Streptococcus pneumoniae (the pneumococus) ranks among the five leading causes of infectious death worldwide. This single species accounts for a large proportion of respiratory tract (pneumonia, otitis media) and invasive (sepsis, meningitis) bacterial diseases. The development of efficacious conjugate vaccines for children has been based upon protection against the few capsule types that commonly cause disease. However, this strategy is now being eroded by the selection for and replacement by non-vaccine types. The initial step in the interaction of the pneumococcus with its host is colonization of the nasopharynx. Experience with conjugate vaccines has demonstrated that interrupting colonization results in herd immunity that amplifies prevention of disease in the population. To better understand the biology of colonization, during the prior funding period, we utilized a murine model to characterize bacterial and host factors that allow for pneumococcal persistence and its eventual clearance from the mucosal surface. These studies show that carriage, much like infection in normally sterile sites, induces acute inflammation. However, opsonophagocytic killing by this neutrophil-dominated response is not completely effective in clearing colonizing organisms. Complete clearance of carriage requires cellular immunity, and is mediated by the gradual Th17-dependent influx of tissue macrophages into the nasal lumen. The key to the success of the pneumococcus in colonization (and disease), therefore, is its ability to evade the initial inflammatory response it elicits.
In specific aim#1, we will identify and characterize the complete set of pneumococcal genes and gene products contributing to evasion of opsonization and phagocytic killing by neutrophils in vitro and in vivo. The key to resolution of pneumococcal carriage appears to be recognition and uptake by macrophages. It remains unclear how the unique population of upper respiratory tract macrophages recognizes colonizing pneumococci.
In specific aim#2, we will identify the macrophage receptor(s) (including scavenger receptors and C-type lectins) required for non-opsonic clearance during colonization. Finally, in specific aim#3, we will examine the role of capsule type in colonization and whether type-specific differences are explained by i) evasion of opsonophagocytic clearance by neutrophils and ii) recognition and uptake by upper respiratory tract macrophages. Together these studies will provide mechanistic insight into the three main features of pneumococcal carriage;why it is common, why it is transient, and why it varies greatly among isolates by capsule type.

Public Health Relevance

Streptococcus pneumoniae colonizes the mucosal surface of the human nasopharynx and blocking this initial step in host interaction is the key to prevention of pneumococcal disease in the population. Our prior studies of bacterial and host factors affecting colonization show that pneumococci evade the neutrophil response it elicits, but is eventually cleared by cellular immunity leading to an influx of nasal macrophages. The proposed studies provide a mechanistic understanding of i) its ability to inhibit uptake and killing by neutrophils, ii) its recognition by macrophages, and iii) the role of its capsule type in these interactions with phagocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038446-19
Application #
8488388
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Taylor, Christopher E,
Project Start
1996-04-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
19
Fiscal Year
2013
Total Cost
$343,092
Indirect Cost
$106,720
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hergott, Christopher B; Roche, Aoife M; Tamashiro, Edwin et al. (2016) Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis. Blood 127:2460-71
Wang, Y; Jiang, B; Guo, Y et al. (2016) Cross-protective mucosal immunity mediated by memory Th17 cells against Streptococcus pneumoniae lung infection. Mucosal Immunol :
Mitsi, E; Roche, A M; Reiné, J et al. (2016) Agglutination by anti-capsular polysaccharide antibody is associated with protection against experimental human pneumococcal carriage. Mucosal Immunol :
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
Siegel, Steven J; Weiser, Jeffrey N (2015) Mechanisms of Bacterial Colonization of the Respiratory Tract. Annu Rev Microbiol 69:425-44
Siegel, Steven J; Tamashiro, Edwin; Weiser, Jeffrey N (2015) Clearance of Pneumococcal Colonization in Infants Is Delayed through Altered Macrophage Trafficking. PLoS Pathog 11:e1005004
Lemon, Jamie K; Miller, Megan R; Weiser, Jeffrey N (2015) Sensing of interleukin-1 cytokines during Streptococcus pneumoniae colonization contributes to macrophage recruitment and bacterial clearance. Infect Immun 83:3204-12
Roche, A M; Richard, A L; Rahkola, J T et al. (2015) Antibody blocks acquisition of bacterial colonization through agglutination. Mucosal Immunol 8:176-85
Lemon, Jamie K; Weiser, Jeffrey N (2015) Degradation products of the extracellular pathogen Streptococcus pneumoniae access the cytosol via its pore-forming toxin. MBio 6:
Hergott, Christopher B; Roche, Aoife M; Naidu, Nikhil A et al. (2015) Bacterial exploitation of phosphorylcholine mimicry suppresses inflammation to promote airway infection. J Clin Invest 125:3878-90

Showing the most recent 10 out of 70 publications