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1.
ACS Infect Dis ; 2(1): 62-70, 2016 01 08.
Article in English | MEDLINE | ID: mdl-27622948

ABSTRACT

Stenotrophomonas maltophilia is an emerging, multidrug-resistant pathogen of increasing importance for the immunocompromised, including cystic fibrosis patients. Despite its significance as an emerging pathogen, relatively little is known regarding the specific factors and mechanisms that contribute to its pathogenicity. We identify and characterize a putative ankyrin-repeat protein (Smlt3054) unique to clinical S. maltophilia isolates that binds F-actin in vitro and co-localizes with actin in transfected HEK293a cells. Smlt3054 is endogenously expressed and secreted from clinical S. maltophilia isolates, but not an environmental isolate (R551-3). The in vitro binding of Smlt3054 to F-actin resulted in a thickening of the filaments as observed by TEM. Ectopic expression of Smlt3054-GFP exhibits strong co-localization with F-actin, with distinct, retrograde F-actin waves specifically associated with Smlt3054 in individual cells as well as formation of dense, internal inclusions at the expense of retrograde F-actin waves. Collectively, our results point to an interaction between Smlt3054 and F-actin. Furthermore, as a potentially secreted protein unique to clinical S. maltophilia isolates, Smlt3054 may serve as a starting point for understanding the mechanisms by which S. maltophilia has become an emergent pathogen.


Subject(s)
Actin Cytoskeleton/metabolism , Ankyrin Repeat , Bacterial Proteins/metabolism , Bacterial Proteins/physiology , Stenotrophomonas maltophilia/metabolism , Stenotrophomonas maltophilia/pathogenicity , Actin Cytoskeleton/microbiology , Actins/metabolism , Anti-Bacterial Agents/pharmacology , Cross Infection/microbiology , Cystic Fibrosis/microbiology , Host-Pathogen Interactions/physiology , Humans , Signal Transduction , Stenotrophomonas maltophilia/drug effects , Stenotrophomonas maltophilia/isolation & purification
2.
mBio ; 5(6): e01864, 2014 Nov 04.
Article in English | MEDLINE | ID: mdl-25370491

ABSTRACT

UNLABELLED: The diverse Fusobacterium genus contains species implicated in multiple clinical pathologies, including periodontal disease, preterm birth, and colorectal cancer. The lack of genetic tools for manipulating these organisms leaves us with little understanding of the genes responsible for adherence to and invasion of host cells. Actively invading Fusobacterium species can enter host cells independently, whereas passively invading species need additional factors, such as compromise of mucosal integrity or coinfection with other microbes. We applied whole-genome sequencing and comparative analysis to study the evolution of active and passive invasion strategies and to infer factors associated with active forms of host cell invasion. The evolution of active invasion appears to have followed an adaptive radiation in which two of the three fusobacterial lineages acquired new genes and underwent expansions of ancestral genes that enable active forms of host cell invasion. Compared to passive invaders, active invaders have much larger genomes, encode FadA-related adhesins, and possess twice as many genes encoding membrane-related proteins, including a large expansion of surface-associated proteins containing the MORN2 domain of unknown function. We predict a role for proteins containing MORN2 domains in adhesion and active invasion. In the largest and most comprehensive comparison of sequenced Fusobacterium species to date, we have generated a testable model for the molecular pathogenesis of Fusobacterium infection and illuminate new therapeutic or diagnostic strategies. IMPORTANCE: Fusobacterium species have recently been implicated in a broad spectrum of human pathologies, including Crohn's disease, ulcerative colitis, preterm birth, and colorectal cancer. Largely due to the genetic intractability of member species, the mechanisms by which Fusobacterium causes these pathologies are not well understood, although adherence to and active invasion of host cells appear important. We examined whole-genome sequence data from a diverse set of Fusobacterium species to identify genetic determinants of active forms of host cell invasion. Our analyses revealed that actively invading Fusobacterium species have larger genomes than passively invading species and possess a specific complement of genes-including a class of genes of unknown function that we predict evolved to enable host cell adherence and invasion. This study provides an important framework for future studies on the role of Fusobacterium in pathologies such as colorectal cancer.


Subject(s)
Bacterial Adhesion , Endocytosis , Fusobacterium/physiology , Genes, Bacterial , Genome, Bacterial , Virulence Factors/genetics , Evolution, Molecular , Fusobacterium/genetics , Fusobacterium/growth & development , Sequence Analysis, DNA , Virulence
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