Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease

Barton, Erik S.; Youree, Bryan E.; Ebert, Daniel H.; Forrest, J. Craig; Connolly, Jodi L.; Vályi-Nagy, Tibor; Washington, Kay; Wetzel, J. Denise; Dermody, Terence S.

doi:10.1172/jci200316303

Cited by 32 publications

(53 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Viral particles were Freon extracted from infected cell lysates, layered onto 1.2-to 1.4-g/cm 3 CsCl gradients, and centrifuged at 62,000 ϫ g for 18 h. Bands corresponding to virions (1.36 Generation and infection of primary cardiac myocyte cultures. Primary cardiac myocyte cultures were generated from term fetuses or 1-day-old neonates by successive trypsinization of the apical two-thirds of the heart and selective plating as described previously (43).…”

Section: Cells and Virusesmentioning

confidence: 99%

“…Strain-specific differences in reovirus tropism and virulence are linked to both viral and host factors. Viral factors include receptor utilization (1,3,42) and sensitivity to type 1 interferons (IFNs) (32), while host factors include components of innate and adaptive immunity (38,39). Protection against reovirus infection is mediated by both cell-mediated and humoral immune mechanisms.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Interferon Regulatory Factor 3 Attenuates Reovirus Myocarditis and Contributes to Viral Clearance

Holm

Pruijssers

Li³

et al. 2010

J Virol

Self Cite

View full text Add to dashboard Cite

Apoptosis is a pathological hallmark of encephalitis and myocarditis caused by reovirus in newborn mice. In cell culture models, the antiviral transcription factor interferon regulatory factor 3 (IRF-3) enhances reovirus-induced apoptosis following activation via retinoic acid inducible gene I and interferon promoterstimulating factor 1. To determine the role of IRF-3 in reovirus disease, we infected newborn IRF-3 ؉/؉ and IRF-3 ؊/؊ mice perorally with mildly virulent strain type 1 Lang (T1L) and fully virulent strain type 3 SA؉ (T3SA؉) and monitored infected animals for survival. Both wild-type and IRF-3 ؊/؊ mice succumbed with equivalent frequencies to infection with T3SA؉. However, the absence of IRF-3 was associated with significantly decreased survival rates following infection with T1L. The two virus strains achieved similar peak titers in IRF-3 ؉/؉ and IRF-3 ؊/؊ mice in the intestine, brain, heart, liver, and spleen. However, by day 12 postinoculation, titers in all organs examined were 10-to 100-fold higher in IRF-3 ؊/؊ mice than those in wild-type mice. Increased titers were associated with marked pathological changes in all organs examined, especially in the heart, where absence of IRF-3 resulted in severe myocarditis. Cellular and humoral immune responses were equivalent in wild-type and IRF-3 ؊/؊ animals, suggesting that IRF-3 functions independently of the adaptive immune response to enhance reovirus clearance. Thus, IRF-3 serves to facilitate virus clearance and prevent tissue injury in response to reovirus infection.

show abstract

Section: Cells and Virusesmentioning

confidence: 99%

mentioning

confidence: 99%

Interferon Regulatory Factor 3 Attenuates Reovirus Myocarditis and Contributes to Viral Clearance

Holm

Pruijssers

Li³

et al. 2010

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although no viral agent has been consistently associated with biliary atresia in humans (1-3), the ability of RRV to target murine cholangiocytes and induce a tissue-specific inflammatory injury proves the principle that infectious agents may target neonatal cholangiocytes and trigger an undesired inflammatory response that results in occlusion of extrahepatic bile ducts. The hepatobiliary system of suckling mice has also been shown to be targeted by reovirus type 3, but the inflammatory response has not been shown to cause obstruction of extrahepatic bile ducts (17)(18)(19)(20). In contrast, RRV challenge triggers an immediate infiltration of the hepatobiliary system by neutrophils, followed by predominantly Th1-committed, IFN-γ-producing T lymphocytes at the time of obstruction of extrahepatic bile ducts.…”

Section: Figurementioning

confidence: 99%

Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-γ in experimental biliary atresia

Shivakumar¹,

Campbell²,

Sabla³

et al. 2004

J. Clin. Invest.

192

236

View full text Add to dashboard Cite

The etiology and pathogenesis of bile duct obstruction in children with biliary atresia are largely unknown. We have previously reported that, despite phenotypic heterogeneity, genomic signatures of livers from patients display a proinflammatory phenotype. Here, we address the hypothesis that production of IFN-γ is a key pathogenic mechanism of disease using a mouse model of rotavirus-induced biliary atresia. We found that rotavirus infection of neonatal mice has a unique tropism to bile duct cells, and it triggers a hepatobiliary inflammation by IFN-γ-producing CD4 + and CD8 + lymphocytes. The inflammation is tissue specific, resulting in progressive jaundice, growth failure, and greater than 90% mortality due to obstruction of extrahepatic bile ducts. In this model, the genetic loss of IFN-γ did not alter the onset of jaundice, but it remarkably suppressed the tissue-specific targeting of T lymphocytes and completely prevented the inflammatory and fibrosing obstruction of extrahepatic bile ducts. As a consequence, jaundice resolved, and long-term survival improved to greater than 80%. Notably, administration of recombinant IFN-γ led to recurrence of bile duct obstruction following rotavirus infection of IFN-γ-deficient mice. Thus, IFN-γ-driven obstruction of bile ducts is a key pathogenic mechanism of disease and may constitute a therapeutic target to block disease progression in patients with biliary atresia.

show abstract

“…After infection of newborn mice, reoviruses disseminate systemically, producing injury to a variety of organs, including the CNS, heart, and liver (3). Strain-specific differences in receptor utilization influence some types of reovirus disease (4,5); however, disease pathogenesis at other sites is more complex (6,7).…”

Section: Introductionmentioning

confidence: 99%

Organ-specific roles for transcription factor NF-κB in reovirus-induced apoptosis and disease

O’Donnell

Hansberger²,

Connolly³

et al. 2005

J. Clin. Invest.

Self Cite

118

View full text Add to dashboard Cite

Reovirus induces apoptosis in cultured cells and in vivo.In cell culture models, apoptosis is contingent upon a mechanism involving reovirus-induced activation of transcription factor NF-κB complexes containing p50 and p65/RelA subunits. To explore the in vivo role of NF-κB in this process, we tested the capacity of reovirus to induce apoptosis in mice lacking a functional nfkb1/p50 gene. The genetic defect had no apparent effect on reovirus replication in the intestine or dissemination to secondary sites of infection. In comparison to what was observed in wild-type controls, apoptosis was significantly diminished in the CNS of p50-null mice following reovirus infection. In sharp contrast, the loss of p50 was associated with massive reovirusinduced apoptosis and uncontrolled reovirus replication in the heart. Levels of IFN-β mRNA were markedly increased in the hearts of wild-type animals but not p50-null animals infected with reovirus. Treatment of p50-null mice with IFN-β substantially diminished reovirus replication and apoptosis, which suggests that IFN-β induction by NF-κB protects against reovirus-induced myocarditis. These findings reveal an organspecific role for NF-κB in the regulation of reovirus-induced apoptosis, which modulates encephalitis and myocarditis associated with reovirus infection.

show abstract

Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease

Cited by 32 publications

References 41 publications

Interferon Regulatory Factor 3 Attenuates Reovirus Myocarditis and Contributes to Viral Clearance

Interferon Regulatory Factor 3 Attenuates Reovirus Myocarditis and Contributes to Viral Clearance

Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-γ in experimental biliary atresia

Organ-specific roles for transcription factor NF-κB in reovirus-induced apoptosis and disease

Contact Info

Product

Resources

About