Microbiology & Immunology Faculty

Research | Publications | Lab Members | Biosketch (Pdf format)

Carlos J. Orihuela, Ph.D.
Associate Professor

STRF - Room 289.1
Tel: (210) 562-4192
Fax: (210) 562-4191
Email: orihuela@uthscsa.edu

Research

Streptococcus pneumoniae(the pneumococcus), a Gram-positive bacterium, is a leading cause of otitis media, community-acquired pneumonia, bacterial sepsis, and meningitis. Many factors affect the incidence, severity, and mortality associated with invasive pneumococcal disease (IPD) including 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 the expression of virulence determinants 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 2-4 million people die as a result of IPD every year. For those >65 years of age the case-fatality rate for IPD exceeds 20%. Thus the pneumococcus is a significant health burden and merits attention from researchers and public health initiatives.

My laboratory has multiple

research projects, all of which are focused on host-pathogen interactions for S. pneumoniae. First, is a traditional bacterial pathogenesis project that examines the virulence protein PsrP (pneumococcal serine-rich repeat protein; Figure 2). Over the past 4 years we have determined that PsrP mediates bacterial attachment to Cytokeratin 10 on lung cells as well as to PsrP on other pneumococci. Currently, we believe that PsrP helps mediate biofilm formation in the lungs during pneumonia. Importantly, immunization with recombinant PsrP protects mice against pneumococcal challenge; thus, PsrP is a potential vaccine candidate. A second project examines the role of S. pneumoniae biofilms during asymptomatic nasopharyngeal colonization. For other pathogenic bacteria biofilm formation is a mechanism for persistence on medical implants within the host. Unexpectedly, we have determined that pneumococci in biofilms are avirulent due to reduced virulence protein production. We now suspect that biofilm pneumococci reduce their invasiveness to prevent an immune response that would lead to their clearance. If so this suggests that the pneumococcus alternates between invasive (planktonic) and non-invasive (biofilm) lifestyles. We are exploring this exciting possibility.

A third project links aging and chronic age-associated inflammation with increased susceptibility to IPD (Figure 3). We have recently demonstrated that advanced age is associated with increased lung inflammation and susceptibility to pneumonia. This was due to an increase in the expression of several inflammation-regulated bacterial ligands including pIgR, PAFr, and LR and decreased Toll-like receptor (TLR) function. Briefly, TLRs detect pathogens and initiate the pro-inflammatory immune response. This past year we have shown that cellular senescence during aging is one reason for lung inflammation and that it also contributes to increased Cytokeratin 10 levels in the lungs. Thus, age-associated inflammation enhances the ability of bacteria to adhere to lung cells in healthy elderly. Importantly, we now have evidence that age-associated inflammation may also be responsible for TLR dysfunction as a result of an anti-inflammatory homeostatic response. If so, and we are working towards confirmation, this latter finding suggests that anti-inflammatory agents such as statins, n-3 polyunsaturated fatty acids, may counter this effect and protect the elderly against IPD. We are also investigating these important possibilities.