Abstract

Iron is a critical cofactor for many enzymes and is known to regulate gene expression in many bacterial pathogens. Streptococcus pneumoniae normally inhabits the upper respiratory mucosa but can also invade and replicate in lungs and blood. These anatomic sites vary considerably in both the quantity and form of available iron. The genome of serotype 4 pneumococcal strain TIGR4 encodes a putative iron-dependent transcriptional regulator (IDTR). A mutant deleted at idtr (?idtr) exhibited growth kinetics similar to parent strain TIGR4 in vitro and in mouse blood for up to 48 hours following infection. However, ?idtr was significantly attenuated in a murine model of sepsis. IDTR down-regulates the expression of ten characterized and putative virulence genes in nasopharyngeal colonization and pneumonia. The host cytokine response was significantly suppressed in sepsis with ?idtr. Since an exaggerated inflammatory response is associated with a poor prognosis in sepsis, the decreased inflammatory response could explain the increased survival with ?idtr. Our results suggest that IDTR, which is dispensable for pneumococcal growth in vitro, is associated with regulation of pneumococcal virulence in specific host environments. Additionally, IDTR ultimately modulates the host cytokine response and systemic inflammation that contributes to morbidity and mortality of invasive pneumococcal disease.

Publisher

Public Library of Science

DOI

10.1371/journal.pone.0055157

Publication Date

2-20-2013

College

College of Veterinary Medicine

Department

Department of Basic Sciences

Keywords

Animal, Animals, Bacterial, Bacterial Proteins, Bacterial Proteins: genetics, Bacterial Proteins: metabolism, Colony Count, Cytokines, Cytokines: blood, Disease Models, Gene Expression Regulation, Host-Pathogen Interactions, Host-Pathogen Interactions: genetics, Inbred C57BL, Iron, Iron: metabolism, Mice, Microbial, Microbial Viability, Pneumococcal Infections, Pneumococcal Infections: blood, Pneumococcal Infections: genetics, Pneumococcal Infections: microbiology, Sepsis, Sepsis: microbiology, Sepsis: pathology, Streptococcus pneumoniae, Streptococcus pneumoniae: genetics, Streptococcus pneumoniae: growth & development, Streptococcus pneumoniae: pathogenicity, Trans-Activators, Trans-Activators: genetics, Trans-Activators: metabolism, Virulence, Virulence: genetics

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