouse intestinal nematode parasite, Heligmosomoides polygyrus, as well as with heightened regulatory T cell (Treg) and Th17 responses. Moreover, H. polygyrus raises Lactobacillus species abundance in the duodenum of C57BL/6 mice, which are highly susceptible to H. polygyrus infection, but not in BALB/c mice, which are relatively resistant. Sequencing of samples at the bacterial gyrB locus identified the principal Lactobacillus species as L. taiwanensis, a previously characterized rodent commensal. Experimental administration of L. taiwanensis to BALB/c mice elevates regulatory T cell frequencies and results in greater helminth establishment, demonstrating a causal relationship in which commensal bacteria promote infection with an intestinal parasite and implicating a bacterially-induced expansion of Tregs as a mechanism of greater helminth susceptibility. The discovery of this tripartite interaction between host, bacteria and parasite has important implications for both antibiotic and anthelmintic use in endemic human populations.


Janbon G.,Institute Pasteur Paris | Janbon G.,French National Institute for Agricultural Research | Ormerod K.L.,University of Queensland | Paulet D.,Institute Pasteur Paris | And 56 more authors.
PLoS Genetics | Year: 2014

Cryptococcus neoformans is a pathogenic basidiomycetous yeast responsible for more than 600,000 deaths each year. It occurs as two serotypes (A and D) representing two varieties (i.e. grubii and neoformans, respectively). Here, we sequenced the genome and performed an RNA-Seq-based analysis of the C. neoformans var. grubii transcriptome structure. We determined the chromosomal locations, analyzed the sequence/structural features of the centromeres, and identified origins of replication. The genome was annotated based on automated and manual curation. More than 40,000 introns populating more than 99% of the expressed genes were identified. Although most of these introns are located in the coding DNA sequences (CDS), over 2,000 introns in the untranslated regions (UTRs) were also identified. Poly(A)-containing reads were employed to locate the polyadenylation sites of more than 80% of the genes. Examination of the sequences around these sites revealed a new poly(A)-site-associated motif (AUGHAH). In addition, 1,197 miscRNAs were identified. These miscRNAs can be spliced and/or polyadenylated, but do not appear to have obvious coding capacities. Finally, this genome sequence enabled a comparative analysis of strain H99 variants obtained after laboratory passage. The spectrum of mutations identified provides insights into the genetics underlying the micro-evolution of a laboratory strain, and identifies mutations involved in stress responses, mating efficiency, and virulence. © 2014 Janbon et al.


LOS ANGELES, CA--(Marketwired - Feb 13, 2017) - Ritter Pharmaceuticals, Inc. ( : RTTR) ("Ritter Pharmaceuticals" or the "Company"), a developer of novel therapeutic products that modulate the human gut microbiome to treat gastrointestinal diseases, today announced that it is collaborating with Dr. B Brett Finlay from the Michael Smith Laboratories at the University of British Columbia ("UBC") to study the role of the microbiome and RP-G28 in environmental enteropathy ("EE"). As part of the collaboration, Dr. B. Brett Finlay, an award-winning microbiologist in the fields of innate immunity and microbiome research, plans to explore the microbiome's role in environmental enteropathy. The pre-clinical research is designed to build upon Dr. Finlay's previously published studies demonstrating the gut microbiome's role in contributing to the causes of EE. Ritter Pharmaceuticals is providing its lead compound, RP-G28, for use in the study. RP-G28 is currently in a Phase 2b/3 study in humans for the treatment of lactose intolerance. In previous human studies, RP-G28 has demonstrated significant beneficial changes to the gut microbiome that have been associated with potential to improve a variety of digestive disorders. Andrew J. Ritter, Co-founder and President of Ritter Pharmaceuticals, added, "we are pleased to be collaborating with Dr. Finlay and his team to better understand therapeutic interventions that may reverse signs of environmental enteropathy, a significant worldwide health issue. We're excited to apply our clinical knowledge of RP-G28 in a way that has significant possibilities to produce substantial social benefits in developing countries." Dr. B Brett Finlay, Professor in the Michael Smith Laboratories, and the Departments of Biochemistry and Molecular Biology, and Microbiology and Immunology at the University of British Columbia, added, "We are pleased to be working with Ritter Pharmaceuticals to explore potential treatments and therapies to environmental enteropathy that affects so many of the world's children. Testing RP-G28 in the relevant model will greatly facilitate preclinical testing of this compound for affecting the outcome of EE." Ritter Pharmaceuticals, Inc. (www.RitterPharma.com, @RitterPharma) develops novel therapeutic products that modulate the gut microbiome to treat gastrointestinal diseases. Its lead product, RP-G28, has the potential to become the first FDA-approved treatment for lactose intolerance, a condition that affects millions worldwide. The company is further exploring the functionality and discovering the therapeutic potential gut microbiome changes may have on treating/preventing a variety of conditions including: gastrointestinal diseases, immuno-oncology, metabolic, and liver disease. About the University of British Columbia The University of British Columbia is a global centre for research and teaching, consistently ranked among the top 20 public universities in the world. Since 1915, UBC's entrepreneurial spirit has embraced innovation and challenged the status quo. UBC encourages its students, staff and faculty to challenge convention, lead discovery and explore new ways of learning. At UBC, bold thinking is given a place to develop into ideas that can change the world. This release may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements related to our ability to bring RP-G28 to market. Management believes that these forward-looking statements are reasonable as and when made. However, such statements involve a number of known and unknown risks and uncertainties that could cause the Company's future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with the drug development process generally, including the outcomes of planned clinical trials and the regulatory review process. For a discussion of certain risks and uncertainties affecting Ritter Pharmaceuticals' forward-looking statements, please review the Company's reports filed with the Securities and Exchange Commission, including, but not limited to, its Annual Report on Form 10-K for the period ended December 31, 2015 and Quarterly Reports on Form 10-Q for the periods ended March 31, 2016, June 30, 2016 and September 30, 2016. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date on which they are made. These statements are based on management's current expectations and Ritter Pharmaceuticals does not undertake any responsibility to revise or update any forward-looking statements contained herein, except as expressly required by law.


