Scientific Report 2005

Immunology

Host-Pathogen Interactions: Mechanisms and Applications

E. Li, S.P. Lad, E.Y. Fukuda, J. Li

Our research activities focus on host responses to viral and bacterial infections. We use infections with adenovirus and the obligate intracellular bacterial pathogen Chlamydia trachomatis as model systems.

Chlamydia trachomatis is the most common cause of sexually transmitted infection that can lead to pelvic inflammatory disease and infertility in females. Chlamydial infection of nonimmune cells produces inflammatory factors, including IL-8 and interferons, that play a critical role in the disease process of Chlamydia infection. IL-8 induces inflammatory responses and promotes angiogenesis, resulting in tissue damage and scarring that are characteristic of chlamydial disease. On the other hand, interferon treatment was reported to inhibit growth of Chlamydia. Unlike the inflammatory responses to most invasive bacterial pathogens that induce rapid cytokine production with endotoxins or peptidoglycans, IL-8 production during Chlamydia infection is delayed and relies on bacterial replication. Growth of Chlamydia induces host lipid remodeling for bacterial lipid uptake. We found that this process causes production of inflammatory factors.

Chlamydia infection of cervical epithelial cells, the primary target of chlamydial infection, activates cytosolic phospholipase A₂ for release of arachidonic acid and upregulates cyclooxygenase 2 for conversion of arachidonic acid to prostaglandins, including prostaglandin E₂. Both Chlamydia and prostaglandin E₂ induce IL-8 release through the extracellular signal–regulated kinase/MAP kinase pathway, and inhibition of chlamydial growth or lipid remodeling reduces IL-8 release.

We also examined the host antimicrobial response to Chlamydia infection. We found that cervical epithelial cells produce IFN-β in response to Chlamydia infection. Production of IFN-β induces signal transducer and activator of transcription 1 (STAT1), STAT2, and interferon-stimulated gene factor 3γ, components of the Janus kinase–STAT signal transduction pathway. The upregulation and activation of this pathway are critical for host clearance of chlamydial infection because Chlamydia growth is inhibited in cells with upregulated STAT1 expression; STAT1-deficient cells support Chlamydia propagation more efficiently. Using DNA and protein expression profiles and small interfering RNA, we also showed that STAT1 upregulation is critical for antimicrobial gene expression. These studies provide insights into host innate immune responses to Chlamydia infection. They also highlight the importance of maintaining a balanced habitat for parasitic pathogens as obligate intracellular organisms.

We are also working on the design and modification of adenovirus for targeting gene delivery. Although widely used for gene therapy studies, adenovirus-based vectors cannot target specific tissues. We generated modified adenoviruses that selectively infect cancer cells with upregulated growth factor receptors. Our ultimate goal is to generate modified viruses by fusing tissue-specific antibody to these viruses for selectively targeting tumor cells.

Publications

Fukuda, E.Y., Lad, S.P., Mikolon, D.P., Iacobelli-Martinez, M., Li, E. Activation of lipid metabolism contributes to interleukin-8 production during Chlamydia trachomatis infection of cervical epithelial cells. Infect. Immun. 73:4017, 2005.

Lad, S.P., Fukuda, E.Y., Li, J., de la Maza, L.M., Li, E. Up-regulation of the JAK/STAT1 signal pathway during Chlamydia trachomatis infection. J. Immunol. 174:7186, 2005.