Reduced levels of protein tyrosine phosphatase CD45 protect mice from the lethal effects of Ebola virus infection.
Ebola virus (EBOV) infection of humans is a lethal but accidental dead-end event. Understanding resistance to EBOV in other species may help establish the basis of susceptibility differences among its hosts. Although rodents are resistant to EBOV, a murine-adapted variant is lethal when injected intraperitoneally into mice. We find that mice expressing reduced levels of the tyrosine phosphatase CD45 are protected against EBOV, whereas wild-type, CD45-deficient, or enzymatically inactive CD45-expressing mice succumbed to infection. Protection was dependent on CD8(+) T cells and interferon gamma. Reduced CD45-expressing mice retained greater control of gene expression and immune cell proliferation following EBOV infection, which contributed to reduced apoptosis, enhanced viral clearance, and increased protection against the virus. Together, these findings suggest that host susceptibility to EBOV is dependent on the delicate balance of immune homeostasis, which, as demonstrated here, can be determined by the levels of a single regulator.
Panchal
Rekha G
RG
United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011, USA. rekha.panchal@amedd.army.mil
Bradfute
Steven B
SB
Peyser
Brian D
BD
Warfield
Kelly L
KL
Ruthel
Gordon
G
Lane
Douglas
D
Kenny
Tara A
TA
Anderson
Arthur O
AO
Raschke
William C
WC
Bavari
Sina
S
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004198:Disease Susceptibility; D029043:Ebolavirus / Q000276:immunology* / Q000472:pathogenicity*; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008198:Lymph Nodes / Q000821:virology; D017737:Macrophages, Peritoneal / Q000821:virology; D051379:Mice; D008954:Models, Biological; D013154:Spleen / Q000821:virology; D016019:Survival Analysis
D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse