Immune pathways that regulate neutrophil activation and replenishment prevent persistent pneumococcal colonization.

Area of Science:

• Immunology
• Microbiology
• Infectious Diseases

Background:

• Streptococcus pneumoniae (Spn) is a leading cause of mucosal infections.
• Primary nasopharyngeal colonization by Spn is the initial step in pathogenesis.
• The duration of Spn colonization is influenced by host immune responses.

Purpose of the Study:

• To investigate immune signaling pathways that regulate the duration of Spn nasopharyngeal colonization.
• To elucidate the roles of IL-17RA and IL-1R signaling in controlling Spn infection.
• To understand the involvement of neutrophils in Spn clearance.

Main Methods:

• Utilized wild-type (WT) and knockout mouse models (IL-17RA, IL-1R, dual-knockout).
• Performed RNA-sequencing (RNA-seq) analysis to identify affected pathways.
• Quantified Spn colonization duration and assessed neutrophil numbers, activation, and trafficking.

Main Results:

• Absence of IL-17RA signaling led to persistent Spn colonization (> 6 months).
• IL-17RA signaling is essential for replenishing neutrophils in nasal tissue and promoting their trafficking via endothelial adhesion molecules.
• IL-1R signaling is required for neutrophil activation (CD11b expression) and contributes to Spn phagocytosis.
• IL-17RA and IL-1R pathways are non-redundant and both regulate Cxcl5 chemokine expression, crucial for neutrophil maintenance.

Conclusions:

• Sustained neutrophil presence and activity are critical for preventing persistent mucosal infection by Spn.
• IL-17RA signaling supports neutrophil replenishment and trafficking.
• IL-1R signaling promotes neutrophil activation for pathogen clearance.
• Combined IL-17RA and IL-1R signaling, along with Cxcl5, ensures effective control of Spn colonization.