Respiratory syncytial virus induces interleukin-10 by human alveolar macrophages. Suppression of early cytokine production and implications for incomplete immunity.

Panuska, James R.; Merolla, Rocco; Rebert, Nancy A.; Hoffmann, Stephen; Tsivitse, Paul; Cirino, Nick M.; Silverman, Robert H.; Rankin, John A.

doi:10.1172/jci118302

Cited by 130 publications

(71 citation statements)

References 44 publications

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“…The A2 strain has been shown either not to express IL-13 and mucus or to down-regulate those responses 11,13 while generating significant levels of IL-10 and interferon-␥. [35][36][37] Previous studies have examined the consequences of IL-10 depletion in knockout animals and in animals overexpressing IL-10 but not neutralization during infection in a normal animal during primary infection. 38,39 The overexpression of IL-13 in lungs of mice has been clearly linked to pathophysiological changes in not only allergic responses but in several other instances, including RSV infection.…”

Section: Discussionmentioning

confidence: 99%

Differential Immune Responses and Pulmonary Pathophysiology Are Induced by Two Different Strains of Respiratory Syncytial Virus

Lukacs

Moore

Rudd

et al. 2006

The American Journal of Pathology

143

159

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Section: Discussionmentioning

confidence: 99%

Differential Immune Responses and Pulmonary Pathophysiology Are Induced by Two Different Strains of Respiratory Syncytial Virus

Lukacs

Moore

Rudd

et al. 2006

The American Journal of Pathology

143

159

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“…Cells then were washed twice in MEM and subsequently covered in OptiMEM, 100 units͞ml penicillin, 100 g͞ml streptomycin, 50 mM Hepes (pH 7.5), 100 mM MgSO 4 , and 1.5% glycerol. After 5 h at 37ЊC, cells were scraped and sonicated as previously described (25). Aliquots of cell sonicates were flash-frozen in ethanol͞dry ice within 20 min of scraping.…”

Section: Methodsmentioning

confidence: 99%

“…When applied to HeLa cells, the 2-5A-antisense resulted in the ablation of PKR mRNA and enzymatic activity (24). The previous demonstration of elevated levels of RNase L after RSV infections of human alveolar macrophages (25) suggested that RSV might be susceptible to antiviral approaches involving RNase L. Here we show that the recruitment and activation of RNase L to an RSV mRNA with 2-5A-antisense oligonucleotides results in a potent inhibition of RSV replication in human tracheal epithelial cells.…”

mentioning

confidence: 94%

Targeting RNA decay with 2′,5′ oligoadenylate-antisense in respiratory syncytial virus-infected cells

Cirino

Xiao

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Treatment of human cells with 2 ,5 oligoadenylate covalently linked to antisense (2-5A-antisense) results in the selective cleavage of targeted RNA species by 2-5A-dependent RNase L. Here we show that 2-5A-antisense containing stabilizing modifications at both termini are effective in suppressing the replication of respiratory syncytial virus (RSV) in human tracheal epithelial cells. The affinity of 2-5A-antisense for different regions in the RSV M2 and L mRNAs was predicted from a computer-generated model of the RNA secondary structure. The most potent 2-5A-antisense molecule caused a highly effective, dose-dependent suppression of RSV yields when added to previously infected cells. In contrast, control oligonucleotides, including an inactive dimeric form of 2-5A linked to antisense, 2-5A linked to a randomized sequence of nucleotides, and antisense molecules lacking 2-5A, had minimal effects on virus replication. The specificity of this approach was shown by reverse transcriptase-coupled PCR analysis of RSV M2, P, and N mRNA and of cellular glyceraldehyde-3-phosphate dehydrogenase mRNA. The RSV M2 mRNA amounts were depleted after treating RSV-infected cells with 2-5A-antisense targeted to this mRNA, whereas the amounts of the other RNA species were unchanged. These studies demonstrate that 2 ,5 oligoadenylate covalently linked to antisense (2-5A-antisense) can effectively suppress RSV replication by directing the cellular RNase L to selectively degrade an essential viral mRNA.Respiratory syncytial virus (RSV), a nonsegmented, negativestrand RNA virus in the pneumovirus genus of Paramyxoviridae, is a major cause of lower respiratory disease, resulting in 90,000 hospitalizations and 4500 deaths per year in infants and young children in the United States (1). Of growing concern are outbreaks of RSV within institutionalized elderly (2) and immunodeficient (1) adults. There is only one approved anti-RSV compound, ribavirin, which reduces virus shedding in infected children, but has no effect on mortality or duration of hospitalization (3). In the search for alternative antiviral strategies, we have investigated the potential of novel chimeric antisense molecules, 2-5A-antisense, in the control of RSV infections.Zamecnik and Stephenson were the first to report an antiviral effect of antisense oligonucleotides by showing that replication of the retrovirus Rous sarcoma virus could be inhibited by the addition of oligonucleotides complementary in sequence to reiterated terminal sequences of the viral 35S RNA (4). Subsequently, antisense oligonucleotides have been used against a wide range of different types of viruses, including the negative-strand RNA viruses such as rabies virus (5) and influenza virus (6), positive-strand RNA viruses such as dengue virus (7), DNA viruses including hepatitis B (8) and herpes simplex virus type 1 (9), and the retrovirus HIV-1 (10, 11). Despite encouraging results, significant challenges remain in the development of antisense oligonucleotides as antiviral agents. For instance, ...

