Infection with the gram positive organism Streptococcus pneumoniae (the pneumococcus) is responsible for over one million deaths world wide in children less than five years of age. Individuals with immunodeficiency and adults over the age of 65 are also at high risk of pneumococcal disease. Pneumococcal infection causes a wide spectrum of diseases from otitis media and sinusitis to meningitis, bacteremia and necrotizing pneumonias. Despite the severity of invasive disease, most children carry pneumococcus in their nasopharynx completely asymptomatically. Colonized children are the thought to be the reservoir of disease causing pneumococcus for the rest of the population. These children are serially colonized with a changing array of pneumococcal isolates and are often colonized with more than one isolate at a time. The recent introduction of the seven valent pneumococcal vaccine into the routine infant immunization schedule dramatically reduced the incidence of invasive disease due to the vaccine targeted serotypes, however, increases in the rate of invasive disease due to “serotype replacement” strains (those not targeted by the vaccine) have been reported in a number of communities.
My laboratory is interested in understanding the bacterial factors that promote successful colonization by the diverse population of pneumococci. This organism spends majority of its life in the polymicrobial environment of the nasopharynx where it is exposed to attack by the host immune system as well as by other inhabiting or invading organisms. Although the interaction of the bacteria with the host immune system in controlling or modifying colonization has been the focus of intense study by others, the role of inter-bacterial interactions that impact successful colonization in a polymicrobial environment are less well understood. We have recently identified a heterogeneous locus in pneumococcus encoding antimicrobial peptides called pneumocins. These peptides target unrelated pneumococci as well as other members of the respiratory flora and presumably give producing strains an advantage during colonization. We have shown that these peptides are produced during murine colonization, allowing producing strains to out-compete sensitive competitors. We are currently examining several aspects of pneumocin production based on these observations:
- Pneumocin production is highly regulated in pneumococcus. We have shown that pneumocin activity is controlled by at the transcriptional and post transcriptional level by 2 two component systems and an outer surface protease. We are currently examining the environmental factors that influence this complex regulatory network and working to identify upstream regulators. In addition, we are investigating the regulatory mechanism underlying transcriptionally silent strains, the phenotype found in the majority of clinical isolates.
- We are currently studying a panel of isolates from a densely colonized population in South Africa that consists of pneumococci derived from duel and singly colonized individuals. By characterizing the pneumocin locus from this strain collection, we hope to better understand the importance of the pneumocin locus in promoting successful colonization and enabling co-colonization.
- This strain collection has already allowed us to identify novel broadly active loci that inhibit the growth of a majority of pneumococci tested. Further work on these loci involves characterizing and purifying the active peptides for testing in animal models of colonization and disease. We will also use this information to better understand the components of pneumocin immunity.