Date of Award

January 2011

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Sumita Bhaduri-McIntosh

Subject Area(s)

Medicine, Immunology

Abstract

STAT3 is important for the emergence of human B Cells predicted to proliferate after infection with Epstein-Barr Virus

Amanda Z. de la Paz and Sumita Bhaduri-McIntosh. Section of Infectious Diseases, Department of Pediatrics, Yale University, School of Medicine, New Haven, CT.

Many unanswered questions surround the early changes in B cells that lead to establishment of latency and immortalization following Epstein-Barr virus (EBV) infection. Data from the Bhaduri-McIntosh lab revealed that EBV differentially infects B cells into distinct sub-populations, only one of which, those marked CD23hi CD58+ IL6-, can be predicted to proliferate as early as 3 days after exposure to EBV. Other cells produced IL6 but did not proliferate, perhaps assisting a select few to do so. They also found that high levels of signal transducer and activator of transcription 3 (STAT3) correlate with resistance to lytic cycle induction and hence maintenance of the immortalized state. We hypothesized that 1) IL6 is necessary for the emergence of CD23hi CD58+ B cells following infection with EBV, and that 2) phosphorylation of STAT3 is necessary for the emergence of this B cell sub-population that is predicted to proliferate. We tested these hypotheses and showed that blocking IL6 by infecting human primary B cells with EBV in the presence of neutralizing antibodies did not have an effect on the emergence of CD23hi CD58+ cells. However, the STAT3 inhibitors Stattic and AG490, abrogated the emergence of this sub-population, especially within 24 hours of exposure to EBV. We concluded that phosphorylation of STAT3 is important for the emergence of human B cells predicted to proliferate during the process of immortalization after EBV infection.

Comments

This is an Open Access Thesis.

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