IL-12p40 and IL-18 Modulate Inflammatory and Immune Responses to Respiratory Syncytial Virus Infection

Wang, Shan Ze; Bao, Yi; Rosenberger, Cynthia L.; Tesfaigzi, Yohannes; Stark, James M.; Harrod, Kevin S.

doi:10.4049/jimmunol.173.6.4040

Cited by 32 publications

(25 citation statements)

References 70 publications

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“…MyD88 also regulates IL-1 and IL-18 signaling (51, 52). IL-18 has already been shown to participate in the outcome of RSV infection centered on development of Th1 immune responses, whereas IL-1 has not been thoroughly examined (43,53). Finally, it was recently demonstrated that multiple TLR ligands synergize in the production of IL-12 and delta-like4 in DCs (31).…”

Section: Discussionmentioning

confidence: 99%

MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

Rudd

Schaller

Smit

et al. 2007

The Journal of Immunology

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Respiratory syncytial virus (RSV) is the leading cause of respiratory disease in infants worldwide. The induction of innate immunity and the establishment of adaptive immune responses are influenced by the recognition of pathogen-associated molecular patterns by TLRs. One of the primary pathways for TLR activation is by MyD88 adapter protein signaling. The present studies indicate that MyD88 deficiency profoundly impacts the pulmonary environment in RSV-infected mice characterized by the accumulation of eosinophils and augmented mucus production. Although there was little difference in CD4 T cell accumulation, there was also a significant decrease in conventional dendritic cells recruitment to the lungs of MyD88−/− mice. The exacerbation of RSV pathophysiology in MyD88−/− mice was associated with an enhanced Th2 cytokine profile that contributed to an inappropriate immune response. Furthermore, bone marrow-derived dendritic cells (BMDC) isolated from MyD88−/− mice were incapable of producing two important Th1 instructive signals, IL-12 and delta-like4, upon RSV infection. Although MyD88−/− BMDCs infected with RSV did up-regulate costimulatory molecules, they did not up-regulate class II as efficiently and stimulated less IFN-γ from CD4+ T cells in vitro compared with wild-type BMDCs. Finally, adoptive transfer of C57BL/6 BMDCs into MyD88−/− mice reconstituted Th1 immune responses in vivo, whereas transfer of MyD88−/− BMDCs into wild-type mice skewed the RSV responses toward a Th2 phenotype. Taken together, our data indicate that MyD88-mediated pathways are essential for the least pathogenic responses to this viral pathogen through the regulation of important Th1-associated instructive signals.

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Section: Discussionmentioning

confidence: 99%

MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

Rudd

Schaller

Smit

et al. 2007

The Journal of Immunology

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“…It has been shown that airway epithelial cells are a major source of IL-12p40 in the lung (33), and therefore it is reasonable to speculate that removal of an AM-driven negative signal/mediator may result in the increased production seen in our studies. Studies have shown that mice deficient in IL-12p40 have more severe airway inflammation and greater AHR after infection with RSV (34) or hMPV (35), and overexpression of IL12p80 in mouse lung epithelium primes the host for a protective response against a lethal respiratory infection with parainfluenza virus (36). Therefore, the increase in the number of IL-12p80 homodimers (which represents a sizable percent of the total measurable IL-12p40) in our model could explain in part the milder disease, inflammation, and AHR in AM-depleted mice that were infected with hMPV.…”

Section: Discussionmentioning

confidence: 99%

Alveolar Macrophages Contribute to the Pathogenesis of Human Metapneumovirus Infection while Protecting against Respiratory Syncytial Virus Infection

Kolli¹,

Gupta²,

Sbrana³

et al. 2014

Am J Respir Cell Mol Biol

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Human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are leading causes of upper and lower respiratory tract infections in young children and among elderly and immunocompromised patients. The pathogenesis of hMPVinduced lung disease is poorly understood. The lung macrophage population consists of alveolar macrophages (AMs) residing at the luminal surface of alveoli and interstitial macrophages present within the parenchymal lung interstitium. The involvement of AMs in innate immune responses to virus infections remains elusive. In this study, BALB/c mice depleted of AMs by intranasal instillation of dichloromethylene bisphosphonate (L-CL 2 MBP) liposomes were examined for disease, lung inflammation, and viral replication after infection with hMPV or RSV. hMPV-infected mice lacking AMs exhibited improved disease in terms of body weight loss, lung inflammation, airway obstruction, and hyperresponsiveness compared with AM-competent mice. AM depletion was associated with significantly reduced hMPV titers in the lungs, suggesting that hMPV required AMs for early entry and replication in the lung. In contrast, AM depletion in the context of RSV infection was characterized by an increase in viral replication, worsened disease, and inflammation, with increased airway neutrophils and inflammatory dendritic cells. Overall, lack of AMs resulted in a broad-spectrum disruption in type I IFN and certain inflammatory cytokine production, including TNF and IL-6, while causing a virus-specific alteration in the profile of several immunomodulatory cytokines, chemokines, and growth factors. Our study demonstrates that AMs have distinct roles in the context of human infections caused by members of the Paramyxoviridae family.

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“…On the other hand, although both cytokines were found to be important for control of HSV-2 by innate immunity, neither was needed for generation of adaptive immune effector mechanisms (17). Finally, neither IL-12p40 nor IL-18 were found to be necessary for the control of respiratory syncytial virus infection or IFN-␥ production, although both cytokines contributed to limiting lung inflammation and Th2 responses (18). There are at least two possible explanations why IL-12p40 or IL-18 may play important roles in some viral infections but not others.…”

Section: P Roduction Of the Th1 Cytokine Ifn-␥ By Nk And T Cells Is Cmentioning

confidence: 99%

IL-12p40 and IL-18 Play Pivotal Roles in Orchestrating the Cell-Mediated Immune Response to a Poxvirus Infection

Wang

Chaudhri

Jackson

et al. 2009

The Journal of Immunology

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A strong cell-mediated immune response is critical for controlling viral infections and is regulated by a number of cytokines, including IL-12 and IL-18. Indeed, some viruses have evolved to specifically target these pathways to counter the host immune response. Orthopoxviruses, including ectromelia virus, encode immune evasion molecules that specifically target IL-18 and IFN-γ. We hypothesized that IL-12 and IL-18 are pivotal for induction of IFN-γ production and subsequent generation of an effective host response to ectromelia virus infection. In this study, we demonstrate that absence of both IL-12p40 and IL-18 resulted in increased susceptibility to infection that was associated with skewing of the cytokine response to Th2 and a reduction in NK and CTL responses. The decrease in CTL response correlated with a defect in CD8+ T cell proliferation and lower numbers of virus-specific CD8+ T cells. Lack of either IL-12p40 and/or IL-18 was also associated with reduced numbers of CD8+ T cells at sites of infection and with an increase in the numbers of splenic T regulatory cells. Taken together, our data indicate that IL-12p40 and IL-18 act in concert and play an important antiviral role through the up-regulation of IFN-γ production and cell-mediated immune responses.

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IL-12p40 and IL-18 Modulate Inflammatory and Immune Responses to Respiratory Syncytial Virus Infection

Cited by 32 publications

References 70 publications

MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

Alveolar Macrophages Contribute to the Pathogenesis of Human Metapneumovirus Infection while Protecting against Respiratory Syncytial Virus Infection

IL-12p40 and IL-18 Play Pivotal Roles in Orchestrating the Cell-Mediated Immune Response to a Poxvirus Infection

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