The establishment and persistence of a microbe on a host surface will depend on its ability to compete with other species as well as members of the same species. Manipulations, such as antibiotics and vaccines, alter the dynamics of these relationships, sometimes with undesirable consequences. Recent introduction of a conjugate vaccine for Streptococcus pneumoniae has lowered the burden of carriage and disease by this leading pathogen for the included serotypes. However, the growing problem of replacement with non-vaccine serotypes shows that the vaccine has diminished the competitive selective pressure that had been suppressing these previously less common serotypes. Clinical experience, therefore, has revealed the importance of intraspecies competition for this species and the need to better understand factors affecting it in order to maintain or improve an otherwise successful prevention strategy. A mechanism that may underlie this intraspecies competition is based on the elaboration of pneumococcal bacteriocins (pneumocins). These small antimicrobial peptides expressed by the blp locus target members of the same species that do not produce a cognate immunity protein. In the mouse model of colonization, pneumocins dictate the outcome of competition between two isolates. We have identified isolates expressing broadly active pneumocins that inhibit all other pneumococci tested.
In Specific Aim #1, we will characterize the broadly acting pneumocins that contribute to intraspecies competition. Specifically, we will 1) identify the broadly acting pneumocins and the basis of immunity to these pneumocins, 2) determine the contribution of pneumocins and their immunity to competition among clinical isolates, and 3) test whether these pneumocins can be used to reduce pneumococcal colonization. We have also shown that isolates expressing the same pneumocin alleles and lacking direct bacterial-bacterial inhibition are still able to compete in vivo. Preliminary data, therefore, indicates that host factors can also dictate the outcome of competition. Thus, in Specific Aim #2 we will determine whether host innate immune responses and differential bacterial resistance to these responses contribute to intraspecies competition during colonization. We will focus on the major mechanisms of pneumococcal clearance, involving complement and phagocytes;and the major virulence factor and determinant of resistance to clearance, capsule type, to determine their role in competition. Defining these two non-mutually exclusive mechanisms of competition, involving the elaboration of anti-pneumococcal factors by competing pneumococci or by the host, will provide a molecular explanation for why some pneumococcal strains or types prevail.

Public Health Relevance

The recent introduction of childhood vaccination against Streptococus pneumoniae has altered the spectrum of disease-causing strains and revealed the importance of the competitive balance for the ecology of this species and prevention of disease. The focus of this project is to define how competition occurs for this leading human pathogen. The project will 1) characterize the elaboration of bacterial factors called bacteriocins that target members of the same species and 2) define how this pathogen takes advantage of the host immune response to promote its competitive success.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078538-04
Application #
8197203
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Taylor, Christopher E,
Project Start
2008-12-25
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$380,011
Indirect Cost
$134,986
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Langereis, Jeroen D; de Jonge, Marien I; Weiser, Jeffrey N (2014) Binding of human factor H to outer membrane protein P5 of non-typeable Haemophilus influenzae contributes to complement resistance. Mol Microbiol 94:89-106
Siegel, Steven J; Roche, Aoife M; Weiser, Jeffrey N (2014) Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source. Cell Host Microbe 16:55-67
Langereis, Jeroen D; Weiser, Jeffrey N (2014) Shielding of a lipooligosaccharide IgM epitope allows evasion of neutrophil-mediated killing of an invasive strain of nontypeable Haemophilus influenzae. MBio 5:e01478-14
DeBardeleben, Hilary K; Lysenko, Elena S; Dalia, Ankur B et al. (2014) Tolerance of a phage element by Streptococcus pneumoniae leads to a fitness defect during colonization. J Bacteriol 196:2670-80
Kochan, Travis J; Dawid, Suzanne (2013) The HtrA protease of Streptococcus pneumoniae controls density-dependent stimulation of the bacteriocin blp locus via disruption of pheromone secretion. J Bacteriol 195:1561-72
Weiser, Jeffrey N (2013) The battle with the host over microbial size. Curr Opin Microbiol 16:59-62
Davis, Kimberly M; Weiser, Jeffrey N (2011) Modifications to the peptidoglycan backbone help bacteria to establish infection. Infect Immun 79:562-70
Son, Matthew R; Shchepetov, Mikhail; Adrian, Peter V et al. (2011) Conserved mutations in the pneumococcal bacteriocin transporter gene, blpA, result in a complex population consisting of producers and cheaters. MBio 2:
Bachman, Michael A; Oyler, Jennifer E; Burns, Samuel H et al. (2011) Klebsiella pneumoniae yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2. Infect Immun 79:3309-16
Clarke, Thomas B; Francella, Nicholas; Huegel, Alyssa et al. (2011) Invasive bacterial pathogens exploit TLR-mediated downregulation of tight junction components to facilitate translocation across the epithelium. Cell Host Microbe 9:404-14

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