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“…First, RSV-infected monocytederived myeloid DCs make very little IFN-␣/␤ relative to that made by HMPV-infected cells (56), and RSV blocks the induction of plasmacytoid DC maturation and IFN production in response to TLR7 and TLR9 agonists (134). Second, compared to influenza virus and HPIV3, RSV induces a somewhat different spectrum of cytokines from cord blood macrophages and DCs; specifically, there was a reduced level of IL-12 and a greater secretion of IL-10, IL-11, and prostaglandin E2, which might suppress T-cell activation and favor an increased Th2/ Th1 balance (7,114). Third, RSV infection of cord blood or monocyte-derived myeloid DCs decreased their capacity to activate CD4 ϩ T cells (7,29).…”

Section: Rsv Is Not Highly Cytopathic or Invasivementioning

confidence: 99%

Viral and Host Factors in Human Respiratory Syncytial Virus Pathogenesis

Collins¹,

Graham

2008

J Virol

429

478

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Human respiratory syncytial virus (RSV) was first isolated in 1956 from a laboratory chimpanzee with upper respiratory tract disease (for general reviews, see references 21, 57, 102, and 145). RSV was quickly determined to be of human origin and was shown to be the leading worldwide viral agent of serious pediatric respiratory tract disease. In a 13-year prospective study of infants and children in the United States, RSV was detected in 43%, 25%, 11%, and 10% of pediatric hospitalizations for bronchiolitis, pneumonia, bronchitis, and croup, respectively (110). Approximately two-thirds of infants are infected with RSV during the first year of life, and 90% have been infected one or more times by 2 years of age. The rate of hospitalization for primary infection is approximately 0.5% but can vary by situation and ethnic group and can be as high as 25% (77).RSV also is a significant cause of morbidity and mortality in the elderly, with an impact approaching that of nonpandemic influenza virus (39). RSV readily infects severely immunocompromised individuals, most notably allogeneic bone marrow transplant recipients, causing high mortality. RSV also makes a substantial contribution to upper respiratory tract disease in individuals of all ages (59,65 Although RSV has a single serotype, reinfection can occur throughout life. RSV in yearly winter/early spring epidemics in temperate regions; elsewhere, the timing of RSV activity can vary widely with the locale. The RSV reservoir in the offseason is unknown. Strains circulate quickly around the earth (150). Neither a vaccine nor an effective antiviral therapy is available, although there is active research in both areas (23,78,138). However, infants at high risk for serious disease can receive passive immunoprophylaxis during the epidemic season by a monthly injection of a commercial RSV-neutralizing monoclonal antibody, palivizumab (Synagis), which provides a 55% reduction in RSV-associated hospitalization (17). THE VIRUSRSV (family Paramyxoviridae, order Mononegavirales) is an enveloped virus with a single-stranded negative-sense RNA genome of 15.2 kb (21). There are animal versions of RSV, including bovine RSV (BRSV) and pneumonia virus of mice (PVM), suggesting that species jumping occurred during the evolution of these viruses. However, there is no animal reservoir for human RSV.Efficient infection by RSV of established cell lines in vitro involves binding to cell-surface glycosaminoglycans (62). However, it is not known how closely this binding models attachment in vivo or whether it is an initial interaction that is followed by a second, higher-affinity step that remains to be identified. The nucleocapsid gains entry to the cytoplasm by membrane fusion; surprisingly, this may involve clathrin-mediated endocytosis rather than surface fusion typical of paramyxoviruses (85). Viral gene expression and RNA replication occur in the cytoplasm, and virions acquire a lipid envelope by budding through the plasmid membrane (Fig. 1). Virions are pleomorphic and include spheres ...

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Respiratory syncytial virus induces interleukin-10 by human alveolar macrophages. Suppression of early cytokine production and implications for incomplete immunity.

Cited by 130 publications

References 44 publications

Differential Immune Responses and Pulmonary Pathophysiology Are Induced by Two Different Strains of Respiratory Syncytial Virus

Differential Immune Responses and Pulmonary Pathophysiology Are Induced by Two Different Strains of Respiratory Syncytial Virus

Targeting RNA decay with 2′,5′ oligoadenylate-antisense in respiratory syncytial virus-infected cells

Viral and Host Factors in Human Respiratory Syncytial Virus Pathogenesis

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