Type I interferons and IRF-1 play a critical role in the control of a gammaherpesvirus infection.
The murine gammaherpesvirus 68 (MHV-68) is an ideal model system for the study of interactions between gammaherpesviruses and their hosts. Intranasal infection of mice with MHV-68 results in replication of the virus in the lung epithelium followed by latent infection of B cells. Resolution of productive MHV-68 infection depends on the adaptive immune system, but little is known about the role of innate immune mechanisms and the early interaction between the host and the virus. In this report, we have used mice that are deficient in components of the early defence system, the common type I interferon (IFN) receptor (IFN R), the transcriptional activator IRF-1, and the inducible nitric oxide synthase, to investigate the contribution of these mechanisms to control of MHV-68 infection. We show that while wild-type mice are highly resistant to infection with MHV-68, mice unresponsive to type I IFNs (IFN-alpha/beta R(-/-) ) are highly susceptible to the virus. At high multiplicities of infection (m.o.i. ; 4 x 10(6) PFU), 80-90% of IFN-alpha/beta R(-/-) mice succumb to infection, and at low m.o.i. (4 x 10(3) PFU), 50% mortality rates occur. Both high and low doses of virus lead to 100- to 1000-fold higher lung virus titres in IFN-alpha/beta R(-/-) mice than are found in wild-type mice and result in systemic dissemination of the virus. Latently infected cells are detectable in the spleens of IFN-alpha/beta R(-/-) mice earlier than in wild-type mice, and the numbers of latently infected cells are 10-fold higher in the IFN-alpha/beta R(-/-) mice during the acute phase of infection. We find IRF-1 has a critical role in protection from fatal disease, whereas inducible nitric oxide synthase does not appear to be important. The results indicate that innate immune mechanisms are critical for the early control of MHV-68 and may play a role in the establishment of latency.
Dutia
B M
BM
Department of Veterinary Pathology, University of Edinburgh, Summerhall, EH9 1QH, United Kingdom. B.M.Dutia@ed.ac.uk
Allen
D J
DJ
Dyson
H
H
Nash
A A
AA
D000818:Animals; D018142:Gammaherpesvirinae / Q000502:physiology*; D006566:Herpesviridae Infections / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D017471:Receptors, Interferon / Q000276:immunology*; D017735:Virus Latency / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
D007370:Interferon Type I; D017471:Receptors, Interferon