Role of interferon gamma in the pathogenesis of primary respiratory syncytial virus infection in BALB/c mice

Schaik, Sandrijn M. van; Obot, Nsedu; Enhörning, Göran; Hintz, Karen H.; Gross, Kara J.; Hancock, Gerry E.; Stack, Anne M.; Welliver, Robert C.

doi:10.1002/1096-9071(200010)62:2<257::aid-jmv19>3.0.co;2-m

Cited by 111 publications

(89 citation statements)

References 24 publications

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“…This finding contradicts an early report, which suggested that IFN-g might contribute to RSV-mediated AHR in mice (25); however, AHR was not documented in this study (e.g., by assessment of airway responsiveness to MCh) nor was the outcome of reinfection examined in IFN-g 2/2 mice. Durbin and colleagues compared the responses of IFN-g 2/2 and WT mice to primary RSV infection and found no differences in lung pathology, cytokine levels, or viral replication and rate of clearance between the two strains of mice even after inoculation with high doses of RSV (i.e., 10 7 PFUs [plaque-forming units]) (26).…”

Section: Discussioncontrasting

confidence: 99%

IFN-γ Production during Initial Infection Determines the Outcome of Reinfection with Respiratory Syncytial Virus

Lee

Miyahara

Takeda

et al. 2008

Am J Respir Crit Care Med

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Rationale: Severe respiratory syncytial virus (RSV) bronchiolitis has been associated with deficient IFN-g production in humans, but the role of this cytokine in determining the outcome of reinfection is unknown. Objectives: To define the role of IFN-g in the development of RSVmediated airway hyperresponsiveness (AHR) and lung histopathology in mice. Methods: Wild-type (WT) and IFN-g knockout mice were infected with RSV in the newborn or weaning stages and reinfected 5 weeks later. Airway responses were assessed on Day 6 after the primary or secondary infection. Measurements and Main Results: Both WT and IFN-g knockout mice developed similar levels of AHR and airway inflammation after primary infection. After reinfection, IFN-g knockout mice, but not WT mice, developed AHR, airway eosinophilia, and mucus hyperproduction. Intranasal administration of IFN-g during primary infection but not during reinfection prevented the development of these altered airway responses on reinfection in IFN-g knockout mice. Adoptive transfer of WT T cells into IFN-g knockout mice before primary infection restored IFN-g production in the lungs and prevented the development of altered airway responses on reinfection. Treatment of mice with IFN-g during primary neonatal infection prevented the enhancement of AHR and the development of airway eosinophilia and mucus hyperproduction on reinfection. Conclusions: IFN-g production during primary RSV infection is critical to the development of protection against AHR and lung histopathology on reinfection. Provision of IFN-g during primary infection in infancy may be a potential therapeutic approach to alter the course of RSV-mediated long-term sequelae.

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Section: Discussioncontrasting

confidence: 99%

IFN-γ Production during Initial Infection Determines the Outcome of Reinfection with Respiratory Syncytial Virus

Lee

Miyahara

Takeda

et al. 2008

Am J Respir Crit Care Med

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“…Nonetheless, in our experiments with either IFN-␥ Ϫ/Ϫ BALB/c or 129SvEv IFN-␥R Ϫ/Ϫ mice, eosinophils were present in infiltrates surrounding vessels and airways of infected lungs, but only at low levels. This observation has been made by others (24,39), who concluded, as we did, that RSV pathogenesis in IFN-␥-deficient animals is similar to that in wild-type animals. We therefore wondered whether, in the absence of IFN-␥, IFN-␣␤ could act in a compensatory manner to inhibit Th2 lymphocyte development and eosinophilic disease (7).…”

Section: Discussionsupporting

confidence: 89%

Role for Innate IFNs in Determining Respiratory Syncytial Virus Immunopathology

Johnson

Mertz²,

Gitiban³

et al. 2005

The Journal of Immunology

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Respiratory syncytial virus (RSV) is the major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. The difficulties involved in RSV vaccine development were recognized in an early vaccine trial, when children immunized with a formalin-inactivated virus preparation experienced enhanced illness after natural infection. Subsequent research in animal models has shown that the vaccine-enhanced disease is mediated at least in part by memory cells producing Th2 cytokines. Previously we had observed enhanced, eosinophilic lung pathology during primary infection of IFN-deficient STAT1−/− mice that are incapable of generating Th1 CD4+ cells. To determine whether these effects depended only on Th2 cytokine secretion or involved other aspects of IFN signaling, we infected a series of 129SvEv knockout mice lacking the IFN-αβR (IFN-αβR−/−), the IFN-γR (IFN-γR−/−), or both receptors (IFN-αβγR−/−). Although both the IFN-γR−/− and the IFN-αβγR−/− animals generated strong Th2 responses to RSV-F protein epitopes, predominantly eosinophilic lung disease was limited to mice lacking both IFNRs. Although the absolute numbers of eosinophils in BAL fluids were similar between the strains, very few CD8+ T cells could be detected in lungs of IFN-αβγR−/− animals, leaving eosinophils as the predominant leukocyte. Thus, although CD4+ Th2 cell differentiation is necessary for the development of allergic-type inflammation after infection and appears to be unaffected by type I IFNs, innate IFNs clearly have an important role in determining the nature and severity of RSV disease.

