Microbial factors and host responses affecting severity of pneumococcal disease and pneumococcal carriage

Streptococcus pneumoniae, also known as the pneumococcus, is a human specific bacterium and causes infections like otitis media, sinusitis, pneumonia, sepsis and meningitis. However, these bacteria are also frequent colonizers of the nasopharynx of healthy individuals, especially children. The major virulence factor in pneumococci is the polysaccharide capsule, which protects against phagocytosis. The death of pneumococci releases high amounts of potent mediators of inflammation. The innate immune system constitutes the first line of host defense against microbial infections. Pattern recognition receptors such as the Toll-Like Receptors (TLRs) mediate innate immune responses upon recognition of bacterial components through adaptor molecules such as MyD88. The overarching goal of the present work was to understand underlying mechanisms in the microbe as well as in the host that contribute to the transition from a local commensal microbe-host interaction to a systemic infection, and the innate immune responses associated with both local microbial control and development of invasive disease. Clinical isolates from patients with invasive disease and from healthy children attending day-care centers were collected in the Stockholm area during 1997. The isolates were characterized using molecular fingerprinting methods such as Pulsed Field Gel Electrophoresis and Multi Locus Sequence Typing. Further, we characterized the virulence of these isolates in mouse infection models. By using wild type mice and mice deficient in the different TLRs and MyD88 we investigated the role of these molecules for resistance against pneumococcal infection. A novel technique using biophotonic real-time in vivo imaging has been applied to understand the infection process within living animals. We found that 40 % of the children attending day-care centers harbored pneumococci; 20 % of the isolates were non-susceptible to penicillin. We could observe cases of spread between children of pneumococ