Wilson D.,Hans Knoell Institute | Wilson D.,The Institute of Medical science | Mayer F.L.,Hans Knoell Institute | Mayer F.L.,Michael Smith Laboratories | And 8 more authors.
Eukaryotic Cell | Year: 2014

Human fungal pathogens are distributed throughout their kingdom, suggesting that pathogenic potential evolved independently. Candida albicans is the most virulent member of the CUG clade of yeasts and a common cause of both superficial and invasive infections. We therefore hypothesized that C. albicans possesses distinct pathogenicity mechanisms. In silico genome subtraction and comparative transcriptional analysis identified a total of 65 C. albicans-specific genes (ASGs) expressed during infection. Phenotypic characterization of six ASG-null mutants demonstrated that these genes are dispensable for in vitro growth but play defined roles in host-pathogen interactions. Based on these analyses, we investigated two ASGs in greater detail. An orf19.6688Δ mutant was found to be fully virulent in a mouse model of disseminated candidiasis and to induce higher levels of the proinflammatory cytokine interleukin-1β (IL-1β) following incubation with murine macrophages. A pga16Δ mutant, on the other hand, exhibited attenuated virulence. Moreover, we provide evidence that secondary filamentation events (multiple hyphae emerging from a mother cell and hyphal branching) contribute to pathogenicity: PGA16 deletion did not influence primary hypha formation or extension following contact with epithelial cells; however, multiple hyphae and hyphal branching were strongly reduced. Significantly, these hyphae failed to damage host cells as effectively as the multiple hypha structures formed by wild-type C. albicans cells. Together, our data show that species-specific genes of a eukaryotic pathogen can play important roles in pathogenicity. © 2014, American Society for Microbiology. All Rights Reserved.


Sharanya D.,McMaster University | Thillainathan B.,McMaster University | Marri S.,McMaster University | Bojanala N.,McMaster University | And 7 more authors.
G3: Genes, Genomes, Genetics | Year: 2012

The nematode Caenorhabditis briggsae is an excellent model organism for the comparative analysis of gene function and developmental mechanisms. To study the evolutionary conservation and divergence of genetic pathways mediating vulva formation, we screened for mutations in C. briggsae that cause the egg-laying defective (Egl) phenotype. Here, we report the characterization of 13 genes, including three that are orthologs of Caenorhabditis elegans unc-84 (SUN domain), lin-39 (Dfd/Scr-related homeobox), and lin-11 (LIM homeobox). Based on the morphology and cell fate changes, the mutants were placed into four different categories. Class 1 animals have normal-looking vulva and vulva-uterine connections, indicating defects in other components of the egg-laying system. Class 2 animals frequently lack some or all of the vulval precursor cells (VPCs) due to defects in the migration of P-cell nuclei into the ventral hypodermal region. Class 3 animals show inappropriate fusion of VPCs to the hypodermal syncytium, leading to a reduced number of vulval progeny. Finally, class 4 animals exhibit abnormal vulval invagination and morphology. Interestingly, we did not find mutations that affect VPC induction and fates. Our work is the first study involving the characterization of genes in C. briggsae vulva formation, and it offers a basis for future investigations of these genes in C. elegans. © 2012 Sharanya et al.


Antunes L.C.M.,Michael Smith Laboratories | Finlay B.B.,Michael Smith Laboratories | Finlay B.B.,University of British Columbia
Gut Microbes | Year: 2011

The intestinal metabolome is a rich collection of molecules with specialized functions and important physiological effects. Many insults such as enteric infection and microbiota disruption by antibiotics can have profound effects in the metabolic homeostasis of the gut. We have recently shown that Salmonella infection and antibiotic treatment of mice drastically alter the intestinal metabolome. Particularly, host hormone metabolism was significantly altered by both insults. Infection resulted in a net increase in the production of both steroids and eicosanoids, whereas antibiotic treatment seemed to reduce the production of these hormones. Our results suggest that both intestinal pathogens and commensals affect common metabolic functions and that this phenomenon may have implications for the interactions between microbes and their hosts. © 2011 Landes Bioscience.


