Monday, September 21, 2009

Overreacting to Infection is Dangerous to Your Health

Contributed by DP "Following soon after a similar paper on anthrax pathogenesis, this paper suggests that the downregulation of a lymphocyte surface protein can single-handedly stem the destruction by the Ebola virus. The authors identified mice expressing about half (62%) the "wild type" levels of the leukocyte membrane tyrosine kinase CD45 are protected from the lethal effects of Ebola infections (compare CD45-62% to control 100% in the top panel), with an overall survival rate of 90% and a complete clearance of the virus 10 days after challenge. CD45-62% mice expressing CD45 without phosphatase activity did not survive viral challenge, highlighting the importance of CD45’s enzymatic function.

The proposed mechanism is via constitutively high levels of activated CD8 T cells and IFN-gamma because antibodies that kill CD8 cells or block IFN-gamma render CD45-62% mice susceptible to the virus (fig 4, panels B & C). Can this protection translate to other infectious pathogens? Can this information be used clinically? Should we worry about modulating surface CD45 or just give IFN-gamma to affected individuals? I like the former, if one can come up with inexpensive small molecules, rather than the huge expense for IFN-gamma. These molecules might be used at higher doses for GVHD." And what is the evolutionary value of having wt levels of CD45 if reduced levels are in fact protective?

Panchal RG, Bradfute SB, Peyser BD, Warfield KL, Ruthel G, Lane D, Kenny TA, Anderson AO, Raschke WC, Bavari S. Reduced levels of protein tyrosine phosphatase CD45 protect mice from the lethal effects of Ebola virus infection. Cell Host Microbe. 2009 Aug 20;6(2):162-73.