Mpi recombinase globally modulates the surface architecture of a human commensal bacterium

Coyne, Michael J.; Weinacht, Katja G.; Krinos, Corinna M.; Comstock, Laurie E.

doi:10.1073/pnas.1832655100

Cited by 116 publications

(128 citation statements)

References 32 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…The creation of a stable acapsular mutant and one that synthesizes only a single polysaccharide in a normal phasevariable manner was not achieved by other mutational strategies (9,22). Because we targeted genes whose products are involved in the synthesis of capsular polysaccharides rather than in their regulation, we obtained mutants with stable phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Role of glycan synthesis in colonization of the mammalian gut by the bacterial symbiont Bacteroides fragilis

Coyne

Chatzidaki‐Livanis

Paoletti

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

103

104

View full text Add to dashboard Cite

Bacteroides species are the most abundant Gram-negative bacteria of the human colonic microbiota. These endogenous organisms are unique in that they synthesize an extensive number of phase-variable surface polysaccharides. Pathogenic bacteria phase vary expression of surface molecules for immune evasion, but the importance of the synthesis of multiple phase-variable polysaccharides to these commensal bacteria is unknown. We previously showed that a Bacteroides fragilis mutant unable to synthesize 4 of the 8 capsular polysaccharides and unable to glycosylate proteins properly is rapidly outcompeted by the wild-type strain for colonization of the gnotobiotic mouse intestine. In the present study, we constructed mutants defective only in capsule polysaccharide synthesis to define better the importance of these surface molecules to intestinal colonization. We discovered a key enzymatic activity required for synthesis of 7 of the 8 capsular polysaccharides. Deletion of its gene resulted in the first B. fragilis mutant able to synthesize only one phase-variable polysaccharide, and further mutation resulted in a stable acapsular mutant. We show that the acapsular mutant is rapidly outcompeted, but synthesis of a single polysaccharide is sufficient for the organism to colonize the gnotobiotic intestine competitively. These data demonstrate that initial colonization of the gnotobiotic mouse intestine by B. fragilis requires that the organism synthesize only a single polysaccharide and suggest that the synthesis of multiple phase-variable polysaccharides is important for the bacteria's long-term maintenance in the normally complex and competitive ecosystem. acapsular ͉ microbiota ͉ phase variation ͉ polysaccharide ͉ glycoprotein T he human intestinal tract is home to a vast and diverse alliance of microbes comprising one of the densest microbial ecosystems in the world and one that provides functions essential to human health. Many species of the order Bacteroidales are abundant members of the human intestinal microbiota and have served as models for studying mutualistic bacterial-host relationships in this ecosystem (1, 2). Despite their importance, relatively little is known about the biology of the predominant members of this ecosystem. Deciphering how these mutualistic microorganisms successfully and stably colonize the human intestine may help us understand how they are tolerated, how different members interact with one another, what additional benefits the microbiota provide us, and how microbiotaassociated diseases are triggered in the susceptible host.The intestinal Bacteroidales synthesize a vast repertoire of surface glycans. A single strain of B. fragilis synthesizes 8 distinct capsular polysaccharides (3), an extracellular polysaccharide (4), and numerous glycoproteins (5). The synthesis of extensive numbers of glycosylated molecules is a general property of the intestinal Bacteroidales (6-8). We estimate that the genome of B. fragilis 9343 encodes Ϸ80 glycosyltransferases and dedicates at least 215,000 bp of ...

show abstract

Section: Discussionmentioning

confidence: 99%

Role of glycan synthesis in colonization of the mammalian gut by the bacterial symbiont Bacteroides fragilis

Coyne

Chatzidaki‐Livanis

Paoletti

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

103

104

View full text Add to dashboard Cite

show abstract

“…The production of these polysaccharides is regulated by a reversible inversion of the DNA segment containing the promoter needed for their expression to an "on" or "off" position (137). These inversions are mediated by invertase genes; mpi, the best known of these genes, codes for a global DNA invertase that is involved in inverting 13 distinct DNA regions, including the promoters of seven of the capsular polysaccharide biosynthesis regions (69). By changing its surface architecture, Bacteroides may avoid the host immune response; other potential effects of surface modification would include the ability to colonize host tissue or form biofilms.…”

