Saturday, May 17, 2025
5/17/2025
Mechanisms of Pneumococcal Persistence During Carriage - PROJECT SUMMARY (See instructions): This is an application for a four year continuation of a R37 Merit Award (years 5-9). For the past 30 years my laboratory has studied Streptococcus pneumoniae (Spn), a leading human respiratory pathogen. Our focus has been on upper respiratory tract (URT) colonization, the first step in all Spn disease. Our mechanistic studies rely on the tools of bacterial genetics and mucosal immunology applied in mouse models that recapitulate key aspects of Spn biology in its natural host. These include i) prolonged colonization, ii) increased duration and density of colonization during infancy, iii) host-to-host transmission, iv) higher colonization density and transmission in the setting of influenza co-infection, and v) serotype and age-dependent pneumonia and bacteremic infection. During the next funding period, we will build on our past studies as follows. Aim#1. Role of innate immunity in clearance of Spn colonization. Our preliminary data based on a host RNA-seq analysis during Spn colonization shows that clearance from the URT, which progresses over weeks to months, requires early IL-1 signaling and late IL-17 signaling. In Aim 1A, using Il1r-/- and Il17ra-/- mice, we will determine how innate immune signaling triggers the influx and activity of cellular effectors that take up and clear Spn. In Aim 1B, we will also define how IL-1 signaling affects IL-17- dependent clearance. In Aim 1C, we will analyze why infants show delayed expression in their IL-17 response to Spn. Aim#2. Spn-mucus interactions in persistence and transmission. Spn is found in the URT mucus layer which it modifies through the activity of exoglycosidases such as neuraminidase. Our preliminary data shows that during colonization Spn is retained by the firm mucus layer (the glycocalyx), but when localized in the loose mucus layer it is cleared through mucociliary flow. In Aim2A, we will study how modulation of mucus production and its physical characteristics inhibit clearance and promote stable colonization. In Aim2B, we will determine how these changes in mucus affect URT shedding with loose mucus, the limiting step in host-to-host transmission. In Aim 2C, we will explore how mucus modifications during co-infection with influenza virus, which also depends on neuraminidase activity, has synergistic effects on Spn colonization, shedding and transmission. Since bacterial infection and transmission generally begin with colonization of mucosal surfaces, our findings should have broad implications for other mucosal pathogens.
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