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Functional Genome Analysis of Bifidobacterium Breve UCC2003

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Functional Genome Analysis of Bifidobacterium Breve UCC2003 Functional genome analysis of Bifidobacterium breve UCC2003 reveals type IVb tight adherence (Tad) pili as an essential and conserved host-colonization factor Mary O’Connell Motherwaya,b,1,2, Aldert Zomera,1, Sinead C. Leahya,b,1, Justus Reunanenc, Francesca Bottacinia,b,d, Marcus J. Claessona, Frances O’Briena, Kiera Flynna, Patrick G. Caseya, Jose Antonio Moreno Munoza, Breda Kearneya, Aileen M. Houstona,e, Caitlin O’Mahonya, Des G. Higginsf, Fergus Shanahana,e, Airi Palvac, Willem M. de Vosc,g, Gerald F. Fitzgeralda,b,h, Marco Venturad, Paul W. O’Toolea,b, and Douwe van Sinderena,b,2 aAlimentary Pharmabiotic Centre and Departments of bMicrobiology, eMedicine, and hFood and Nutritional Sciences, National University of Ireland, Cork, Ireland; dLaboratory of Probiogenomics, Department of Genetics, Biology of Microorganisms, Anthropology, and Evolution, University of Parma, 43100 Parma, Italy; cDivision of Microbiology and Epidemiology, Department of Basic Veterinary Medicine, University of Helsinki, FIN-00014, Helsinki, Finland; fConway Institute, University College Dublin, Belfield, Dublin 4, Ireland; and gLaboratory of Microbiology, Wageningen University, 6703 HB, Wageningen, The Netherlands Edited* by Todd R. Klaenhammer, North Carolina State University, Raleigh, NC, and approved May 25, 2011 (received for review April 7, 2011) Development of the human gut microbiota commences at birth, other bacteria, to host cells, or to environmental surfaces (17, with bifidobacteria being among the first colonizers of the sterile 18). Gram-positive pili are formed by a mechanism involving newborn gastrointestinal tract. To date, the genetic basis of Bifido- specific transpeptidases, called “sortases,” which cross-link in- bacterium colonization and persistence remains poorly understood. dividual pilin monomers and join the resulting covalent polymer Transcriptome analysis of the Bifidobacterium breve UCC2003 2.42- to the cell wall peptidoglycan (19). Recently, the Gram-positive Mb genome in a murine colonization model revealed differential pathogen Mycobacterium tuberculosis was found to express type fi expression of a type IVb tight adherence (Tad) pilus-encoding gene IVb pili similar to those speci ed by the Gram-negative tight cluster designated “tad2003.” Mutational analysis demonstrated that adherence (tad) locus (20). Homologs of tad genes have been fi the tad2003 gene cluster is essential for efficient in vivo murine gut identi ed in the genomes of Corynebacterium diphtheria, Ther- mobifida fusca, and Streptomyces coelicolor (21, 22). The Tad pili colonization, and immunogold transmission electron microscopy fi confirmed the presence of Tad pili at the poles of B. breve biosynthesis apparatus was rst described in Actinobacillus acti- UCC2003 cells. Conservation of the Tad pilus-encoding locus among nomycetemcomitans and allows the production and assembly of other B. breve strains and among sequenced Bifidobacterium ge- pili, which in this bacterium mediate adhesion to surfaces and are essential for colonization and pathogenesis (23, 24). Because nomes supports the notion of a ubiquitous pili-mediated host col- of their simple cell envelope structure, Gram-positive tad loci en- onization and persistence mechanism for bifidobacteria. code fewer pilus assembly functions than do their Gram-negative counterparts, namely TadZ, TadV, TadC, TadB, and TadA (21). MICROBIOLOGY fimbriae | probiotic | prebiotic | genomics TadA, an ATPase localized at the periphery of the cytoplasmic membrane, is believed to energize pilus assembly; TadB and he mammalian gastrointestinal tract (GIT) harbors a complex TadC represent integral membrane proteins that form homo- or Tcommunity of microorganisms, also referred to as the “in- hetero-oligomeric structures in association with TadA to con- testinal microbiota” (1, 2). Although it is well recognized that the stitute the secretion apparatus of the pilus subunit. Based on intestinal microbiota has a profound influence on health and similarity to the septum site-determining protein MinD, TadZ is disease, knowledge on the precise mechanism(s) by which this thought to direct the Tad secretion and assembly apparatus to microbiota exerts such influence remains largely unknown. Bac- the cell poles. The Tad pilus is comprised of homopolymers of terial colonization of the GIT of a newborn commences at birth a single pilin subunit, although some pili possess an adhesive and depends on many factors that include gestational age, mode subunit at the pilus tip or can be decorated with pseudopilins of delivery, local environment, type of feeding, and antibiotic along the pilus (21, 22). The pilin and pseudopilins are synthe- fi fi treatment (3, 4). Bi dobacterium species are among the rst col- sized as precursors (prepilins) with a hydrophobic leader peptide onizers of the essentially sterile GIT of newborns and constitute terminating with a glycine residue that is removed by a dedicated one