Acute respiratory infection (ARI) remains a major source of morbidity and mortality worldwide. Epidemiologic evidence and experience with three vaccines targeting ARIs point to the acquisition of colonization as the key event in eventual progression to disease, transmission and prevention. This application focuses on understanding the first event in host-pathogen interaction, establishment of colonization on the mucosal surface of the upper respiratory tract (URT). Streptococcus pneumoniae, a leading cause of ARI particularly in the setting of viral co- infection, will be used to examine the microbial and host factors contributing to acquisition. Preliminary data show that prior to the establishment of a stable bacterial population along the epithelial surface pneumococci are found entrapped in lumenal mucus. We will use a mouse model of carriage to examine pneumococcal interaction with mucus and how this earliest event dictates success in colonization (Aim#1) and is affected by inflammation (Aim#2) and immunity (Aim#3). Preliminary data support a mechanism to be tested in Aim#1 whereby the ability of the pneumococcus to manipulate sugars allows it to breakdown and utilize mucopolysaccharides for its proliferation, adaptation and to escape mucus entrapment. We propose that these events are required for the development of colonization of sufficient density and duration to allow for transmission. Additional preliminary data suggest that URT inflammation promotes rather than inhibits pneumococcal colonization. The role of pneumococcal-induced inflammation and co- infection with influenza A on mucus production and their role in enhancing early events in colonization will be examined in Aim#2.
In Aim#3 we will examine the contribution of IgG from the serum pool in blocking acquisition and transmission, and determine the mechanism for antibody-mediated inhibition of early events in colonization. Thus, this application addresses basic processes of broad significance to pathogenesis- i) acquisition of a microbe by a host, ii) proliferation in that host, iii) transmisson to a new host, iv) the effect of inflammation in the microbe's niche, and v) the modulation of these parameters in an immune host.

Public Health Relevance

Streptococcus pneumoniae is a leading human pathogen that must first colonize the mucosal surface of the nasopharynx. Blocking this initial step is the key t prevention of pneumococcal disease in the population. We will use a mouse model to investigate how initial interaction with the host dictates success in colonization (Aim#1) and is affected by inflammation (Aim#2) and immunity (Aim#3).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI105168-06
Application #
9388950
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lu, Kristina
Project Start
2015-04-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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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; 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
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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
Kono, Masamitsu; Zafar, M Ammar; Zuniga, Marisol et al. (2016) Single Cell Bottlenecks in the Pathogenesis of Streptococcus pneumoniae. PLoS Pathog 12:e1005887
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
Siegel, Steven J; Weiser, Jeffrey N (2015) Mechanisms of Bacterial Colonization of the Respiratory Tract. Annu Rev Microbiol 69:425-44
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

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