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A Putative Lateral Flagella of the Cystic Fibrosis Pathogen Burkholderia Dolosa Regulates Swimming Motility and Host Cytokine Production

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A Putative Lateral Flagella of the Cystic Fibrosis Pathogen Burkholderia Dolosa Regulates Swimming Motility and Host Cytokine Production A putative lateral flagella of the cystic fibrosis pathogen Burkholderia dolosa regulates swimming motility and host cytokine production The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Roux, Damien, Matthew Schaefers, Bradley S. Clark, Molly Weatherholt, Diane Renaud, David Scott, John J. LiPuma, Gregory Priebe, Craig Gerard, and Deborah R. Yoder-Himes. 2018. “A putative lateral flagella of the cystic fibrosis pathogen Burkholderia dolosa regulates swimming motility and host cytokine production.” PLoS ONE 13 (1): e0189810. doi:10.1371/journal.pone.0189810. http://dx.doi.org/10.1371/journal.pone.0189810. Published Version doi:10.1371/journal.pone.0189810 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:34868948 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA RESEARCH ARTICLE A putative lateral flagella of the cystic fibrosis pathogen Burkholderia dolosa regulates swimming motility and host cytokine production Damien Roux2,3,4☯, Matthew Schaefers5,6☯, Bradley S. Clark1, Molly Weatherholt1, Diane Renaud7, David Scott7, John J. LiPuma8, Gregory Priebe5,6, Craig Gerard9, Deborah R. Yoder-Himes1* a1111111111 a1111111111 1 Department of Biology, University of Louisville, Louisville, Kentucky, United States of America, 2 INSERM, a1111111111 IAME, UMR 1137, Paris, France, 3 Univ Paris Diderot, Sorbonne Paris CiteÂ, Paris, France, 4 AP-HP, Louis a1111111111 Mourier Hospital, Intensive Care Unit, Colombes, France, 5 Division of Critical Care Medicine, Department of a1111111111 Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America, 6 Department of Anesthesia, Harvard Medical School, Boston, Massachusetts, United States of America, 7 Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, Kentucky, United States of America, 8 Division of Pediatrics, University of Michigan, Ann Arbor, Michigan, United States of America, 9 Division of Respiratory Diseases, Boston Children's Hospital, Boston, Massachusetts, United States of America OPEN ACCESS ☯ These authors contributed equally to this work. Citation: Roux D, Schaefers M, Clark BS, * [email protected] Weatherholt M, Renaud D, Scott D, et al. (2018) A putative lateral flagella of the cystic fibrosis pathogen Burkholderia dolosa regulates swimming motility and host cytokine production. PLoS ONE Abstract 13(1): e0189810. https://doi.org/10.1371/journal. pone.0189810 Burkholderia dolosa caused an outbreak in the cystic fibrosis clinic at Boston Children's Hospital and was associated with high mortality in these patients. This species is part of a Editor: Abdelwahab Omri, Laurentian, CANADA larger complex of opportunistic pathogens known as the Burkholderia cepacia complex Received: May 25, 2017 (Bcc). Compared to other species in the Bcc, B. dolosa is highly transmissible; thus under- Accepted: December 1, 2017 standing its virulence mechanisms is important for preventing future outbreaks. The genome Published: January 18, 2018 of one of the outbreak strains, AU0158, revealed a homolog of the lafA gene encoding a Copyright: © 2018 Roux et al. This is an open putative lateral flagellin, which, in other non-Bcc species, is used for movement on solid sur- access article distributed under the terms of the faces, attachment to host cells, or movement inside host cells. Here, we analyzed the con- Creative Commons Attribution License, which servation of the lafA gene and protein sequences, which are distinct from those of the polar permits unrestricted use, distribution, and flagella, and found lafA homologs to be present in numerous β-proteobacteria but notably reproduction in any medium, provided the original author and source are credited. absent from most other Bcc species. A lafA deletion mutant in B. dolosa showed a greater swimming motility than wild-type due to an increase in the number of polar flagella, but did Data Availability Statement: Raw data for described experiments is freely available at the not appear to contribute to biofilm formation, host cell invasion, or murine lung colonization following DOIs: Swimming and swarming data - or persistence over time. However, the lafA gene was important for cytokine production in 10.6084/m9.figshare.5675152.v1 TEM quantitation human peripheral blood mononuclear cells, suggesting it may have a role in recognition by - 10.6084/m9.figshare.5675140.v1 Internalization the human immune response. data - 10.6084/m9.figshare.5675212.v2 Biofilm data - 10.6084/m9.figshare.5675188.v1 Bacterial survival in mouse lungs - 10.6084/m9.figshare. 