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) transmission 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.
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).
|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; ReinÃ©, 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|
|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|
|Weiser, Jeffrey N; Roche, Aoife M; Hergott, Christopher B et al. (2015) Macrophage Migration Inhibitory Factor Is Detrimental in Pneumococcal Pneumonia and a Target for Therapeutic Immunomodulation. J Infect Dis 212:1677-82|
Showing the most recent 10 out of 15 publications