Protection from lethal infection is determined by innate immune responses in a mouse model of Ebola virus infection.
A mouse-adapted strain of Ebola Zaire virus produces a fatal infection when BALB/cj mice are infected intraperitoneally (ip) but subcutaneous (sc) infection with the same virus fails to produce illness and confers long-term protection from lethal ip rechallenge. To identify immune correlates of protection in this model, we compared viral replication and cytokine/chemokine responses to Ebola virus in mice infected ip (10 PFU/mouse), or sc (100 PFU/mouse) and sc "immune" mice rechallenged ip (10(6) PFU/mouse) at several time points postinfection (pi). Ebola viral antigens were detected in the serum, liver, spleen, and kidneys of ip-infected mice by day 2 pi, increasing up to day 6. Sc-infected mice and immune mice rechallenged ip had no detectable viral antigens until day 6 pi, when low levels of viral antigens were detected in the livers of sc-infected mice only. TNF-alpha and MCP-1 were detected earlier and at significantly higher levels in the serum and tissues of ip-infected mice than in sc-infected or immune mice challenged ip. In contrast, high levels of IFN-alpha and IFN-gamma were found in tissues within 2 days after challenge in sc-infected and immune mice but not in ip-infected mice. Mice became resistant to ip challenge within 48 h of sc infection, coinciding with the rise in tissue IFN-alpha levels. In this model of Ebola virus infection, the nonlethal sc route of infection is associated with an attenuated inflammatory response and early production of antiviral cytokines, particularly IFN-alpha, as compared with lethal ip infection.
Mahanty
Siddhartha
S
Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Centers for Infectious Diseases, Centers for Disease Control & Prevention, Atlanta, GA 30333, USA. smahanty@niaid.nih.gov
Gupta
Manisha
M
Paragas
Jason
J
Bray
Mike
M
Ahmed
Rafi
R
Rollin
Pierre E
PE
D000818:Animals; D000956:Antigens, Viral / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000254:growth & development / Q000276:immunology*; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000517:prevention & control*; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007668:Kidney / Q000276:immunology; D008099:Liver / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology; D015996:Survival Rate
D000956:Antigens, Viral