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Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice
Zhe Zhang, … , Thomas B. Clarke, Jeffrey N. Weiser
Zhe Zhang, … , Thomas B. Clarke, Jeffrey N. Weiser
Published June 8, 2009
Citation Information: J Clin Invest. 2009;119(7):1899-1909. https://doi.org/10.1172/JCI36731.
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Research Article Infectious disease

Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice

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Abstract

Microbial colonization of mucosal surfaces may be an initial event in the progression to disease, and it is often a transient process. For the extracellular pathogen Streptococcus pneumoniae studied in a mouse model, nasopharyngeal carriage is eliminated over a period of weeks and requires cellular rather than humoral immunity. Here, we demonstrate that primary infection led to TLR2-dependent recruitment of monocyte/macrophages into the upper airway lumen, where they engulfed pneumococci. Pharmacologic depletion of luminal monocyte/macrophages by intranasal instillation of liposomal clodronate diminished pneumococcal clearance. Efficient clearance of colonization required TLR2 signaling to generate a population of pneumococcal-specific IL-17–expressing CD4+ T cells. Depletion of either IL-17A or CD4+ T cells was sufficient to block the recruitment of monocyte/macrophages that allowed for effective late pneumococcal clearance. In contrast with naive mice, previously colonized mice showed enhanced early clearance that correlated with a more robust influx of luminal neutrophils. As for primary colonization, these cellular responses required Th17 immunity. Our findings demonstrate that monocyte/macrophages and neutrophils recruited to the mucosal surface are key effectors in clearing primary and secondary bacterial colonization, respectively.

Authors

Zhe Zhang, Thomas B. Clarke, Jeffrey N. Weiser

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Figure 6

Accelerated clearance in the secondary pneumococcal challenge is associated with enhanced cellular responses.

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Accelerated clearance in the secondary pneumococcal challenge is associa...
Comparisons of the time course of (A) the density of P1121 colonization, (B) neutrophil recruitment, and (C) monocyte/macrophage recruitment during primary (closed circles) and secondary (open circles) challenge. n = 5–20 mice per group per time point. Values represent mean ± SEM. (D) Quantitative real-time RT-PCR showing increased transcription of chemokine MCP-1 in the colonized epithelium of the nasopharynx. WT (black bars) or Tlr2–/– (white bars) mice were challenged with P1121 (Primary) or rechallenged with P1121 for one day 6 weeks after precolonization (Secondary). WT mice were also treated with GK1.5 antibodies to deplete CD4+ T cells (gray bar) prior to rechallenge. n = 4 mice per group. *P < 0.05, **P < 0.01; ***P < 0.001.

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