5675146.v2 In vivo cytokine analysis - 10.6084/ m9.figshare.5675254.v1 In vitro cytokines - 10. 6084/m9.figshare.5675155.v1 Tn-seq raw data counts - 10.6084/m9.figshare.5671894. PLOS ONE | https://doi.org/10.1371/journal.pone.0189810 January 18, 2018 1 / 29 The putative lateral flagella of the cystic fibrosis pathogen Burkholderia dolosa Funding: This work was supported by the William Introduction Randolph Hearst Fund (https://www.hearstfdn. org/) and the SocieÂte de ReÂanimation de Langue Cystic fibrosis (CF) has a prevalence of ~1/3,000 live Caucasian births, making it a commonly FrancËaise (http://www.srlf.org/en/home/) (DR), inherited disorder leading to a limited lifespan and high morbidity [1]. Mutations within the the University of Louisville (http://louisville.edu/) chloride ion transporter gene, CFTR, result in CF and lead to the production of a thick, sticky, (DRYH; RIG50895, MW), the Slifka Family Fund low pH mucus in the lungs of CF patients, creating a breeding ground for bacteria (reviewed (http://www.slifkafoundation.org/) (CG), and the in [2]). Common pathogens infecting the lungs of CF patients [3] include Pseudomonas aerugi- Cystic Fibrosis Foundation (https://www.cff.org/) (CG; PRIEBE13I0, GPP; YODERH10F0, DRYH; nosa, Staphylococcus aureus, Haemophilus influenzae, Stenotrophomonas maltophilia, and JJL). The funders had no role in study design, members of the Gram negative Burkholderia cepacia complex (Bcc), which is comprised of data collection and analysis, decision to publish, over 20 species closely related species including the intracellular opportunist B. dolosa [4]. or preparation of the manuscript. Members of the Bcc are capable of producing a necrotizing pneumonia in infected patients, Competing interests: The authors have declared characterized by a rapid decline in lung function (1±3 months) with bacteremia and near that no competing interests exist. 100% mortality. This is often called the ªcepacia syndromeº [5]. Certain species within the Bcc are capable of facile patient-to-patient transmission and have caused outbreaks in CF clinics worldwide [6±8]. The most common outbreak strains capable of spreading between CF patients fall within the B. cenocepacia and B. dolosa species [9]. These outbreaks have resulted in the enforcement of strict regulations and segregation for CF patients. One of the outbreaks occurred at Boston Children's Hospital, in which B. dolosa infected over 40 patients and con- tributed to the death of many, if not all, of them [10]. Genomic research on the Bcc has revealed that these bacteria have large genomes, consist- ing of multiple replicons. B. dolosa strain AU1058, one of the outbreak isolates, has a 6.41 Mb genome consisting of 66.81% GC pairs [11] organized in two circular chromosomes and a third chromosome/megaplasmid similar to other Bcc species [12±18]. Virulence traits attrib- uted to B. dolosa and other members of the Bcc include intrinsic antimicrobial resistance (with some strains of B. dolosa and B. cenocepacia being nearly pan-resistant) [19±21], oxygen scav- enging proteins [22], flagella [23, 24], biofilm formation [25, 26], LPS [27, 28], quorum sensing [29±33], siderophore production [34±37], oxygen-sensing transcriptional regulators [38], invasion and intracellular survival within macrophages for up to 5 days [39±41], and Type III Secretion Systems [42±44]. Based on these data, in conjunction with the observed pathogenic- ity of B. dolosa and other Bcc members in CF patients, it is crucial that the mechanism(s) by which these species interact with their hosts be understood before new effective therapeutics can be discovered to combat them. The genome of the AU0158 outbreak isolate of B. dolosa was found to contain genes encod- ing both a polar flagellum (fliC) as well as an additional flagellin gene located at the AK34_RS07895 locus. Preliminary evidence suggests that the protein encoded at AK34_RS07895 serves as the monomer for lateral flagella which are found infrequently in bac- teria but contribute to movement on solid surfaces in other pathogens such as Aeromonas hydrophila and Vibrio parahaemolyticus [45, 46]. These organisms often express the polar fla- gellum alone while grown in liquid culture, but express both polar and lateral flagella when grown on a solid medium. The polar flagellum of A. hydrophila has also been shown to act as a sensor that regulates the expression of the lateral flagellin genes [47]. Additionally, it was found that this polar-flagellum-induced increase in lateral flagella gene expression resulted in an increased formation of linkages between bacterial cells that contributed to
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