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Microbiology & Immunology Faculty
Research | Publications | Lab Members | Biosketch (Pdf format)
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Carlos J. Orihuela, Ph.D.
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Research
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.
Publications
- Rose, L., Hinojosa, E., Rodriguez, A., & Orihuela, C.J. 2008. Antibodies against PsrP, a novel Streptococcus pneumoniae adhesin, block adhesion and protect mice against pneumococcal challenge. J Infect Dis (In press).
- Obert, C., Gao, G., Sublett, J., Tuomanen, E.I. and Orihuela, C.J. 2007. Assessment of molecular typing methods to determine invasiveness and to differentiate clones of Streptococcus pneumoniae. Infect GenetEvol 7(6):708-716.
- Embry, A., Hinojosa, E. and Orihuela, C.J. 2007. Regions of diversity 8, 9 and 13 contribute to Streptococcus pneumoniae virulence. BMC Microbiol 7(1):80.
- Smith, M.W., Schmidt, J.E., Rehg, J.E., Orihuela, C.J. and McCullers, J.A. 2007. Induction of pro- and anti-inflammatory molecules in a mouse model of pneumococcal pneumonia following influenza. Comp Med 57(1):82-89.
- Fillon, S., Soulis, K., Rajasekaran, S., Benedict-Hamilton, H., Radin, J.N., Orihuela, C.J., El Kasmi, K.C., Murti, G., Kaushal, D., Gaber, M.W., Weber, J.R., Murray, P.J. and Tuomanen, E.I. 2006. Platelet-activating factor receptor and innate immunity: uptake of gram-positive bacterial cell wall into host cells and cell-specific pathophysiology. J Immunol 177(9):6182-6191.
- Obert, C., Sublett, J., Kaushal, D., Hinojosa, E., Barton, T., Tuomanen, E.I. and Orihuela, C.J. 2006. Identification of a candidate Streptococcus pneumoniae core genome and regions of diversity correlated with invasive pneumococcal disease. Infect Immun 74:4766-4777
- Orihuela, C.J., and Tuomanen, E.I. Streptococcus pneumoniae: Invasion and Inflammation. In: Gram-Positive Pathogens, 2nd Edition. Fischetti V., Novick R. et al. (eds.). ASM Press, Washington, DC: 2006, pp. 253-267.
- Orihuela, C.J., Fillon, S., Smith-Sielicki, S.H., El Kasmi, K.C., Gao, G., Soulis, K., Patil, A., Murray, P.J., Tuomanen, E.I. 2006. Cell wall-mediated neuronal damage in early sepsis. Infect Immun 74:3783-3789.
- Orihuela, C.J. and Tuomanen, E.I. 2006. Models of pneumococcal disease. Drug Discovery Today: Disease Models 3:69-75.
- Mann, B., Orihuela, C., Antikainen, J., Gao, G., Sublett, J., Korhonen, T.K. and Tuomanen, E. 2006. Multifunctional role of choline binding protein G in pneumococcal pathogenesis. Infect Immun 74:821-829.
- Orihuela, C.J., Fogg, G., DiRita, V. and Tuomanen, E. Bacterial Interactions with Mucosal Epithelial Cells. In: Mucosal Immunology, 3rd Edition. Mestecky J, Strober W, et al. (eds.). Academic Press, NY; 2005.
- Radin, J.N., Orihuela, C., Murti, G., Guglielmo, C., Murray, P.J. and Tuomanen, E.I. 2005. β-Arrestin 1 Participates in Platelet-Activating Factor Receptor-Mediated Endocytosis of Streptococcus pneumoniae. Infect Immun 73:7827-7835.
- Kadurugamuwa, J.L., Modi, K., Yu, J., Francis, K.P., Orihuela,C., Tuomanen, E., Purchio, A.F. and Contag, P.R. 2005. Noninvasive monitoring of pneumococcal meningitis and evaluation of treatment efficacy in an experimental mouse model. Mol Imaging 4:137-142.
- Sandgren, A., Albiger, B., Orihuela, C.J., Tuomanen, E., Normark, S. and Henriques-Normark, B. 2005. Virulence in mice of pneumococcal clonal types with known invasive disease potential in humans. J Infect Dis 192:791-800.
- Orihuela, C.J., Gao, G., Francis, K.P., Yu, J. and Tuomanen, E.I. 2004. Tissue-specific contributions of pneumococcal virulence factors to pathogenesis. J Infect Dis 190:1661-1669.
- Orihuela, C.J., Radin, J.N., Sublett, J.E., Gao, G., Kaushal, D. and Tuomanen, E.I. 2004. Microarray analysis of pneumococcal gene expression during invasive disease. Infect Immun 72:5582-5596.
- Orihuela, C.J., Gao, G., McGee, M., Yu, J., Francis, K.P. and Tuomanen, E. 2003. Organ-specific models of Streptococcus pneumoniae disease. Scand J Infect Dis 35:647-652.
- Xue, L., Morris, S.W. Orihuela, C., Tuomanen, E., Cui, X., Wen, R. and Wang, D. 2003. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nat Immunol 4:857-865.
- Orihuela, C.J., Mills, J., Robb, C.W., Wilson, C.J., Watson, D.A. and Niesel, D.W. 2001. Streptococcus pneumoniae PstS production is phosphate responsive and enhanced during growth in the murine peritoneal cavity. Infect Immun 69:7565-7571.
- Robb, C.W., Orihuela, C.J., Ekkelenkamp, M.B. and Niesel, D.W. 2001. Identification and characterization of an in vivo regulated D15/Oma87 homologue in Shigella flexneri using differential display polymerase chain reaction. Gene 262:169-177.
- Orihuela, C.J., Janssen, R., Robb, C.W., Watson, D.A. and Niesel, D.W. 2001. Peritoneal culture alters Streptococcus pneumoniae protein profiles and virulence properties. Infect Immun 68:6082-6086.
- Orihuela, C.J. and Watson, D.A. 1997. Poor man's dot-blot apparatus. Biotechniques 23:1010.
Lab Members
Lab Rooms: 5.025V
- Ernesto Hinojosa, Senior Research Assistant
- Pooja Shivshankar, Research Scientist
Graduate Student: