The role of interferons in rotavirus infections and protection.
Type I and type II interferons (IFNs) play a critical role in control of a number of viral infections. To study whether altered and reduced functional capacities of type I and type II IFNs would affect rotavirus-induced diarrhea and viral replication, we obtained signal transducers and activators of transcription 1 (Stat1) knock-out mice (Stat1(-/-)) that lack many IFN-induced responses. We found that suckling Stat1(-/-) and immunocompetent mice orally infected with rotavirus experienced diarrhea and shed rotavirus with similar intensity. However, adult Stat1(-/-) mice shed up to 100-fold more homologous murine rotavirus and heterologous rhesus rotavirus antigen in their stools than did immunocompetent mice 2-6 days after infection. Clearance of rotavirus in stools from adult Stat1(-/-) mice occurred at the same time as in wild-type (WT) control mice. Clearance in Stat1(-/-) mice correlated with a potent antibody response and a mixed Th1 and Th2 response, whereas in WT control mice, clearance correlated with a weaker antibody response and a polarized Th1 response. Stat1(-/-) mice were fully protected against subsequent challenge. Moreover, vaccination of adult Stat1(-/-) mice with a rotavirus VP6 protein and the mucosal adjuvant Escherichia coli heat-labile toxin LT (R192G) elicited 94% protection, as measured by the total reduction in viral shedding for the group in comparison to unimmunized controls. Thus, modulating IFN function through the loss of Stat1 caused a defective innate immune response in adult mice but had no effect on rotavirus-induced diarrhea and replication in suckling mice. Furthermore, adult Stat1(-/-), IFN-gamma, and IFN-alpha/beta receptor(-/-) (IFNAR-2(-/-)) mice infected with rotavirus or vaccinated with VP6 vaccine and adjuvant were fully protected against rotavirus shedding following a subsequent challenge with rotavirus.
Vancott
John L
JL
Division of Infectious Diseases, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
McNeal
Monica M
MM
Choi
Anthony H C
AH
Ward
Richard L
RL
D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D000956:Antigens, Viral; D036022:Capsid Proteins / Q000276:immunology; D003967:Diarrhea / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D007370:Interferon Type I / Q000378:metabolism* / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012401:Rotavirus / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D012400:Rotavirus Infections / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D013997:Time Factors; D014765:Viral Vaccines / Q000008:administration & dosage; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
D000956:Antigens, Viral; D036022:Capsid Proteins; D007370:Interferon Type I; D011993:Recombinant Fusion Proteins; C061332:VP6 protein, Rotavirus; D014765:Viral Vaccines; D007371:Interferon-gamma