Because of the widespread dissemination of antibiotic resistance among pneumococci, novel strategies based on broader understanding of its pathogenesis are required for the prevention of pneumococcal disease. Dr. Weiser's group has been among the first to note spontaneous, reversible phenotypic variations (phase variation) in the pneumococcus. The transparent phenotype is more adherent to cultured human type II lung epithelial cells, and is associated with the ability to colonize the mucosal surface of the nasopharynx in an animal model of pneumococcal carriage. At least one of the endothelial receptors for transparent organisms is the receptor for platelet activating factor (PAFr). Chromosomal loci contributing to the expression of variation in colony opacity have been isolated and their contribution confirmed by the introduction of defined mutations in the pneumococcal chromosome. These mutants will be used to identify the genes involved in expression of colony opacity and to determine the molecular mechanisms controlling phase variations in their phenotype. Phenotypically stable mutants will be used to determine the structural basis of differences in colonial morphology. For example, some preliminary evidence suggests that changes in the exposure of the unique phosphorylcholine determinant of pneumococcal teichoic acid may correlate with phenotypic variation and may facilitate binding to the PAF receptor. Lastly, these phenotypically stable mutants will be used to determine the contribution of each phenotype to the different stages of pneumococcal infection including adherence and clearance by phagocytosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038446-04
Application #
2887061
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Klein, David L
Project Start
1996-04-01
Project End
2000-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hamaguchi, Shigeto; Zafar, M Ammar; Cammer, Michael et al. (2018) Capsule prolongs survival of Streptococcus pneumoniae during starvation. Infect Immun :
Weiser, Jeffrey N; Ferreira, Daniela M; Paton, James C (2018) Streptococcus pneumoniae: transmission, colonization and invasion. Nat Rev Microbiol 16:355-367
Ortigoza, Mila Brum; Blaser, Simone B; Zafar, M Ammar et al. (2018) An Infant Mouse Model of Influenza Virus Transmission Demonstrates the Role of Virus-Specific Shedding, Humoral Immunity, and Sialidase Expression by Colonizing Streptococcus pneumoniae. MBio 9:
Mitsi, E; Roche, A M; Reiné, J et al. (2017) Agglutination by anti-capsular polysaccharide antibody is associated with protection against experimental human pneumococcal carriage. Mucosal Immunol 10:385-394
Jochems, Simon P; Weiser, Jeffrey N; Malley, Richard et al. (2017) The immunological mechanisms that control pneumococcal carriage. PLoS Pathog 13:e1006665
Zafar, M Ammar; Wang, Yang; Hamaguchi, Shigeto et al. (2017) Host-to-Host Transmission of Streptococcus pneumoniae Is Driven by Its Inflammatory Toxin, Pneumolysin. Cell Host Microbe 21:73-83
Zafar, M Ammar; Hamaguchi, Shigeto; Zangari, Tonia et al. (2017) Capsule Type and Amount Affect Shedding and Transmission of Streptococcus pneumoniae. MBio 8:
Zangari, Tonia; Wang, Yang; Weiser, Jeffrey N (2017) Streptococcus pneumoniae Transmission Is Blocked by Type-Specific Immunity in an Infant Mouse Model. MBio 8:
Wang, Y; Jiang, B; Guo, Y et al. (2017) Cross-protective mucosal immunity mediated by memory Th17 cells against Streptococcus pneumoniae lung infection. Mucosal Immunol 10:250-259
Zafar, M Ammar; Kono, Masamitsu; Wang, Yang et al. (2016) Infant Mouse Model for the Study of Shedding and Transmission during Streptococcus pneumoniae Monoinfection. Infect Immun 84:2714-22

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