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“…Constitutive BAL IL-18 concentration was significantly higher in Nrf 2 2/2 mice than in Nrf 2 1/1 mice, and IL-18 was significantly more elevated by RSV in Nrf 2 2/2 mice than in Nrf 2 1/1 mice after 5 days. BAL concentrations of the Th1 cytokine IFN-g in Nrf 2 1/1 mice were not significantly increased relative to controls until 7 days after RSV infection as shown in previous kinetic studies of murine RSV models (7,34), but lung IFN-g was not significantly increased at any time in Nrf 2 2/2 mice. Among BAL Th2 cytokines, IL-10 was not significantly changed in Nrf 2 1/1 mice but was significantly elevated in Nrf 2 2/ 2 mice at 7 days.…”

Section: Differential Pulmonary Cytokine Profiles After Rsv Infectionsupporting

confidence: 61%

“…Particularly in the clinical situation of RSV infection, many studies demonstrated that the Th1/Th2 cytokine balance in the serum of children with severe RSV disease was more skewed toward Th2 cytokines (4). In addition, IFN-g has been determined as a dominant host response factor for RSV clearance clinically and in animal studies (7,50). Therefore, a lack of IFN-g and Th2-skewed cytokine profile in Nrf 2 2/2 mice may explain their delayed viral clearance and support the enhanced RSV susceptibility.…”

Section: Discussionmentioning

confidence: 99%

“…Extensive research on host immune responses to RSV has been conducted in humans and in laboratory animals, and roles for innate immune receptors, including toll-like receptor 4 (5), chemokines such as Cx3cl1 (6), Th1 IFN-g (7) and Th2 IL-4 (8) cytokines, and intracellular adhesion molecule-1 (9), have been suggested in RSV pathogenesis. However, details of molecular mechanisms underlying RSV disease are not well understood.…”

mentioning

confidence: 99%

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Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease

Cho

Imani

Miller-DeGraff

et al. 2009

Am J Respir Crit Care Med

175

170

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Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of significant lower respiratory illness in infants and young children, but its pathogenesis is not fully understood. The transcription factor Nrf 2 protects lungs from oxidative injury and inflammation via antioxidant response element (ARE)-mediated gene induction. Objectives: The current study was designed to determine the role of Nrf 2-mediated cytoprotective mechanisms in murine airway RSV disease. Methods: Nrf 2-deficient (Nrf 2 2/2 ) and wild-type (Nrf 2 1/1 ) mice were intranasally instilled with RSV or vehicle. In a separate study, Nrf 2 1/1 and Nrf 2 2/2 mice were treated orally with sulforaphane (an Nrf 2-ARE inducer) or phosphate-buffered saline before RSV infection. Measurements and Main Results: RSV-induced bronchopulmonary inflammation, epithelial injury, and mucus cell metaplasia as well as nasal epithelial injury were significantly greater in Nrf 2 2/2 mice than in Nrf 2 1/1 mice. Compared with Nrf 2 1/1 mice, significantly attenuated viral clearance and IFN-g, body weight loss, heightened protein/ lipid oxidation, and AP-1/NF-kB activity along with suppressed antioxidant induction was found in Nrf 2 2/2 mice in response to RSV. Sulforaphane pretreatment significantly limited lung RSV replication and virus-induced inflammation in Nrf 2 1/1 but not in Nrf 2 2/2 mice. Conclusions: The results of this study support an association of oxidant stress with RSV pathogenesis and a key role for the Nrf 2-ARE pathway in host defense against RSV.

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Role of interferon gamma in the pathogenesis of primary respiratory syncytial virus infection in BALB/c mice

Cited by 111 publications

References 24 publications

IFN-γ Production during Initial Infection Determines the Outcome of Reinfection with Respiratory Syncytial Virus

IFN-γ Production during Initial Infection Determines the Outcome of Reinfection with Respiratory Syncytial Virus

Role for Innate IFNs in Determining Respiratory Syncytial Virus Immunopathology

Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease

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