Inna Sekirov

University of British Columbia - Vancouver, Vancouver, British Columbia, Canada

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Publications (10)104.14 Total impact

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    ABSTRACT: The intestinal microbiota has been found to play a central role in the colonization of Salmonella enterica serovar Typhimurium in the gastrointestinal tract. In this study, we present a novel process through which Salmonella benefit from inflammatory induced changes in the microbiota in order to facilitate disease. We show that Salmonella infection in mice causes recruitment of neutrophils to the gut lumen, resulting in significant changes in the composition of the intestinal microbiota. This occurs through the production of the enzyme elastase by neutrophils. Administration of recombinant neutrophil elastase to infected animals under conditions that do not elicit neutrophil recruitment caused shifts in microbiota composition that favored Salmonella colonization, while inhibition of neutrophil elastase reduced colonization. This study reveals a new relationship between the microbiota and the host during infection.
    PLoS ONE 01/2012; 7(11):e49646. · 3.73 Impact Factor
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    ABSTRACT: Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.
    Physiological Reviews 07/2010; 90(3):859-904. · 30.17 Impact Factor
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    ABSTRACT: Gastrointestinal infections involve an interactive tripartite relationship between the invading pathogen, the host, and the host's resident intestinal microbiota. To characterize the host inflammatory response and microbiota alterations during enteric salmonellosis, C57BL/6 mice were pre-treated with a low dose of streptomycin (LD model) and then infected with S. typhimurium strains, including mutants in the two Type III secretion systems, SPI-1 and SPI-2 (invAmut and ssaRmut, respectively). Cecal colonization and inflammation in the LD model were evaluated to assess infection success and progression, and compared to the traditional high dose (HD) model. Perturbations to the microbial community in the LD model were assessed via evaluation of total microbial numbers, the proportion of intestinal γ-Proteobacteria and tRFLP analysis. In the LD model, consistently high colonization by the parental strain (WT) and invAmut S. typhimurium was associated with significant intestinal pathology. However, microbial community profiles were more similar both in numbers and composition between mice infected with the mutant strains, than with the WT strain. Consequently, significant infection-induced inflammation did not always produce similar microbiota perturbations. Large numbers of luminal neutrophils were observed in the ceca of WT-infected, but not in invAmut or ssaRmut infected mice. Neutrophils were thus implicated as a potential mediator of microbiota perturbations during WT enteric salmonellosis. These studies offer a new model of S. typhimurium-induced intestinal disease that retains the three participants of the disease process and further defines the role of virulence factors, the host microbiota, and inflammation in S. typhimurium-induced intestinal disease.
    Gut Microbes 01/2010; 1(1):30-41.
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    Inna Sekirov, B Brett Finlay
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    ABSTRACT: The consortia of microorganisms inhabiting the length of the gastrointestinal tract, the gastrointestinal microbiota, are vital to many aspects of normal host physiology. In addition, they are an active participant in the progression of many diseases, among them enteric infections. Healthy intestinal microbiota contribute to host resistance to infection through their involvement in the development of the host immune system and provision of colonization resistance. It is not surprising then that disruptions of the microbial community translate into alterations of host susceptibility to infection. Additionally, the process of the infection itself results in a disturbance to the microbiota. This disturbance is often mediated by the host inflammatory response, allowing the pathogen to benefit from the inflammation at the intestinal mucosa. Uncovering the mechanisms underlying the host-pathogen-microbiota interactions will facilitate our understanding of the infection process and promote design of more effective and focused prophylactic and therapeutic strategies.
    The Journal of Physiology 07/2009; 587(Pt 17):4159-67. · 4.38 Impact Factor
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    ABSTRACT: Intestinal microbiota comprises microbial communities that reside in the gastrointestinal tract and are critical to normal host physiology. Understanding the microbiota's role in host response to invading pathogens will further advance our knowledge of host-microbe interactions. Salmonella enterica serovar Typhimurium was used as a model enteric pathogen to investigate the effect of intestinal microbiota perturbation on host susceptibility to infection. Antibiotics were used to perturb the intestinal microbiota. C57BL/6 mice were treated with clinically relevant doses of streptomycin and vancomycin in drinking water for 2 days, followed by oral infection with Salmonella enterica serovar Typhimurium. Alterations in microbiota composition and numbers were evaluated by fluorescent in situ hybridization, differential plating, and Sybr green staining. Antibiotics had a dose-dependent effect on intestinal microbiota composition. The chosen antibiotic regimen did not significantly alter the total numbers of intestinal bacteria but altered the microbiota composition. Greater preinfection perturbations in the microbiota resulted in increased mouse susceptibility to Salmonella serovar Typhimurium intestinal colonization, greater postinfection alterations in the microbiota, and more severe intestinal pathology. These results suggest that antibiotic treatment alters the balance of the microbial community, which predisposes the host to Salmonella serovar Typhimurium infection, demonstrating the importance of a healthy microbiota in host response to enteric pathogens.