of the dominant genera of the microbiota of healthy breast- peptidase (TadV). fed infants, although they become less abundant in weaned To enhance our understanding of bifidobacteria and the role infants and adults (5, 6). they play in the intestinal ecosystem, we determined the genome GIT colonization by microbes is believed to play an essential part in metabolism and energy balance, in resisting pathogen colonization, in the maturation of the intestine, and in the ed- ucation of the immune system (7–10). The specific contribution Author contributions: M.O.M., A.Z., S.C.L., J.R., D.G.H., F.S., W.M.d.V., G.F.F., and D.v.S. fi designed research; M.O.M., A.Z., S.C.L., J.R., F.O., K.F., P.G.C., J.A.M.M., and B.K. per- of members of the Bi dobacterium genus to such activities is formed research; A.M.H., C.O., and A.P. contributed new reagents/analytic tools; M.O.M., subject to much investigation and speculation (11), although it is A.Z., S.C.L., J.R., F.B., M.J.C., F.S., W.M.d.V., M.V., P.W.O., and D.v.S. analyzed data; and M.O.M., widely accepted that their presence in the GIT may confer health A.Z., J.R., F.S., W.M.d.V., G.F.F., M.V., P.W.O., and D.v.S. wrote the paper. benefits (12–14). The global analysis of the bifidobacterial gene The authors declare no conflict of interest. expression in babies indicated the activities include the pro- *This Direct Submission article had a prearranged editor. duction of folic acid and exopolysaccharides (EPS) (15). Although Data deposition: The sequence reported in this article has been deposited in the GenBank the latter property could be involved in persistence, the details database (accession no. CP000303). The array data for the comparative genome hybrid- of the molecular mechanisms that allow bifidobacteria to colo- ization and transcription studies have been deposited in the GEO database (accession no. nize the GIT have not yet been elucidated. GSE27491). Recently, Kankainen et al. (16) showed that adherence and 1M.O.M., A.Z., and S.L. contributed equally to this work. colonization of Lactobacillus rhamnosus GG is mediated by 2To whom correspondence may be addressed. E-mail: [email protected] or sortase-dependent pili. In Gram-positive bacteria, these pili are [email protected]. the most frequently described nonflagellar, proteinaceous, mul- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tisubunit surface appendages that are involved in adhesion to 1073/pnas.1105380108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1105380108 PNAS | July 5, 2011 | vol. 108 | no. 27 | 11217–11222 Downloaded by guest on September 27, 2021 sequence of a Bifidobacterium breve strain isolated from a nurs- from a common ancestor (26). The UCC2003 genome contains ling stool. Analysis of this genome sequence coupled with in vivo a single prophage-like remnant and one CRISPR (clustered transcriptome studies identified a tad locus essential for efficient regularly interspaced short palindromic repeats) locus, which host colonization of the murine intestine. This locus is conserved have been described previously (27–29). Extracellular proteins in all B. breve strains tested and in currently available Bifido- and structures are considered to be important for interaction of bacterium genomes, so the elucidation of its function represents the bacterium with its environment, for example in adherence, a significant step toward understanding the molecular details of degradation of complex carbohydrates, and microbe–microbe/ the interaction between bifidobacteria and their host. microbe–host communication. In silico prediction of the bacte- rial secretome enables functional characterization of possible Results and Discussion adhesins, as shown by the identification of sortase-anchored B. breve UCC2003 Genome. The 2,422,684-bp genome of B. breve adhesins in Lactobacillus salivarius (30). The predicted B. breve UCC2003 (Fig. 1) has a guanine-cytosine (G+C) content of UCC2003 secretome (Fig. S2) consists of 216 proteins with an 58.7%, similar to that of currently available Bifidobacterium Sec-type signal peptide (31), of which 41 contain an N-terminal genomes (Table S1), and is predicted to harbor 1,985 genes, of lipoprotein motif for anchoring to the cell membrane (32) and 10 which 1,854 are protein-coding sequences with an average length contain a C-terminal LPxTG-like motif for sortase-dependent – of 1,099 bp. The genome contains two rRNA-encoding operons anchoring to peptidoglycan or pilus biosynthesis (33 35). Exam- and 54 tRNA genes. A functional role or general function was ples of the latter category include seven genes that are predicted assignable for 1,597 (86%) of the protein-coding sequences, 250 to specify sortase-dependent pilin subunits, organized into three (14%) protein-coding sequences represent conserved genes for gene clusters (see below), and two extracellular glycosidases, which no functional role could be assigned, and only seven ApuB and GalA, which function in the hydrolysis of particular protein-coding sequences lack similarity to entries in the public glucose- and galactose-containing polysaccharides, respectively databases.
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