The pneumococcus ranks among the four 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 vaccines for children has been based upon protection against the few capsule serotypes that commonly cause disease. However, this strategy is being eroded by the selection for and replacement by non-vaccine serotypes. The initial step in the interaction of the pneumococcus with its human host is colonization of the nasopharynx. Experience with childhood vaccination has demonstrated the critical importance to public health of this step, since interrupting colonization decreases transmission to the unvaccinated adult population and greatly amplifies prevention of disease among the population. Since higher rates and duration of carriage enhance the risk of transmission and disease, we have studied how pneumococci persist and are eventually cleared from the host mucosal surface. We have utilized a murine model to show that the acute inflammatory response to carriage is ineffective at clearing colonizing organisms. The key to the success of the pneumococcus in colonization (and disease), therefore, is its ability to evade the initial inflammatory response it elicits. Our findings during the prior funding cycle identified pneumococcal genes required to evade killing by neutrophils. Our recent results reveal that an esterase (Pce) capable of cleaving choline-containing substrates including host platelet-activating factor (PAF), a paracrine neutrophil activator, enhances colonization.
Aim#1 examines how pneumococci target PAF to suppress neutrophil-mediated clearance during colonization. After the neutrophil response peaks, eventual clearance follows a CCL2-dependent influx of monocytes/macrophages to the nasal lumen. Recent data show that for this process to be sustained over the multiple weeks needed to clear colonization requires cytosolic signaling and sensing of cytokines by the IL1 receptor.
Aim#2 determines how inflammasome activation and IL-1-signaling by this extracellular pathogen contributes to the eventual clearance of colonization. The increased burden of disease that characterizes early childhood is associated with higher carriage rates in part because each episode lasts longer. Through our insight in to the dynamics of carriage, in Aim#3 we will explore why there is a delayed influx of mucosal macrophages that leads to prolonged colonization during infancy. Thus, our continuing project is focused on the fundamental importance of bacterial interactions with professional phagocytes; the evasion of neutrophils and clearance by macrophages. Since mucosal colonization is the first step for many infectious agents, the detailed mechanistic understanding of the biology of colonization from this project will have broad relevance to microbial pathogenesis research.

Public Health Relevance

Pneumococci colonize the human nasopharynx and blocking this initial step is the key to prevention of disease. We will investigate how the organism evades neutrophils, but is eventually cleared by a sustained influx of macrophages. This later effect is dysfunctional during infancy, when the risk of infection is greatest.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038446-24
Application #
9497773
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lu, Kristina
Project Start
1996-04-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
24
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
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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