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Disease-promoting effects of type I interferons in viral, bacterial, and coinfections.

Davidson S, Maini MK, Wack A - J. Interferon Cytokine Res. (2015)

Bottom Line: While type I interferons (IFNs) are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral and bacterial infections.The underlying mechanisms by which type I IFNs promote susceptibility or severity include direct tissue damage by apoptosis induction or suppression of proliferation in tissue cells, immunopathology due to excessive inflammation, and cell death induced by TRAIL- and Fas-expressing immune cells, as well as immunosuppression through IL-10, IL-27, PD-L1, IL-1Ra, and other regulatory molecules that antagonize the induction or action of IL-1, IL-12, IL-17, IFN-γ, KC, and other effectors of the immune response.This review discusses current understanding of the parameters of signal strength, duration, timing, location, and cellular recipients that determine whether type I IFNs have beneficial or detrimental effects in infection.

View Article: PubMed Central - PubMed

Affiliation: 1 Division of Immunoregulation, MRC National Institute for Medical Research , Mill Hill, London, United Kingdom .

ABSTRACT
While type I interferons (IFNs) are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral and bacterial infections. The underlying mechanisms by which type I IFNs promote susceptibility or severity include direct tissue damage by apoptosis induction or suppression of proliferation in tissue cells, immunopathology due to excessive inflammation, and cell death induced by TRAIL- and Fas-expressing immune cells, as well as immunosuppression through IL-10, IL-27, PD-L1, IL-1Ra, and other regulatory molecules that antagonize the induction or action of IL-1, IL-12, IL-17, IFN-γ, KC, and other effectors of the immune response. Bacterial superinfections following influenza infection are a prominent example of a situation where type I IFNs can misdirect the immune response. This review discusses current understanding of the parameters of signal strength, duration, timing, location, and cellular recipients that determine whether type I IFNs have beneficial or detrimental effects in infection.

No MeSH data available.


Related in: MedlinePlus

Moderate IFN-αβ responses to infection are protective, while excessive IFN-αβ amounts contribute to immunopathology. (A) Bell-shaped curve displaying resistance to influenza severity as a function of IFN-αβ responses, based on experimental findings in Davidson and others (2014) and other studies. High IFN-αβ-expressing mouse strains (eg, 129, DBA, agouti, and gray symbols) are highly susceptible to influenza, and genetic removal of IFN-αβ from such strains increases resistance (1). Conversely, exogenous addition of IFN-αβ to resistant, low IFN-αβ-expressing mouse strains (eg, C57BL/6, Balb/C, black, and white symbols) reduces their resistance to influenza (2). However, if the moderate IFN-αβ responses in C57BL/6 mice are genetically removed, influenza resistance is reduced (3). Linking these data points generates a dose–response curve (4) where moderate IFN-αβ responses protect and high IFN-αβ responses are detrimental. (B) Induction of antiviral (green) versus proinflammatory, antiproliferative, and apoptosis-promoting (red) genes as a function of IFN-αβ signal strength based on results and hypotheses, as reviewed in (Piehler and others 2012). We hypothesize that moderate IFN-αβ responses are protective in influenza infections as effective antiviral responses are balanced with moderate inflammation and apoptosis induction. Higher IFN-αβ signals increase inflammation and cell death, but do not further enhance induction of antiviral effectors.
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f2: Moderate IFN-αβ responses to infection are protective, while excessive IFN-αβ amounts contribute to immunopathology. (A) Bell-shaped curve displaying resistance to influenza severity as a function of IFN-αβ responses, based on experimental findings in Davidson and others (2014) and other studies. High IFN-αβ-expressing mouse strains (eg, 129, DBA, agouti, and gray symbols) are highly susceptible to influenza, and genetic removal of IFN-αβ from such strains increases resistance (1). Conversely, exogenous addition of IFN-αβ to resistant, low IFN-αβ-expressing mouse strains (eg, C57BL/6, Balb/C, black, and white symbols) reduces their resistance to influenza (2). However, if the moderate IFN-αβ responses in C57BL/6 mice are genetically removed, influenza resistance is reduced (3). Linking these data points generates a dose–response curve (4) where moderate IFN-αβ responses protect and high IFN-αβ responses are detrimental. (B) Induction of antiviral (green) versus proinflammatory, antiproliferative, and apoptosis-promoting (red) genes as a function of IFN-αβ signal strength based on results and hypotheses, as reviewed in (Piehler and others 2012). We hypothesize that moderate IFN-αβ responses are protective in influenza infections as effective antiviral responses are balanced with moderate inflammation and apoptosis induction. Higher IFN-αβ signals increase inflammation and cell death, but do not further enhance induction of antiviral effectors.