Russell S.L.,Michael Smith Laboratories | Russell S.L.,University of British Columbia | Gold M.J.,University of British Columbia | Reynolds L.A.,University of British Columbia | And 15 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015

Background Resident gut microbiota are now recognized as potent modifiers of host immune responses in various scenarios. Recently, we demonstrated that perinatal exposure to vancomycin, but not streptomycin, profoundly alters gut microbiota and enhances susceptibility to a TH2 model of allergic asthma.Objective Here we sought to further clarify the etiology of these changes by determining whether perinatal antibiotic treatment has a similar effect on the TH1/TH17-mediated lung disease, hypersensitivity pneumonitis.Methods Hypersensitivity pneumonitis was induced in C57BL/6 wild-type or recombination-activating gene 1-deficient mice treated perinatally with vancomycin or streptomycin by repeated intranasal administration of Saccharopolyspora rectivirgula antigen. Disease severity was assessed by measuring lung inflammation, pathology, cytokine responses, and serum antibodies. Microbial community analyses were performed on stool samples via 16S ribosomal RNA pyrosequencing and correlations between disease severity and specific bacterial taxa were identified.Results Surprisingly, in contrast to our findings in an allergic asthma model, we found that the severity of hypersensitivity pneumonitis was unaffected by vancomycin, but increased dramatically after streptomycin treatment. This likely reflects an effect on the adaptive, rather than innate, immune response because the effects of streptomycin were not observed during the early phases of disease and were abrogated in recombination-activating gene 1-deficient mice. Interestingly, Bacteroidetes dominated the intestinal microbiota of streptomycin-treated animals, while vancomycin promoted the expansion of the Firmicutes.Conclusions Perinatal antibiotics exert highly selective effects on resident gut flora, which, in turn, lead to very specific alterations in susceptibility to TH2- or TH1/TH17-driven lung inflammatory disease. © 2014 American Academy of Allergy, Asthma & Immunology.


PubMed | Michael Smith Laboratories
Type: Journal Article | Journal: Journal of bacteriology | Year: 2012

The virulence of many Gram-negative pathogens is associated with type III secretion systems (T3SSs), which deliver virulence effector proteins into the cytoplasm of host cells. Components of enteropathogenic Escherichia coli (EPEC) T3SS are encoded within the locus of enterocyte effacement (LEE). While most LEE-encoded T3SS proteins in EPEC have assigned names and functions, a few of them remain poorly characterized. Here, we studied a small LEE-encoded protein, Orf15, that shows no homology to other T3SS/flagellar proteins and is only present in attaching and effacing pathogens, including enterohemorrhagic E. coli and Citrobacter rodentium. Our findings demonstrated that it is essential for type III secretion (T3S) and that it is localized to the periplasm and associated with the inner membrane. Membrane association was driven by the N-terminal 19 amino acid residues, which were also shown to be essential for T3S. Consistent with its localization, Orf15 was found to interact with the EPEC T3SS outer membrane ring component, EscC, which was previously shown to be embedded within the outer membrane and protruding into the periplasmic space. Interestingly, we found that the predicted coiled-coil structure of Orf15 is critical for the proteins function. Overall, our findings suggest that Orf15 is a structural protein that contributes to the structural integrity of the T3S complex, and therefore we propose to rename it EscA.


PubMed | Michael Smith Laboratories
Type: Journal Article | Journal: Journal of bacteriology | Year: 2011

We characterized Orf5 and SepQ, two type III secretion (T3S) system proteins in enteropathogenic Escherichia coli, and showed that they are essential for T3S, associated with the bacterial membrane, and interact with EscN. Our findings suggest that Orf5 and SepQ are homologs of YscL and YscQ from Yersinia, respectively.


PubMed | Michael Smith Laboratories
Type: | Journal: Annual review of microbiology | Year: 2014

Although antibiotics have significantly improved human health and life expectancy, their disruption of the existing microbiota has been linked to significant side effects such as antibiotic-associated diarrhea, pseudomembranous colitis, and increased susceptibility to subsequent disease. By using antibiotics to break colonization resistance against Clostridium, Salmonella, and Citrobacter species, researchers are now exploring mechanisms for microbiota-mediated modulation against pathogenic infection, revealing potential roles for different phyla and family members as well as microbiota-liberated sugars, hormones, and short-chain fatty acids in regulating pathogenicity. Furthermore, connections are now being made between microbiota dysbiosis and a variety of different diseases such as rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, atopy, and obesity. Future advances in the rapidly developing field of microbial bioinformatics will enable researchers to further characterize the mechanisms of microbiota modulation of disease and potentially identify novel therapeutics against disease.

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