Microbiology & Immunology Faculty
Carlos J. Orihuela, Ph.D.
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.
Boyd AR, Shivshankar P, Jiang S, Berton MT, Orihuela CJ. Age-related defects in TLR2 signaling diminish the cytokine response by alveolar macrophages during murine pneumococcal pneumonia. Exp Gerontol. 2012. [Epub available ahead of print] doi:10.1016/j.exger.2012.04.004
- Streptococcus pneumoniae in biofilms are unable to cause invasive disease due to altered virulence determinant production. Sanchez CJ, Kumar N, Lizcano A, Shivshankar P, Dunning Hotopp JC, Jorgensen JH, Tettelin H, Orihuela CJ. PLoS One. 2011;6(12):e28738.
- Cellular senescence increases expression of bacterial ligands in the lungs and is positively correlated with increased susceptibility to pneumococcal pneumonia. Shivshankar P, Boyd AR, Le Saux CJ, Yeh IT, Orihuela CJ. Aging Cell. 2011 Oct;10(5):798-806.
- PsrP, a protective pneumococcal antigen, is highly prevalent in children with pneumonia and is strongly associated with clonal type. Muñoz-Almagro C, Selva L, Sanchez CJ, Esteva C, de Sevilla MF, Pallares R, Orihuela CJ. Clin Vaccine Immunol. 2010 Nov;17(11):1672-8.
- The pneumococcal serine-rich repeat protein is an intra-species bacterial adhesin that promotes bacterial aggregation in vivo and in biofilms. Sanchez CJ, Shivshankar P, Stol K, Trakhtenbroit S, Sullam PM, Sauer K, Hermans PW, Orihuela CJ. PLoS Pathog. 2010 Aug 12;6(8):e1001044.
- Pneumococci: immunology of the innate host response. Paterson GK, Orihuela CJ. Respirology. 2010 Oct;15(7):1057-63.
- Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease. Rosch JW, Boyd AR, Hinojosa E, Pestina T, Hu Y, Persons DA, Orihuela CJ, Tuomanen EI. J Clin Invest. 2010 Feb 1;120(2):627-35.
- The Streptococcus pneumoniae adhesin PsrP binds to Keratin 10 on lung cells. Shivshankar P, Sanchez C, Rose LF, Orihuela CJ. Mol Microbiol. 2009 Aug;73(4):663-79.
- Age-associated inflammation and toll-like receptor dysfunction prime the lungs for pneumococcal pneumonia. Hinojosa E, Boyd AR, Orihuela CJ. J Infect Dis. 2009 Aug 15;200(4):546-54.
- Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. Orihuela CJ, Mahdavi J, Thornton J, Mann B, Wooldridge KG, Abouseada N, Oldfield NJ, Self T, Ala'Aldeen DA, Tuomanen EI. J Clin Invest. 2009 Jun;119(6):1638-46.
- Antibodies against PsrP, a novel Streptococcus pneumoniae adhesin, block adhesion and protect mice against pneumococcal challenge. Rose L, Shivshankar P, Hinojosa E, Rodriguez A, Sanchez CJ, Orihuela CJ. J Infect Dis. 2008 Aug 1;198(3):375-83.
- For more publications, please click on link NCBI.NLM.NIH.gov
Lab Rooms: STRF - 275.1 A-F Phone: (210) 562-4172
- Ramya Akula Suresh Babu, BS, Senior Research Assistant
- Cecilia Hinojosa, Senior Research Assistant
Anel Lizcano, BS, Graduate Student
Armand Brown, BS, Graduate Student
Krystle Blanchette, BS, Graduate Student