Streptococcus pneumoniae (the pneumococcus) is the leading cause of community-acquired pneumonia, otitis media, and a leading cause of bacteremia and meningitis. Invasive disease is characterized by the spread of the pneumococcus from the nasopharynx to normally sterile sites such as the lungs, blood, and central nervous system. Many factors affect the incidence, severity, and mortality associated with invasive pneumococcal disease. Host-related factors include the immune status of the host, the presence of underlying chronic diseases (e.g. cardiovascular disease, diabetes), age, and vaccine status. Equally important are microorganism-related factors such as colonization rate, the expression of virulence factors, and antimicrobial resistance which complicates treatment. Annually the Center for Disease Control estimates that the pneumococcus is responsible for over 60,000 cases of pneumonia, 30,000 cases of bacteremia, and 3,000 cases of meningitis in the United States (Figure 1). Worldwide, the World Health Organization estimates that 1.6 million people die every year as a result of pneumococcal disease. Thus the pneumococcus is a significant health burden and merits attention from researchers and public health initiatives.

Currently, my laboratory has two research projects. First, a classic bacterial pathogenesis project, where we examine PsrP, a putative adhesin that we have demonstrated is required for virulence in a mouse model of pneumonia; second, a more immunology related project, where we examine age-related changes in the lungs that increase the susceptibility of the elderly to pneumonia. It is the immediate goal of my laboratory to characterize the host::pathogen interactions that are responsible for the development of pneumonia. Our long-term goal is to use these discoveries as the basis for therapeutics that will improve patient outcome.

Pneumococcal Serine-rich Repeat Protein (PsrP). In 2006, our laboratory published findings from a comparative genomic analysis of 43 invasive and 30 non-invasive clinical isolates of S. pneumoniae. We determined that not all pneumococcal genes were equally distributed among invasive and non-invasive isolates and that the presence of some genes was positively correlated with the ability to cause human disease. One of the regions we identified was psrP-secY2A2, a pneumococcal pathogenicity island that we have since demonstrated to be required for virulence in intranasal, and intratracheal challenge models of infection. Analysis of psrP-secY2A2 concluded that the locus encodes a serine-rich repeat protein (PsrP), 9 glycosyltransferases, and an alternate SecY2A2 transport system composed of 8 genes. PsrP is a member of the serine-rich repeat protein (SRRP) family. In oral streptococci, SRRPs are glycosylated and form stalk-like structures on the surface of the bacteria that mediate adhesion. SRRPs are required for biofilm formation and contribute to the attachment of the bacteria to the dental surface. More recently, they have also been implicated in the development of infective endocarditis. Mature SRRPs are composed of a serine-rich repeat region (SRR1), a basic region (BR), a second extremely long serine-rich repeat region (SRR2) and a cell wall anchor domain (Figure 2A). It is known that the basic region of SRRPs mediates adhesion and that the SRR2 domain serves to extend this domain outward from the cell surface. S. pneumoniae is not associated with colonization of the dental surface, nor is it a frequent cause of endocarditis, thus a role for PsrP in the disease process unknown. Our goal is to determine how PsrP contributes to the S. pneumoniae disease process. We are currently investigating whether the BR of PsrP is an adhesin, how psrP-secY2A2 gene expression is regulated, and how the length of the SRR2 domain affects PsrP function.

Age-associated inflammation increases susceptibility to pneumococcal disease. Aging is associated with increased inflammation; the result of multiple factors including underlying disease (e.g. cardiovascular disease, periodontal disease), exposure to environmental toxins (e.g. cigarette smoke) obesity, and the aging process itself (i.e. cellular senescence). Likewise, inflammation is requisite for S. pneumoniae adhesion and invasion. Briefly, the bacterium attaches to and co-opts the proteins polymeric immunoglobulin receptor (pIgR) & platelet activating factor receptor (PAFr) on the host cell surface that are expressed during cell inflammation (i.e. NFkB activation). Long standing evidence supports the notion that increased inflammation increases the risk for community-acquired pneumonia and that underlying inflammation increases the severity of disease during infection. Nonetheless, little to no information is known in regards to the expression of pIgR and PAFr in the aged lungs, nor the effects of chronic inflammation on their expression. Our goal is to determine how age-associated inflammation contributes to the susceptibility of the elderly to infection (Figure 3). We are currently investigating levels of pIgR and PAFr in healthy and infected young, mature, and aged rodents. We are also investigating whether cellular senescence contributes to inflammation in the lungs.