Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1β Responses

Russell, Ryan F.; McDonald, Jacqueline U.; Ivanova, Maria; Zhong, Ziyun; Bukreyev, Alexander; Tregoning, John S.

doi:10.1128/jvi.01070-15

Cited by 47 publications

(42 citation statements)

References 58 publications

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“…Interference with NF-B activation often results in the reduction of apoptosis and a reduced expression of proinflammatory cytokines such as TNF-␣ or IL-1␤, providing more time for virus replication (21,36,53). We did not observe MuV SH to have a severe impact on virus replication in cell culture, which is in line with previous findings by Malik et al (33).…”

Section: Discussionsupporting

confidence: 82%

Mumps Virus SH Protein Inhibits NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes

Franz

Rennert

Woznik

et al. 2017

J Virol

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The mumps virus (MuV) small hydrophobic protein (SH) is a type I membrane protein expressed in infected cells. SH has been reported to interfere with innate immunity by inhibiting tumor necrosis factor alpha (TNF-␣)-mediated apoptosis and NF-B activation. To elucidate the underlying mechanism, we generated recombinant MuVs (rMuVs) expressing the SH protein with an N-terminal FLAG epitope or lacking SH expression due to the insertion of three stop codons into the SH gene. Using these viruses, we were able to show that SH reduces the phosphorylation of IKK␤, IB␣, and p65 as well as the translocation of p65 into the nucleus of infected A549 cells. Reporter gene assays revealed that SH interferes not only with TNF-␣-mediated NF-B activation but also with IL-1␤-and poly(I·C)-mediated NF-B activation, and that this inhibition occurs upstream of the NF-B pathway components TRAF2, TRAF6, and TAK1. Since SH coimmunoprecipitated with tumor necrosis factor receptor 1 (TNFR1), RIP1, and IRAK1, we hypothesize that SH exerts its inhibitory function by interacting with TNFR1, interleukin-1 receptor type 1 (IL-1R1), and TLR3 complexes in the plasma membrane of infected cells.IMPORTANCE The MuV SH has been shown to impede TNF-␣-mediated NF-B activation and is therefore thought to contribute to viral immune evasion. However, the mechanisms by which SH mediates NF-B inhibition remained largely unknown. In this study, we show that SH interacts with TNFR1, IL-1R1, and TLR3 complexes in infected cells. We thereby not only shed light on the mechanisms of SH-mediated NF-B inhibition but also reveal that SH interferes with NF-B activation induced by interleukin-1␤ (IL-1␤) and double-stranded RNA.

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Section: Discussionsupporting

confidence: 82%

Mumps Virus SH Protein Inhibits NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes

Franz

Rennert

Woznik

et al. 2017

J Virol

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“…The measurement of cytokines in the serum may not fully reflect the situation at the site of injection; however, as seen in previous studies (25), MF59 did induce an acute wave of CCL2, CXCL1, and IL-5 expression. The treatment regimen used for the IL-1␤ blockade or YVAD treatment may have led to incomplete blockade of the inflammasome, though, in previous studies, blocking IL-1␤ with the same protocol significantly altered the immune response to viral infection (35) and in vivo YVAD treatment has been shown to reduce IL-1␤ in the lungs (36). Studies suggest a role for activation of autophagy pathways by NanoSiO2 which may trigger an inflammation independently of caspase 1 (37).…”

Section: Discussionmentioning

confidence: 99%

Use of the Microparticle Nanoscale Silicon Dioxide as an Adjuvant To Boost Vaccine Immune Responses against Influenza Virus in Neonatal Mice

