Key Points
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Most, if not all, cells in humans and mice express the receptor for type I interferons (IFNs). Therefore, these cytokines have a range of direct and indirect effects on various cell types during infection with viruses, bacteria, parasites and fungi.
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Type I IFNs are important for host defence against viruses, through the induction of antiviral effector molecules that are encoded by IFN-stimulated genes. These IFNs can, however, cause immunopathology in acute viral infections. Conversely, they can lead to immunosuppression and loss of virus control during chronic viral infections.
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During bacterial infections, low levels of type I IFNs may be required early, to initiate cell-mediated immune responses. By contrast, type I IFNs have been shown to have adverse effects in infections with intracellular bacteria such as Listeria monocytogenes and Mycobacterium tuberculosis.
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In bacterial infections, high concentrations of type I IFNs may block B cell responses or may lead to the production of immunosuppressive molecules such as interleukin-10.
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Type I IFNs also antagonize the action of type II IFN (that is, IFNγ) by reducing the responsiveness of macrophages to activation by type II IFN.
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Another important antagonism is between type I IFNs and interleukin-1. This antagonism was recently shown to be important in M. tuberculosis infection and to be mediated by eicosanoids, in particular prostaglandin E2.
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Thus, type I IFNs are part of a complex cross-regulatory network, which leads mostly, but not always, to protection of the host against infectious diseases with minimum damage to the host.
Abstract
Type I interferons (IFNs) have diverse effects on innate and adaptive immune cells during infection with viruses, bacteria, parasites and fungi, directly and/or indirectly through the induction of other mediators. Type I IFNs are important for host defence against viruses. However, recently, they have been shown to cause immunopathology in some acute viral infections, such as influenza virus infection. Conversely, they can lead to immunosuppression during chronic viral infections, such as lymphocytic choriomeningitis virus infection. During bacterial infections, low levels of type I IFNs may be required at an early stage, to initiate cell-mediated immune responses. High concentrations of type I IFNs may block B cell responses or lead to the production of immunosuppressive molecules, and such concentrations also reduce the responsiveness of macrophages to activation by IFNγ, as has been shown for infections with Listeria monocytogenes and Mycobacterium tuberculosis. Recent studies in experimental models of tuberculosis have demonstrated that prostaglandin E2 and interleukin-1 inhibit type I IFN expression and its downstream effects, demonstrating that a cross-regulatory network of cytokines operates during infectious diseases to provide protection with minimum damage to the host.
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Acknowledgements
The authors' work was supported by the Medical Research Council, UK (grants U117565642 to A.O.G. and U117597139 to A.W.), the European Research Council (grant 294682-TB-PATH to A.O.G.) and the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (grants to K.M.-B. and A.S.).
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Glossary
- Cytosolic GAMP synthase
-
(cGAS). A cytosolic DNA sensor that catalyses the production of the second messenger cyclic di-GMP-AMP (cGAMP) in response to DNA, which is then recognized by the sensor and signalling intermediate STING (stimulator of interferon genes), triggering type I interferon production.
- Plasmacytoid dendritic cells
-
(pDCs). Immature dendritic cells with a morphology that resembles that of plasma cells. On a per-cell basis, pDCs are the main producers of type I interferons in response to viral infections or Toll-like receptor stimulation.
- Ribavirin
-
A drug that interferes with RNA metabolism and blocks viral replication. Ribavirin is used in combination with interferon-α to treat hepatitis C virus infection.
- M1 macrophage
-
A pro-inflammatory, or 'classically activated', subset of macrophages that are characterized by phagocytic activity and the expression of particular pro-inflammatory cytokines (such as tumour necrosis factor) and inflammatory mediators (such as inducible nitric oxide synthase).
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McNab, F., Mayer-Barber, K., Sher, A. et al. Type I interferons in infectious disease. Nat Rev Immunol 15, 87–103 (2015). https://doi.org/10.1038/nri3787
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DOI: https://doi.org/10.1038/nri3787
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