Low-Dose Oral Type I Interferons Reduce Early Virus Replication of Murine CytomegalovirusIn Vivo

Abstract

Immunity to viral infections involves both innate and antigen-specific immune responses. The antiviral properties of interferons (IFNs) are part of the innate immune response. Low doses of type I IFNs (IFN-alpha and IFN-beta) administered daily (10 IU per mouse) by the oral route significantly reduced the early replication of murine cytomegalovirus (MCMV) in both the spleen and liver of MCMV-infected susceptible BALB/c mice. Significant inhibition of virus replication was observed for two different inoculum doses of virus (2 x 10(4) pfu per mouse [0.6 LD50] and 2 x 10(4.12) pfu per mouse [0.8 LD50]). Analysis of IFN retention, using [35S]-labeled IFN-alpha1 compared with the nonreceptor binding mutant IFN-alpha1 (R33M) administered orally to mice, revealed binding of wild-type IFN-alpha1 to several tissues. In particular, IFN was retained by tissues proximal to lymphoid regions, including the posterior nasal cavity, posterior tongue, small intestine, and rectum. These findings suggest that type I IFNs may inhibit MCMV replication by distal binding of the orally administered IFN to various tissues, which in turn augment the primary immune response to virus infection.

Efficacy of Low-Dose Oral Use of Type I Interferon in Cytomegalovirus Infections In Vivo

“…Furthermore, we have characterized tissues of the gastrointestinal (GI) tract displaying dense type I IFN receptors to be located in both the anterior and posterior tongue, regions proximal to Peyer's patches of the small intestine, and the rectum. These sites correlate with specific binding of labeled IFNa 1 identified in our previous study (17) and may represent the initial sites of interaction of the orally administered IFNs. These findings imply the potential for the wide application of LDOA IFN as antiviral therapy for CMV infections.…”

“…(17) In the present study we expand the investigations of the efficacy of LDOA IFN treatment for MCMV replication in vivo. BALB/c mice were treated with different concentrations of IFN-a /b ranging from 1 to 1,000 IU daily by the oral-mucosal route for 1 week prior to i.p.…”

“…(17) In the present study, we characterized the location of IFN receptor-bearing tissues of the GI tract in mice. Frozen tissue samples, posterior nasal cavity, anterior tongue, posterior tongue, masticatory muscle, esophagus, small intestine, and rectum, from a norm al uninfected BALB/c mouse were analyzed by immunohistoch emistry for IFN receptor-bearing cells.…”

“…Unanaesthetised mice (5 per group) were administered 10 IU/10 m l by the oral-mucosal route daily for 7 days prior to virus infection and a further 2-3 days after virus infection as previously described. (17) Another group of mice received 10 m l of saline similarly via the oral-mucosal route and served as controls. In addition, a separate group of mice received 20,000 IU IFN-a /b by the i.p.…”

“…Previously, we have reported the antiviral efficacy of LDOA IFN therapy for a natural mouse pathogen, murine cytomegalovirus (MCMV), (17) a model used for human CMV infection and disease. (18) Daily treatm ent of BALB/c mice with 10 IU of IFN-a /b by the oral-mucosal route, starting 1 week prior to virus inoculation and continuing for the duration of the experiment, significantly reduced early virus replication in the spleen and liver.…”