Heads of Laboratories
Associate Professor
Laboratory of Lymphocyte Biology
papavasiliou@rockefeller.edu
One of the unique features of the immune system is that it has evolved to raise antibodies against an unlimited number of antigens, a number too large to be encoded in the genome. At the same time, many pathogens have evolved similar mechanisms to alter their surface antigens, thereby evading the immune response. Dr. Papavasiliou’s research focuses on the different processes that immune cells and certain pathogens, such as parasites, employ to generate surface receptor diversity.
Using a combination of biochemistry, cell and molecular biology, Dr. Papavasiliou is establishing new assays to study the molecular basis of somatic hypermutation, the mutagenic process that, in B lymphocytes, is essential for their ability to recognize diverse antigens. When B cells, specialized cells that produce antibodies against foreign molecules, encounter an antigen, mutations are introduced in the genes of their B cell receptors that recognize that antigen. This process helps some of those B cells to acquire a higher affinity for the antigen, and those cells then become selected for survival, i.e., the immune system selects the B cells that are the best candidates for long-term memory against the antigen. Without somatic hypermutation, an individual may become immunocompromised in the ability to deal with antigens. However, unregulated, hypermutation can also lead to cancer.
Hypermutation in B cells is dependent on a protein called AID (activation-induced cytidine deaminase). AID is exclusively expressed in B cells and acts by changing cytidine residues in the DNA to uracil, which is then recognized as DNA damage. When the base pair is repaired, the uracil is traded for a thymidine. Dr. Papavasiliou’s lab has demonstrated that AID belongs to a novel class of cytidine deaminases that can act exclusively on single-stranded DNA. A number of processes in the cell can transiently generate single-stranded DNA, and Dr. Papavasiliou’s lab has shown that it is the process of gene transcription that generates the proper substrate for AID and has developed biochemical assays with purified protein components that recapitulate the Ig reaction in the test tube. The mechanism by which AID engages and mutagenizes only the transcribed specific gene sequences for antibody production, sparing the rest of the genome where mutations would be dangerous, remains a mystery and an active area of research.
Dr. Papavasiliou’s lab is also interested in understanding how hypermutation evolved. It turns out that several organisms use hypermutation as a weapon against viruses. Dr. Papavasiliou’s lab had hypothesized that AID was co-opted from an innate antiviral response and they have recently shown that AID, aside from its role in antibody gene hypermutation, is also active in protecting the organism from infection by viruses that cause cancer. For example, when a retrovirus infects a cell, AID acts by damaging the DNA of the infected cell, which then stops proliferating. At the same time, AID-mediated DNA damage results in expression of certain markers on the surface of the damaged cells that target them for clearance. Thus AID expression after viral infection leads to the demise of the infected cell and of the virus that infected it. The role of AID and of related deaminases in the innate antiviral response is a second active area of interest in the lab.
In vertebrate immune systems, AID deaminates transcribed antibody genes, resulting in either hypermutation or gene conversion, depending on the DNA repair pathway used to repair the uridine lesion. Recent evidence suggests that gene conversion may be the real driving force behind the generation of adaptive immunity in jawless vertebrates, and that it is still used to generate antigen receptor diversity in most organisms (cattle, rabbits, sheep, etc.). Gene conversion is also used by many pathogens to evade immune recognition by diversifying their surface receptors. For instance, surface antigen variation in parasites such as Plasmodium falciparum (the causative agent of malaria) and Trypanosoma brucei (the causative agent of sleeping sickness) is generated by gene conversion between silent cassettes and one expression site. In collaboration with George A.M. Cross’s lab, the Papavasiliou lab is very interested in understanding the mechanism that initiates targeted gene conversion in these parasites.
CAREER
Originally from Greece, Dr. Papavasiliou received her undergraduate degree in biology, with a minor in German literature, from Oberlin College in 1992. She completed her Ph.D. in molecular immunology in 1998 at Rockefeller University. After postdoctoral studies at Yale University, Dr. Papavasiliou returned to Rockefeller as assistant professor in 2001, becoming associate professor in 2007.
In 2005 Dr. Papavasiliou received the Alexandrine and Alexander L. Sinsheimer Fund Scholar Award. She is a 2003 Searle
Scholar and a 2002 Keck Fellow.
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