Section: The Bad Virulencementioning

confidence: 99%

Bacteroides: the Good, the Bad, and the Nitty-Gritty

2007

View full text Add to dashboard Cite

SUMMARY Summary: Bacteroides species are significant clinical pathogens and are found in most anaerobic infections, with an associated mortality of more than 19%. The bacteria maintain a complex and generally beneficial relationship with the host when retained in the gut, but when they escape this environment they can cause significant pathology, including bacteremia and abscess formation in multiple body sites. Genomic and proteomic analyses have vastly added to our understanding of the manner in which Bacteroides species adapt to, and thrive in, the human gut. A few examples are (i) complex systems to sense and adapt to nutrient availability, (ii) multiple pump systems to expel toxic substances, and (iii) the ability to influence the host immune system so that it controls other (competing) pathogens. B. fragilis, which accounts for only 0.5% of the human colonic flora, is the most commonly isolated anaerobic pathogen due, in part, to its potent virulence factors. Species of the genus Bacteroides have the most antibiotic resistance mechanisms and the highest resistance rates of all anaerobic pathogens. Clinically, Bacteroides species have exhibited increasing resistance to many antibiotics, including cefoxitin, clindamycin, metronidazole, carbapenems, and fluoroquinolones (e.g., gatifloxacin, levofloxacin, and moxifloxacin).

show abstract

“…In various pathogens, including bacteria and protozoan parasites, several fundamental mechanisms of DNA change are used during invasion of the host. DNA recombination [148][149][150][151] , gene conversion [152][153][154] and gene hypermutation can lead to the evasion of host detection and to the subsequent clonal selection of the pathogenic variant. For example, in trypanosomes, DNA recombination and gene conversion rapidly modify variant surface glycoproteins and allow evasion of host detection 155,156 .…”

Section: Box 2 Mechanistic Similarities Between Pathogenicity and Promentioning

confidence: 99%

Reconstructing immune phylogeny: new perspectives

2005

View full text Add to dashboard Cite

Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection.The evolutionary development of the METAZOANS was associated with the diversification of a wide range of specialized cell-surface molecules that mediate key metabolic processes, as well as provide crucial contact interfaces and carry out a broad range of other essential functions. It is not unexpected that some of these molecules also came to function as barriers to pathogenic invasion and, in doing so, began to carry out dedicated innate immune protective functions. Whereas the simplest form of protection, barrier formation, is essentially mechanical in nature, relentless pressure from genetic variation in pathogens probably drove the evolution of such innate immune protective molecules towards diversification and, in parallel, towards integration of signalling pathways to regulate cellular responses to external stimulation. However, despite the sophistication that such innate immune mediators achieved over time, their biological complexity, by definition, would be limited by genome space, so with increasing complexity of body plan and/or increasing pathogen sophistication, they could be overwhelmed. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMore than 500 million years ago, a TRANSPOSITION event, probably involving a recombinationactivating gene (RAG)-bearing element, might have given rise to the predecessors of the rearranging antigen-binding receptors of the jawed vertebrates, which encompass the vertebrate radiations that extend from the cartilaginous fish through to humans. This is considered the defining point in the emergence of RAG-mediated (conventional) adaptive immunity 1,2 , which has evolved to create a mechanism for deriving almost limitless variation from very few genes. Studies in traditional and non-traditional animal models, such as sharks, bony fish and birds, have brought this event and its ramifications for host defence into sharper focus. We can now predict much about how these rearranging antigenbinding receptors probably arose, what alternative pathways of immune-receptor gene evolution have occurred, what relationships exist between B-and T-cell-mediated immunity and natural killer (NK)-cell function, how complex immune ...

show abstract

Mpi recombinase globally modulates the surface architecture of a human commensal bacterium

Cited by 116 publications

References 32 publications

Role of glycan synthesis in colonization of the mammalian gut by the bacterial symbiont Bacteroides fragilis

Role of glycan synthesis in colonization of the mammalian gut by the bacterial symbiont Bacteroides fragilis

Bacteroides: the Good, the Bad, and the Nitty-Gritty

Reconstructing immune phylogeny: new perspectives

Contact Info

Product

Resources

About