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.
- Hinojosa CA, Mgbemena V, Van Roekel S, Austad SN, Miller RA, Bose S, Orihuela CJ. Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence. Exp Gerontol. 2012 Dec;47(12):958-65.
- 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 Jul;47(7):507-18.
- Blanchette KA, Orihuela CJ. Future perspective on host-pathogen interactions during bacterial biofilm formation within the nasopharynx. Future Microbiol. 2012 Feb;7(2):227-39.
- Andisi VF, Hinojosa CA, de Jong A, Kuipers OP, Orihuela CJ, Bijlsma JJ. Pneumococcal gene complex involved in resistance to extracellular oxidative stress. Infect Immun. 2012 Mar;80(3):1037-49.
- Sanchez CJ, Kumar N, Lizcano A, Shivshankar P, Dunning Hotopp JC, Jorgensen JH, Tettelin H, Orihuela CJ. Streptococcus pneumoniae in biofilms are unable to cause invasive disease due to altered virulence determinant production. PLoS One. 2011;6(12):e28738.
- Shivshankar P, Boyd AR, Le Saux CJ, Yeh IT, Orihuela CJ. Cellular senescence increases expression of bacterial ligands in the lungs and is positively correlated with increased susceptibility to pneumococcal pneumonia. Aging Cell. 2011 Oct;10(5):798-806.
- Sanchez CJ, Shivshankar P, Stol K, Trakhtenbroit S, Sullam PM, Sauer K, Hermans PW, Orihuela CJ. The pneumococcal serine-rich repeat protein is an intra-species bacterial adhesin that promotes bacterial aggregation in vivo and in biofilms. PLoS Pathog. 2010 Aug
- Paterson GK, Orihuela CJ. Pneumococcal microbial surface components recognizing adhesive matrix molecules targeting of the extracellular matrix. Mol Microbiol. 2010 Jul 1;77(1):1-5.
- Rosch JW, Boyd AR, Hinojosa E, Pestina T, Hu Y, Persons DA, Orihuela CJ, Tuomanen EI. Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease. J Clin Invest. 2010 Feb;120(2):627-35.
- Li Z, Wang H, Xue L, Shin DM, Roopenian D, Xu W, Qi CF, Sangster MY, Orihuela CJ, Tuomanen E, Rehg JE, Cui X, Zhang Q, Morse HC 3rd, Morris SW. Emu-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-kappaB pathways generating marginal
zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma. Blood. 2009 Nov 5;114(19):4158-68.
- Shivshankar P, Sanchez C, Rose LF, Orihuela CJ. The Streptococcus pneumoniae adhesin PsrP binds to Keratin 10 on lung cells. Mol Microbiol. 2009 Aug;73(4):663-79.
- Orihuela CJ, Mahdavi J, Thornton J, Mann B, Wooldridge KG, Abouseada N, Oldfield NJ, Self T, Ala'Aldeen DA, Tuomanen EI. Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. J Clin Invest. 2009 Jun;119(6):1638-46.
- 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
Ryan Gilley , BS, Graduate Student
Anel Lizcano, BS, Graduate Student
Armand Brown, BS, Graduate Student
Krystle Blanchette, BS, Graduate Student