Mentions: The role of type I IFN in influenza infection remains unclear, and the aforementioned studies are difficult to interpret as they do not allow for the distinction of virus versus host-specific factors that can contribute to pathology. Interestingly, 2 studies that did look specifically at host factors contributing to severe influenza-induced disease associated high IFN-αβ concentrations in the lung during influenza infection with increased disease severity. Boon and others (2009) demonstrated a host-specific correlation between expression of type I IFN and other proinflammatory cytokines with disease severity through the backcrossing of influenza-susceptible (DBA/1) and -resistant (C57BL/6) mouse strains. Moreover, Davidson and others (2014) showed that genetic blockade of IFN-αβ signaling in susceptible 129S7 mice decreased amounts of proinflammatory cytokines and chemokines in the pulmonary environment and concomitantly increased resistance to influenza-induced disease (Fig. 2A). Similarly, infection of Ifnar1−/− mice, deficient in the IFN-αβR, with respiratory syncytial virus correlated with lower cytokine secretion in the pulmonary environment compared with wild-type controls, and although this associated with slightly elevated viral loads, it did not impact on host survival (Goritzka and others 2014).


Disease-promoting effects of type I interferons in viral, bacterial, and coinfections.

Davidson S, Maini MK, Wack A - J. Interferon Cytokine Res. (2015)