Russell

McDonald

Lambert

et al. 2016

J Virol

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Neonates are at a high risk of infection, but vaccines are less effective in this age group; tailored adjuvants could potentially improve vaccine efficacy. Increased understanding about danger sensing by the innate immune system has led to the rational design of novel adjuvants. But differences in the neonatal innate immune response, for example, to Toll-like receptor (TLR) agonists, can reduce the efficacy of these adjuvants in early life. We therefore targeted alternative danger-sensing pathways, focusing on a range of compounds described as inflammasome agonists, including nanoscale silicon dioxide (NanoSiO2), calcium pyrophosphate dihydrate (CPPD) crystals, and muramyl tripeptide (M-Tri-DAP), for their ability to act as adjuvants. In vitro, these compounds induced an interleukin 1-beta (IL-1␤) response in the macrophage-like cell line THP1. In vivo, adult CB6F1 female mice were immunized intramuscularly with H1N1 influenza vaccine antigens in combination with NanoSiO2, CPPD, or M-Tri-DAP and subsequently challenged with H1N1 influenza virus (A/England/195/2009). The adjuvants boosted anti-hemagglutinin IgG and IgA antibody levels. Both adult and neonatal animals that received NanoSiO2-adjuvanted vaccines lost significantly less weight and recovered earlier after infection than control animals treated with antigen alone. Administration of the adjuvants led to an influx of activated inflammatory cells into the muscle but to little systemic inflammation measured by serum cytokine levels. Blocking IL-1␤ or caspase 1 in vivo had little effect on NanoSiO2 adjuvant function, suggesting that it may work through pathways other than the inflammasome. Here we demonstrate that NanoSiO2 can act as an adjuvant and is effective in early life. IMPORTANCEVaccines can fail to protect the most at-risk populations, including the very young, the elderly, and the immunocompromised. There is a gap in neonatal immunity between the waning of maternal protection and routine infant immunization schedules, exacerbated by the failure of vaccines to work in the first months of life. One approach is to design age-specific formulations, with more-effective adjuvants, based on our understanding of the nature of the neonatal immune response. We chose to target the inflammasome, a molecular complex capable of detecting infection and cell damage and of triggering IL-1␤-driven inflammation. We screened a range of compounds in vitro and in vivo and identified three lead candidates: NanoSiO2, CPPD, and MTri-DAP. Of these, NanoSiO2 was the most effective and boosted the anti-influenza virus response in both adult and neonatal mice. This finding is important for the development of age-specific vaccines, designed using our knowledge of the neonatal immune response. Infants bear the brunt of mortality and morbidity from infectious diseases, with 36% of the annual 3.3 million deaths in newborn children caused by infections (1). Influenza virus infection is especially prevalent in early life, with high rates of hospitalization (50 to 100 cases ...

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“…5G–H). Specifically, IL-1β, a cytokine recently linked to the regulation of RSV replication [30], was significantly increased in infant lungs with an increasing trend also observed in adult animals (Fig. 5G).…”

Section: Resultsmentioning

confidence: 54%

Age predicts cytokine kinetics and innate immune cell activation following intranasal delivery of IFNγ and GM-CSF in a mouse model of RSV infection

et al. 2017

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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children and is further associated with increased healthcare utilization and cost of care in the first years of life. Severe RSV disease during infancy has also been linked to the later development of allergic asthma, yet there remains no licensed RSV vaccine or treatment. Pre-clinical and clinical studies have shown that disease severity and development of allergic asthma are associated with differences in cytokine production. As a result, stimulation of the innate host immune response with immune potentiators is gaining attention for their prospective application in populations with limited immune responses to antigenic stimuli or against pathogens for which vaccines do not exist. Specifically, macrophage-activating cytokines such as interferon gamma (IFNγ) and granulocyte colony-stimulating factor (GM-CSF) are commercially available immune potentiators used to prevent infections in patients with chronic granulomatous disease and febrile neutropenia, respectively. Moreover, an increasing number of reports describe the protective function of IFNγ and GM-CSF as vaccine adjuvants. Although a positive correlation between cytokine production and age has previously been reported, little is known about age-dependent cytokine metabolism or immune activating responses in infant compared to adult lungs. Here we use a non-compartmental pharmacokinetic model in naïve and RSV-infected infant and adult BALB/c mice to determine the effect of age on IFNγ and GM-CSF elimination and innate cell activation following intranasal delivery.

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Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1β Responses

Cited by 47 publications

References 58 publications

Mumps Virus SH Protein Inhibits NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes

Mumps Virus SH Protein Inhibits NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes

Use of the Microparticle Nanoscale Silicon Dioxide as an Adjuvant To Boost Vaccine Immune Responses against Influenza Virus in Neonatal Mice

Age predicts cytokine kinetics and innate immune cell activation following intranasal delivery of IFNγ and GM-CSF in a mouse model of RSV infection

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