Discovering

INDIVIDUAL RESEARCHER

Jing-Ren Zhang , D.V.M. , Ph.D.
Associate Professor
e-mail: zhangj@mail.amc.edu

Education

1984 - D.V.M. from Gansu Agricultural University
1997 - Ph.D. from University of Texas-Houston

Current Research

My laboratory is interested in the pathogenic mechanisms of two human pathogens, Streptococcus pneumoniae and Francisella tularensis. We have applied genetic and molecular approaches to identify the bacterial genes that are required for infection in various experimental models including cell cultures and animals. S. pneumoniae (pneumococcus) is a Gram-positive bacterium that naturally colonizes at the nasopharynx of humans and can cause various infections including pneumonia, otitis media (ear infection), bacteremia/sepsis, and meningitis. Each year in the US, pneumococcal infections account for at least 1 million cases of pneumonia, 7 million cases of otitis media, 50,000 cases of sepsis, and 3,000 to 6,000 cases of bacterial meningitis. At least 1 million children die of pneumococcal infections each year worldwide. One of our current research areas focuses on identifying pneumococcal genes that are necessary for bacterial survival in the middle ear environment. Because successful replication and survival of S. pneumoniae in the middle ear is essential for causing intense inflammation, a hallmark of the disease, identifying the key factors that promoting bacterial infectivity in the middle ear will allow us to better understand the pathogenic mechanisms of pneumococcal otitis media and to provide molecular targets for future development of therapeutic agents to combat the disease. To begin to understand the genetic basis of S. pneumoniae ear infection, we've performed a genome-scale screen for bacterial genes required for ear infection with a low-passage serotype 19F multi-drug resistant otitis media S. pneumoniae isolate using the signature-tagged mutagenesis (STM) approach. STM is a high throughput mutant screen technique for discovering bacterial virulence factors. This screen identified a total of 169 genes that are required for the full infectivity of S. pneumoniae in the middle ear. Surprisingly, only 52 of these genes were required for pneumococcal nasopharyngeal colonization in a murine model, suggesting that a subset of the bacterial genes are involved in tissue-specific infections. This infection site-specific gene requirement was verified by targeted mutagenesis in the selected genes. This screen re-discovered some of the previously described S. pneumoniae virulence factors. However, the vast majority of the genes identified in this screen had not been reported in literature. We are conducting focused studies to understand how these putative ear infection-associated genes contribute to S. pneumoniae infectivity. F. tularensis is a broadly distributed Gram-negative pathogen that causes life-threatening infections in humans and has potential for use as a biological weapon. The genetic basis of the F. tularensis pathogenesis is poorly understood. To better understand the pathogenic mechanisms of F. tularensis, we have recently screened a STM library of of live vaccine strain (LVS) for the loss of infectivity in the lungs of mice. This screen identified a total of 95 different genes required for the survival of F. tularensis in the lungs. Virtually all of the identified LVS genes are also present in the genome of human pathogenic F. tularensis strain Schu S4. This genome-wide screening has thus provided valuable information for further characterizing the molecular basis of F. tularensis pathogenesis.

References

1. Lu L, Y. Ma, and J.-R. Zhang. 2006. Streptococcus pneumoniae recruits complement factor H through the amino terminus of CbpA. Journal of Biological Chemistry. 281:15464-15474.



2. Ma, Z., and J.-R. Zhang. 2007. RR06 activates the transcription of spr1996 and cbpA in Streptococcus pneumoniae. Journal of Bacteriology 189:2497-2509.



3. Su, J., J. Yang, D. Zhao, T. H. Kawula, J. A. Banas, and J.-R. Zhang. 2007. Genome-wide identification of Francisella tularensis virulence determinants. Infection and Immunity 75:3089-3101.



4. Lu, L., Z. Ma, T. S. Jokiranta, A. R. Whitney, F. R. DeLeo, and J.-R. Zhang. 2008. Species-specific interaction of Streptococcus pneumoniae with human complement factor H. Journal of Immunology 181:7138-7146.



5. Chen, H., Y. Ma, J. Yang, C. O'Brien, S. L. Lee, J. E. Mazurkiewicz, S. Haataja, J.H. Yan, G.F. Gao, and J.-R. Zhang. 2008. Genetic requirement for pneumococcal ear infection. PLoS One 3:e2950.