Chlamydia iron starvation links nutritional immunity to pathogen recognition
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Nutritional immunity is an antimicrobial strategy that evolved to starve pathogens of essential nutrients, with death as the desired outcome. Here, we report that transient iron starvation of the obligate intracellular pathogen Chlamydia trachomatis , growing in endocervical epithelial cells, enhances pathogen recognition by the host cell through the dysregulation of a peptidoglycan (PG) remodeling enzyme, resulting in the activation of the nucleotide-binding oligomerization domain 2 (NOD2) pathway that recognizes PG fragments, increased production of tumor necrosis factor alpha (TNF) via increased activation of NF-κB, which correlated with death of infected cells. Activation of the NOD2/ NF-κB signaling axis is linked to the dysregulated overexpression of the PG remodeling enzyme AmiA and the subsequent cleavage and mislocalization of D-Ala-D-Ala analog. Inhibiting amiA transcriptional upregulation by CRISPR interference reduced pathogen recognition. We propose that nutritional immunity in general mediate abnormal expression of bacterial genes linked to pathogen-associated molecular patterns.
Importance
Limiting pathogen access to essential nutrients is the central tenet of nutritional immunity, with the outcome being severe starvation and eventual death of the pathogen. However, pathogen starvation induces several physiological changes prior to its death. They include errors in several biological processes, including metabolism and gene expression, which could lead to pathogen death. Here, we demonstrate that iron starvation of the clinically relevant human pathogen Chlamydia trachomatis significantly dysregulates the expression of a peptidoglycan remodeling amidase, AmiA to enhance chlamydial recognition by the host cell and the subsequent increased production of tumor necrosis factor and death of infected cells to the detriment of Chlamydia .
