Cardioselective infection with coxsackievirus B3 requires intact type I interferon signaling: implications for mortality and early viral replication.
BACKGROUND
Interferons (IFNs) play an important role in antiviral defense and have therapeutic potential in coxsackievirus heart disease. However, little is known about the relative contributions of type I and type II IFN signaling in coxsackievirus B3 (CVB3) infection or their role in the cardioselective nature of CVB3 infection.


RESULTS
Wild-type mice and mice deficient for either the type I or the type II IFN receptor (IFNR) were infected with CVB3. Infection of the type I IFNR-deficient mice with >10(3) plaque-forming units (pfu) of CVB3 resulted in 100% mortality within 2 to 4 days after infection. Death was rare in wild-type and type II IFNR-deficient mice after inoculation with as much as 10(8) pfu of CVB3. Surprisingly, the early mortality in the type I IFNR-deficient mice was not accompanied by higher virus titers in the heart. Unexpectedly, a dramatic increase of viral RNA in the liver was found to correlate with early mortality in type I IFNR-deficient mice.


CONCLUSIONS
Type I but not type II IFN signaling is essential for the prevention of early death due to CVB3 infection. Interestingly, neither type I or type II IFN signaling has a dramatic effect on early viral replication in the heart. However, lethal viral replication in the liver is controlled by type I IFNs. These results demonstrate that the IFN system is capable of modulating both viral pathogenicity and tissue tropism.
Wessely
R
R
Deutsches Herzzentrum and 1 Medizinische Klinik, Technische Universität, Munich, Germany.
Klingel
K
K
Knowlton
K U
KU
Kandolf
R
R
D000818:Animals; D003384:Coxsackievirus Infections / Q000517:prevention & control / Q000821:virology*; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology; D006321:Heart / Q000821:virology; D007370:Interferon Type I / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000502:physiology / Q000627:therapeutic use; D008099:Liver / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012367:RNA, Viral / Q000378:metabolism; D015398:Signal Transduction; D014779:Virus Replication / Q000187:drug effects
D007370:Interferon Type I; D012367:RNA, Viral; D007371:Interferon-gamma