Moderate IFN-αβ responses to infection are protective, while excessive IFN-αβ amounts contribute to immunopathology. (A) Bell-shaped curve displaying resistance to influenza severity as a function of IFN-αβ responses, based on experimental findings in Davidson and others (2014) and other studies. High IFN-αβ-expressing mouse strains (eg, 129, DBA, agouti, and gray symbols) are highly susceptible to influenza, and genetic removal of IFN-αβ from such strains increases resistance (1). Conversely, exogenous addition of IFN-αβ to resistant, low IFN-αβ-expressing mouse strains (eg, C57BL/6, Balb/C, black, and white symbols) reduces their resistance to influenza (2). However, if the moderate IFN-αβ responses in C57BL/6 mice are genetically removed, influenza resistance is reduced (3). Linking these data points generates a dose–response curve (4) where moderate IFN-αβ responses protect and high IFN-αβ responses are detrimental. (B) Induction of antiviral (green) versus proinflammatory, antiproliferative, and apoptosis-promoting (red) genes as a function of IFN-αβ signal strength based on results and hypotheses, as reviewed in (Piehler and others 2012). We hypothesize that moderate IFN-αβ responses are protective in influenza infections as effective antiviral responses are balanced with moderate inflammation and apoptosis induction. Higher IFN-αβ signals increase inflammation and cell death, but do not further enhance induction of antiviral effectors.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f2: Moderate IFN-αβ responses to infection are protective, while excessive IFN-αβ amounts contribute to immunopathology. (A) Bell-shaped curve displaying resistance to influenza severity as a function of IFN-αβ responses, based on experimental findings in Davidson and others (2014) and other studies. High IFN-αβ-expressing mouse strains (eg, 129, DBA, agouti, and gray symbols) are highly susceptible to influenza, and genetic removal of IFN-αβ from such strains increases resistance (1). Conversely, exogenous addition of IFN-αβ to resistant, low IFN-αβ-expressing mouse strains (eg, C57BL/6, Balb/C, black, and white symbols) reduces their resistance to influenza (2). However, if the moderate IFN-αβ responses in C57BL/6 mice are genetically removed, influenza resistance is reduced (3). Linking these data points generates a dose–response curve (4) where moderate IFN-αβ responses protect and high IFN-αβ responses are detrimental. (B) Induction of antiviral (green) versus proinflammatory, antiproliferative, and apoptosis-promoting (red) genes as a function of IFN-αβ signal strength based on results and hypotheses, as reviewed in (Piehler and others 2012). We hypothesize that moderate IFN-αβ responses are protective in influenza infections as effective antiviral responses are balanced with moderate inflammation and apoptosis induction. Higher IFN-αβ signals increase inflammation and cell death, but do not further enhance induction of antiviral effectors.
Mentions: The role of type I IFN in influenza infection remains unclear, and the aforementioned studies are difficult to interpret as they do not allow for the distinction of virus versus host-specific factors that can contribute to pathology. Interestingly, 2 studies that did look specifically at host factors contributing to severe influenza-induced disease associated high IFN-αβ concentrations in the lung during influenza infection with increased disease severity. Boon and others (2009) demonstrated a host-specific correlation between expression of type I IFN and other proinflammatory cytokines with disease severity through the backcrossing of influenza-susceptible (DBA/1) and -resistant (C57BL/6) mouse strains. Moreover, Davidson and others (2014) showed that genetic blockade of IFN-αβ signaling in susceptible 129S7 mice decreased amounts of proinflammatory cytokines and chemokines in the pulmonary environment and concomitantly increased resistance to influenza-induced disease (Fig. 2A). Similarly, infection of Ifnar1−/− mice, deficient in the IFN-αβR, with respiratory syncytial virus correlated with lower cytokine secretion in the pulmonary environment compared with wild-type controls, and although this associated with slightly elevated viral loads, it did not impact on host survival (Goritzka and others 2014).

Bottom Line: While type I interferons (IFNs) are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral and bacterial infections.The underlying mechanisms by which type I IFNs promote susceptibility or severity include direct tissue damage by apoptosis induction or suppression of proliferation in tissue cells, immunopathology due to excessive inflammation, and cell death induced by TRAIL- and Fas-expressing immune cells, as well as immunosuppression through IL-10, IL-27, PD-L1, IL-1Ra, and other regulatory molecules that antagonize the induction or action of IL-1, IL-12, IL-17, IFN-γ, KC, and other effectors of the immune response.This review discusses current understanding of the parameters of signal strength, duration, timing, location, and cellular recipients that determine whether type I IFNs have beneficial or detrimental effects in infection.

View Article: PubMed Central - PubMed

Affiliation: 1 Division of Immunoregulation, MRC National Institute for Medical Research , Mill Hill, London, United Kingdom .

ABSTRACT
While type I interferons (IFNs) are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral and bacterial infections. The underlying mechanisms by which type I IFNs promote susceptibility or severity include direct tissue damage by apoptosis induction or suppression of proliferation in tissue cells, immunopathology due to excessive inflammation, and cell death induced by TRAIL- and Fas-expressing immune cells, as well as immunosuppression through IL-10, IL-27, PD-L1, IL-1Ra, and other regulatory molecules that antagonize the induction or action of IL-1, IL-12, IL-17, IFN-γ, KC, and other effectors of the immune response. Bacterial superinfections following influenza infection are a prominent example of a situation where type I IFNs can misdirect the immune response. This review discusses current understanding of the parameters of signal strength, duration, timing, location, and cellular recipients that determine whether type I IFNs have beneficial or detrimental effects in infection.

No MeSH data available.


Related in: MedlinePlus