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 (Δidtr) exhibited growth kinetics similar to parent strain TIGR4 in vitro and in mouse blood for up to 48 hours following infection. However, Δidtr 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 Δidtr. Since an exaggerated inflammatory response is associated with a poor prognosis in sepsis, the decreased inflammatory response could explain the increased survival with Δidtr. 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.
Highlights
The Gram-positive bacterium Streptococcus pneumoniae is an opportunistic human pathogen whose primary niche is the human nasopharynx
Since pneumococci can replicate in different host environments with varying iron availability it is likely that pneumococci sense changes in iron availability in the host environment and regulate gene expression in response
deleted at idtr (Didtr) entered the exponential phase of growth slightly faster than TIGR4 in both chemically-defined medium (CDM) and iron-depleted CDM (Figure 1A)
Summary
The Gram-positive bacterium Streptococcus pneumoniae (pneumococcus) is an opportunistic human pathogen whose primary niche is the human nasopharynx. The mechanisms of translocation of pneumococci from nasopharynx to sterile sites, and changes in its physiology to adapt to these different niches are still not clearly understood. The different anatomic sites of pneumococcal infection vary considerably in the quantity as well as the form of available iron sources. Lactoferrin, transferrin, ferritin (released from cell turnover at mucosal surfaces) and possibly small amounts of hemoglobin and its breakdown products are potential iron sources in the respiratory tract. Since pneumococci can replicate in different host environments with varying iron availability it is likely that pneumococci sense changes in iron availability in the host environment and regulate gene expression in response. We hypothesize that iron is potentially an important environmental signal which regulates expression of genes required for pneumococcal survival and virulence in the host
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