    Infection and immunity 09/2008; 76(10):4726-36. · 4.21 Impact Factor
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    ABSTRACT: Escherichia coli O157:H7 is an important food- and water-borne pathogen of humans, causing Hemorrhagic Colitis and Haemolytic Uremic Syndrome. Colonization of both cattle and human hosts is mediated through the action of effector molecules secreted via a Type III secretion system, a mechanism shared by other enterohemorrhagic E. coli (EHEC). We recently reported that vaccination of cattle with Type III-secreted proteins (TTSPs) resulted in decreased shedding of the organism following both experimental infection as well as under conditions of natural exposure. In order to extend this to non-O157 EHEC serotypes, we examined the serological cross reactivity of TTSPs of serotypes O26:H11, O103:H2, O111:NM and O157:H7. Western blotting experiments with polyclonal antisera directed against serotype O157:H7 TTSPs suggested that there was significant cross reactivity, although there was limited cross reactivity when two Tir- and EspA-specific monoclonal antibodies were used. Groups of cattle were then vaccinated with TTSPs produced from each of the above serotypes and the magnitude and specificity of the responses were measured. All animals responded well with antibodies to TTSPs of the homologous serotype. However, limited cross reactivity was observed against the others. No cross reactivity was observed against Tir and EspA of serotype O157:H7. These results suggest that vaccination of cattle with TTSPs as a means of reducing the risk of EHEC transmission to humans will induce protection that is serotype specific.
    Vaccine 12/2007; 25(49):8262-9. · 3.49 Impact Factor
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    Bryan Coburn, Inna Sekirov, B Brett Finlay
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    ABSTRACT: Type III secretion systems (T3SSs) are complex bacterial structures that provide gram-negative pathogens with a unique virulence mechanism enabling them to inject bacterial effector proteins directly into the host cell cytoplasm, bypassing the extracellular milieu. Although the effector proteins vary among different T3SS pathogens, common pathogenic mechanisms emerge, including interference with the host cell cytoskeleton to promote attachment and invasion, interference with cellular trafficking processes, cytotoxicity and barrier dysfunction, and immune system subversion. The activity of the T3SSs correlates closely with infection progression and outcome, both in animal models and in human infection. Therefore, to facilitate patient care and improve outcomes, it is important to understand the T3SS-mediated virulence processes and to target T3SSs in therapeutic and prophylactic development efforts.
    Clinical Microbiology Reviews 11/2007; 20(4):535-49. · 17.31 Impact Factor
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    ABSTRACT: While the normal microbiota has been implicated as a critical defense against invading pathogens, the impact of enteropathogenic infection and host inflammation on intestinal microbial communities has not been elucidated. Using mouse models of Citrobacter rodentium, which closely mimics human diarrheal pathogens inducing host intestinal inflammation, and Campylobacter jejuni infection, as well as chemically and genetically induced models of intestinal inflammation, we demonstrate that host-mediated inflammation in response to an infecting agent, a chemical trigger, or genetic predisposition markedly alters the colonic microbial community. While eliminating a subset of indigenous microbiota, host-mediated inflammation supported the growth of either the resident or introduced aerobic bacteria, particularly of the Enterobacteriaceae family. Further, assault by an enteropathogen and host-mediated inflammation combined to significantly reduce the total numbers of resident colonic bacteria. These findings underscore the importance of intestinal microbial ecosystems in infectious colitis and noninfectious intestinal inflammatory conditions,such as inflammatory bowel disease.
    Cell host & microbe 10/2007; 2(3):204. · 13.02 Impact Factor
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    Inna Sekirov, B Brett Finlay
    Nature Medicine 08/2006; 12(7):736-7. · 22.86 Impact Factor
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    ABSTRACT: Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 uses a specialized protein translocation apparatus, the type III secretion system (TTSS), to deliver bacterial effector proteins into host cells. These effectors interfere with host cytoskeletal pathways and signalling cascades to facilitate bacterial survival and replication and promote disease. The genes encoding the TTSS and all known type III secreted effectors in EHEC are localized in a single pathogenicity island on the bacterial chromosome known as the locus for enterocyte effacement (LEE). In this study, we performed a proteomic analysis of proteins secreted by the LEE-encoded TTSS of EHEC. In addition to known LEE-encoded type III secreted proteins, such as EspA, EspB and Tir, a novel protein, NleA (non-LEE-encoded effector A), was identified. NleA is encoded in a prophage-associated pathogenicity island within the EHEC genome, distinct from the LEE. The LEE-encoded TTSS directs translocation of NleA into host cells, where it localizes to the Golgi apparatus. In a panel of strains examined by Southern blot and database analyses, nleA was found to be present in all other LEE-containing pathogens examined, including enteropathogenic E. coli and Citrobacter rodentium, and was absent from non-pathogenic strains of E. coli and non-LEE-containing pathogens. NleA was determined to play a key role in virulence of C. rodentium in a mouse infection model.
    Molecular Microbiology 04/2004; 51(5):1233-49. · 4.96 Impact Factor