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Journal articleGoritzka M, Makris S, Kausar F, et al., 2015,
Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes
, Journal of Experimental Medicine, Vol: 212, Pages: 699-714, ISSN: 0022-1007Type I interferons (IFNs) are important for host defense from viral infections, acting to restrict viral production in infected cells and to promote antiviral immune responses. However, the type I IFN system has also been associated with severe lung inflammatory disease in response to respiratory syncytial virus (RSV). Which cells produce type I IFNs upon RSV infection and how this directs immune responses to the virus, and potentially results in pathological inflammation, is unclear. Here, we show that alveolar macrophages (AMs) are the major source of type I IFNs upon RSV infection in mice. AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)–coupled retinoic acid–inducible gene 1 (RIG-I)–like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV. This is largely attributable to loss of type I IFN–dependent induction of monocyte chemoattractants and subsequent reduced recruitment of inflammatory monocytes (infMo) to the lungs. Notably, the latter have potent antiviral activity and are essential to control infection and lessen disease severity. Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN–mediated antiviral activity. Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation.
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Conference paperPytel KM, 2015,
Production of therapeutically relevant levels of FVIII after transduction of lungs with F/HN-pseudotyped lentivirus
, American Society for Gene and Cell Therapy, 18th Annual Meeting -
Journal articleChiu C, Openshaw PJ, 2015,
Antiviral B cell and T cell immunity in the lungs
, NATURE IMMUNOLOGY, Vol: 16, Pages: 18-26, ISSN: 1529-2908- Author Web Link
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- Citations: 114
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Journal articleGoritzka M, Durant LR, Pereira C, et al., 2014,
Alpha/Beta Interferon Receptor Signaling Amplifies Early Proinflammatory Cytokine Production in the Lung during Respiratory Syncytial Virus Infection
, Journal of Virology, Vol: 88, Pages: 6128-6136, ISSN: 0022-538XType I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFN-α/β) receptor (IFNAR) to induce genes that encode proteins important for limiting viral replication and directing immune responses. To investigate the extent to which type I IFNs play a role in the local regulation of inflammation in the airways, we examined their importance in early lung responses to infection with respiratory syncytial virus (RSV). IFNAR1-deficient (IFNAR1−/−) mice displayed increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was markedly reduced in the lungs of IFNAR1−/− mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemokines in the lungs of RSV-infected mice were also greatly reduced in the absence of IFNAR signaling. Furthermore, low levels of proinflammatory cytokines were also detected in the lungs of IFNAR1−/− mice challenged with noninfectious innate immune stimuli such as selected Toll-like receptor (TLR) agonists. Finally, recombinant IFN-α was sufficient to potentiate the production of inflammatory mediators in the lungs of wild-type mice challenged with innate immune stimuli. Thus, in addition to its well-known role in antiviral resistance, type I IFN receptor signaling acts as a central driver of early proinflammatory responses in the lung. Inhibiting the effects of type I IFNs may therefore be useful in dampening inflammation in lung diseases characterized by enhanced inflammatory cytokine production.
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Journal articleSchnoeller C, Roux X, Sawant D, et al., 2014,
Attenuated <i>Bordetella pertussis</i> Vaccine Protects against Respiratory Syncytial Virus Disease via an IL-17-Dependent Mechanism
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, Pages: 194-202, ISSN: 1073-449X- Cite
- Citations: 41
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Journal articleDurant LR, Makris S, Voorburg CM, et al., 2013,
Regulatory T Cells Prevent Th2 Immune Responses and Pulmonary Eosinophilia during Respiratory Syncytial Virus Infection in Mice
, JOURNAL OF VIROLOGY, Vol: 87, Pages: 10946-10954, ISSN: 0022-538X- Cite
- Citations: 89
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Journal articleTregoning JS, Wang BL, McDonald JU, et al., 2013,
Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection
, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 5576-5581, ISSN: 0027-8424- Cite
- Citations: 36
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Journal articleLoebbermann J, Durant L, Thornton H, et al., 2013,
Defective immunoregulation in RSV vaccine-augmented viral lung disease restored by selective chemoattraction of regulatory T cells
, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 2987-2992, ISSN: 0027-8424- Author Web Link
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- Citations: 56
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Journal articleSridhar S, Begom S, Bermingham A, et al., 2012,
Predominance of heterosubtypic IFN-?-only-secreting effector memory T cells in pandemic H1N1 naive adults
, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 42, Pages: 2913-2924, ISSN: 0014-2980- Author Web Link
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- Citations: 28
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Journal articleEveritt A, Clare S, Pertel T, et al., 2012,
IFITM3 restricts the morbidity and mortality associated with influenza
, INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, Vol: 16, Pages: E79-E79, ISSN: 1201-9712- Author Web Link
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- Citations: 4
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