The discovery of a major pathway that cells infected with the common Epstein-Barr virus (EBV) activate to keep it in check, led US scientists to suggest they may have discovered a natural defence mechanism that invaded cells use against viruses that can cause cancer.
These are the findings of a study published today in the journal Cell Host and Microbe.
Senior author Dr Micah Luftig, Assistant Professor of Molecular Genetics and Microbiology at Duke University School of Medicine in Durham, North Carolina, told the press that:
“Using cell culture studies, we have uncovered a major pathway that the infected host cell activates to prevent an oncogenic virus from causing cancer.”
Luftig and colleagues suggested that when cells sense that the virus is trying to “take over”, a process known as “oncogenic stress“, they switch on a signal that keeps the virus in check.
“Now we know why,” said Luftig.
The Epstein-Barr virus (EBV) infects about nine out of every ten people at some point in their lives, in most cases with no ill effects. But people with immune systems weakened by HIV infection, or because they have had an organ transplant, or some other reason, are at greater risk of developing cancer from an EBV infection.
EBV infection also develops differently in different people at different life stages. For example, in children around the age of 4 or 5, a first infection of EBV can be mild, but if a first infection occurs later, during adolescence, it can cause mononucleosis with heavy fatigue and other symptoms. In people with weakened immune systems this can go on to develop forms of lymphoma.
Scientists have already discovered that as a result of early infection with EBV, many people’s bodies develop large numbers of immune system “B” cells infected with EBV. However, because their immune system is healthy and responds to this “oncogenic stress”, it kills off many of the infected cells.
The authors wrote that when lab cultures of primary human B cells are infected with EBV, they remain in an “immortal” state, producing lymphoblastoid cell lines indefinitely, and suggested this could be a “model” of how EBV, if unchecked, eventually causes cancer in the human body.
Luftig and colleagues found two enzymes, the kinases ATM and Chk2, that play an important role in helping the immune system respond to the “oncogenic stress” that EBV creates when it infects and “immortalizes” human B cells.
When they blocked the action of ATM and Chk2, unchecked growth led to a tenfold increase in infected B cells.
Such a large burden of EBV-infected B cells is linked to several types of cancer, including post-transplant lymphoproliferative disorder, which is where a transplant patient develops a type of lymphoma caused by B-cell proliferation, and HIV-associated B-cell lymphomas, among others.
Luftig said this finding suggests there is a good reason to believe this is how any virus oncogene triggers tumors to start forming.
“About 20 percent of all human cancers are caused by infectious agents, where about 80 percent of these infections are viral,” he told the press.
Luftig and colleagues also proposed a possible route through which EBV overcomes the host cell’s own response to being invaded.
One of the cell’s early responses to EBV-induced immortalization is to release an innate tumor suppressor, a process they called DNA damage response (DDR). But EBV has a “viral latent oncoprotein” called EBNA3C that counteracts the cell’s DDR.
“We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR that is attenuated by viral latency products to induce cell immortalization,” wrote the authors.
“The findings may eventually yield therapies to benefit people who don’t have good immune systems and who need protection from a threatening EBV infection,” said Luftig.
“Pathway Suppresses Epstein-Barr Virus Transformation of Primary Human B Cells.”
Pavel A. Nikitin, Christopher M. Yan, Eleonora Forte, Alessio Bocedi, Jason P. Tourigny, Robert E. White, Martin J. Allday, Amee Patel, Sandeep S. Dave, William Kim, Katherine Hu, Jing Guo, David Tainter, Elena Rusyn, Micah A. Luftig.
Cell Host & Microbe, Volume 8, Issue 6, pp 510-522, 16 December 2010
Additional source: Duke University Medical Center.
Written by: Catharine Paddock, PhD