6205 Marsico Hall, CB #7290
919-966-2627 - Office
919-966-5612 - Lab
Our research is focused on understanding how bacteria cause respiratory tract infections. We are specifically interested in understanding how some bacterial species typically colonize the nasopharynx of their hosts chronically and asymptomatically (behaving almost like commensals), but occasionally cause overt serious disease such as pneumonia or meningitis. By contrast with the strictly human-adapted pathogens that fall into this category, such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis, Bordetella bronchiseptica has a broad host range that includes animals commonly studied in the laboratory such as rabbits, rats, guinea pigs and mice. We have therefore been using B. bronchiseptica and some of its natural hosts as models to investigate the molecular mechanisms used by bacteria to manipulate the innate and adaptive immune responses of their hosts so that they can set up persistent, long-term infections. Because B. bronchiseptica is an extremely close relative of Bordetella pertussis, our studies also shed light on the molecular bases by which this organism causes whooping cough, a serious illness that persists worldwide despite the availability of efficacious vaccines.
Bacterial control of inflammation in the respiratory tract
Using B. bronchiseptica and a mouse lung inflammation model, we discovered recently that filamentous hemagglutinin (FHA), a large protein virulence factor that is both surface associated and released into the extracellular environment, allows Bordetella to suppress the inflammatory response of its host. We have identified the domain within FHA that is responsible for this activity and are currently working to identify the host cell receptor(s) involved and to characterize the host signal transduction pathways that are affected in response to FHA binding. Using both genetic and biochemical approaches, we have also identified several additional Bordetella factors involved in controlling inflammation and are currently identifying their functional domains as well as their host cell receptors.
Mechanism of Two-Partner Secretion
Two-Partner Secretion (TPS) systems export large ‘exoproteins’ (TpsA family members) across the outer membranes of Gram-negative bacteria using channel-forming β-barrel proteins (TpsB family members). TPS systems are present in nearly all groups of Gram-negative bacteria and TpsB proteins belong to a large family of outer membrane protein-translocating porin-type proteins with members in the animal, plant and fungal kingdoms, making this general secretion mechanism the most widely distributed in nature. Filamentous hemagglutinin (FHA) is one of the prototypical members of the TPS family. Our studies with FHA revealed important aspects of the TPS mechanism, such as how the FHA protein is oriented topologically on the bacterial cell surface, and these results were critical in understanding FHA function during infection. Current projects are aimed at understanding how, biophysically, this very large protein is translocated across the bacterial outer membrane in the absence of an obvious energy source and how the large, C-terminal pro-domain controls the proper folding of the C-terminal domain of the mature protein.
Burkholderia pseudomallei is a Gram-negative, soil saprophyte endemic to Southeast Asia and Northern Australia and the etiological agent of melioidosis, a severe and invasive human disease associated with high morbidity and mortality. B. pseudomallei infects humans through inhalation, oral ingestion, or direct contact with skin abrasions, and causes disease symptoms that range from localized skin abscesses to chronic or acute pneumonia to fulminant septicemia. Because of its low dose of infectivity, aerosol transmission, severe course of disease, and easy cultivation in the laboratory, B. pseudomallei is classified as a category B potential biothreat agent. Deciphering the molecular basis of the early steps in the infection process of this understudied pathogen will be crucial to the development of rapid diagnostics, effective vaccines and therapeutics for melioidosis. Whole genome sequence analyses indicate that B. pseudomallei strains have the potential to encode several TPS systems and ten or more proteins of the autotransporter (AT) family. Like TPS family members, nearly all AT proteins that have been characterized so far have been proven or postulated to play roles in virulence. We are currently characterizing the expression, maturation and cellular localization of the B. pseudomallei TPS and AT proteins and are investigating their potential roles in adherence, immunomodulation, and other aspects of B. pseudomallei pathogenesis.
Noel, C. R., J. Mazar, J. A. Melvin, J. A. Sexton, and P. A. Cotter. (2012) The Prodomain of the Bordetella Two-Partner Secretion Pathway Protein FhaB Remains Intracellular yet Affects the Conformation of the Mature C-terminal Domain. Molecular Microbiology. In Press
Llewellyn, A. C., Zhao, J., Song, F., Parvathareddy, J., Xu, Q., Napier, B. A., Laroui, H., Gallo. R. L., Bina, J. E., Cotter, P. A., Miller, M. A., Raetz, C. R. H. and D. S. Weiss. (2012) RtzC is a deacetylase required for lipid A modification and Francisella pathogenesis. Molecular Microbiology. In Press
Anderson, M. S., Garcia, E. C. and P. A. Cotter. (2012) The Burkholderia bcpAIOB genes define unique classes of two-partner secretion and contact-dependent growth inhibition systems. PLoS Genetics. 8(8):e1002877.
Henderson, M. W., Inatsuka, C. S., Sheets, A. J., Williams, C. L., Benaron, D. J., Donato, G. M., Gray, M. C., Hewlett, E. L. and P. A. Cotter. (2012) Contribution of Bordetella filamentous hemagglutinin and adenylate cyclase toxin to suppression and evasion of IL-17-mediated inflammation. Infection and Immunity. 80:2061-2075.
Cotter P. (2011) Microbiology: Molecular syringes scratch the surface. Nature. 475(7356):301-3. doi: 10.1038/475301a.
Aoki, S. K., E. J. Diner, C. t’Kint de Roodenbeke, B. R. Burgess, S. J. Poole, B. A. Braaten, A. M. Jones, J. S. Webb, C. S. Hayes, P. A. Cotter, and D. A. Low. (2010) A Widespread Family of Polymorphic Contact-Dependent Toxin Delivery Systems in Bacteria. Nature. 468(7322):439-442.
Jani, A. J. and P. A. Cotter. (2010) Type VI Secretion: Not Just for Pathogenesis Anymore. Cell Host and Microbe. 8:2-6.
Inatsuka, C. S., Q. Xu, I. Vujkovic-Cvijin, S. Wong, S. Stibitz, J. F. Miller, and P. A. Cotter. (2010) Pertactin is required for Bordetella to resist neutrophil-mediated clearance. Infection and Immunity 78:2901-2909.
Julio, S. M., C. S. Inatsuka, J. Mazar, C. Dieterich, D. A. Relman, and P. A. Cotter. (2009) Natural-host animal models indicate functional interchangeability between the filamentous hemagglutinins of Bordetella pertussis and Bordetella bronchiseptica and reveal a role for the mature C-terminal domain, but not the RGD motif, during infection. Molecular Microbiology. 71:1574-1590.
Williams, C. L., R. Haines, and P. A. Cotter. (2008) Serendipitous discovery of an immunoglobulin-binding autotransporter in Bordetella. Infection and Immunity. 76:2966-2977.
Mazar, J. and P. A. Cotter. (2007) New Insight into the Molecular Mechanisms of Two-Partner Secretion. Trends in Microbiology. 15:508-515.
Cotter, P.A. and S. Stibitz. (2007) c-di-GMP-mediated regulation of virulence and biofilm formation. Current Opinion in Microbiology. 10:17-23.
Williams, C. L. and P. A. Cotter. (2007) Autoregulation is essential for precise temporal and steady-state regulation by the Bordetella BvgAS phosphorelay. Journal of Bacteriology 189:1974-1982.
Mazar, J. and P. A. Cotter. (2006) Topology and maturation of filamentous hemagglutinin suggest a new model for two-partner secretion. Molecular Microbiology. 62(3):641-654.