Inflammasomes and Anti-Viral Immunity

Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Journal of Clinical Immunology (Impact Factor: 3.18). 09/2010; 30(5):632-7. DOI: 10.1007/s10875-010-9431-4
Source: PubMed


Type I Interferons are the hallmark cytokines deployed during infection to combat invading viruses. However, inflammatory cytokines such as Interleukin (IL)-1beta and IL-18 also play important roles in anti-viral defenses. The activity of IL-1beta and IL18 are regulated at the level of expression, processing, and secretion. Several classes of innate immune receptors control the expression of these cytokines, which must then be proteolytically processed via caspase-1. In this review, we provide an overview of how caspase-1-activating inflammasomes participate during viral infections and their role in regulating anti-viral immunity.

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    • "Innate immunity comprises the first line of defense against invading pathogens [4]–[7]. IL-1β is a pyrogenic cytokine that is produced during innate immune response following pathogenic invasion. "
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    ABSTRACT: Human respiratory syncytial virus (RSV) constitute highly pathogenic virus that cause severe respiratory diseases in newborn, children, elderly and immuno-compromised individuals. Airway inflammation is a critical regulator of disease outcome in RSV infected hosts. Although "controlled" inflammation is required for virus clearance, aberrant and exaggerated inflammation during RSV infection results in development of inflammatory diseases like pneumonia and bronchiolitis. Interleukin-1β (IL-1β) plays an important role in inflammation by orchestrating the pro-inflammatory response. IL-1β is synthesized as an immature pro-IL-1β form. It is cleaved by activated caspase-1 to yield mature IL-1β that is secreted extracellularly. Activation of caspase-1 is mediated by a multi-protein complex known as the inflammasome. Although RSV infection results in IL-1β release, the mechanism is unknown. Here in, we have characterized the mechanism of IL-1β secretion following RSV infection. Our study revealed that NLRP3/ASC inflammasome activation is crucial for IL-1β production during RSV infection. Further studies illustrated that prior to inflammasome formation; the "first signal" constitutes activation of toll-like receptor-2 (TLR2)/MyD88/NF-κB pathway. TLR2/MyD88/NF-κB signaling is required for pro-IL-1β and NLRP3 gene expression during RSV infection. Following expression of these genes, two "second signals" are essential for triggering inflammasome activation. Intracellular reactive oxygen species (ROS) and potassium (K(+)) efflux due to stimulation of ATP-sensitive ion channel promote inflammasome activation following RSV infection. Thus, our studies have underscored the requirement of TLR2/MyD88/NF-κB pathway (first signal) and ROS/potassium efflux (second signal) for NLRP3/ASC inflammasome formation, leading to caspase-1 activation and subsequent IL-1β release during RSV infection.
    PLoS ONE 01/2012; 7(1):e29695. DOI:10.1371/journal.pone.0029695 · 3.23 Impact Factor
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    • "importance of IL-1b (and IL-18) in anti-viral defenses that are supported by the enhanced susceptibility of mice lacking the cytokine receptors to virus infection [38]. Therefore, during salmon IPNV infection, lack of induction of IL-1b and IL-8 expression in the immune organs may actually weaken anti-viral activity and impair resolution of the infection. "
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    ABSTRACT: IPNV is the agent of a well-characterized acute disease that produces a systemic infection and high mortality in farmed fish species and persistent infection in surviving fish after outbreaks. Because modulation of the host expression of pro and anti-inflammatory cytokines can help establish persistence, in this study, we examined the expression of IL-1β, IL-8, IFNα1 and IL-10 during acute and persistent IPNV infection of Atlantic salmon. Results showed that IPNV infection induces an increase of the IFNα1 and IL-10 mRNA levels in the spleen and head kidney (HK) of fish after acute experimental infection. Levels of the pro-inflammatory cytokines IL-1β and IL-8 did not rise in the spleen although an increase of IL-1β, but not of IL-8, was observed in head kidney. In carrier asymptomatic salmon, cytokine gene expression of IFNα1 in the spleen and IL-10 in head kidney were also significantly higher than expression in non-carrier fish. Interestingly, a decrease of IL-8 expression was also observed. IPNV infection of SHK-1, which is a macrophage-like cell line of salmon, also induced an increase of expression of the anti-inflammatory cytokine IL-10 with no effects on the expression of IL-1β and IL-8. The effects are induced by an unknown mechanism during viral infection because poly I:C and the viral genomic dsRNA showed the opposite effects on cytokine expression in SHK-1 cells. In summary, IPNV always induces up-regulation of the anti-inflammatory cytokine IL-10 in Atlantic salmon. As this is accompanied by a lack of induction of the pro-inflammatory cytokines IL-1β and IL-8, the anti-inflammatory milieu may explain the high frequency, prevalence and persistence of IPNV in salmon. Effects might be part of the viral mechanisms of immune evasion.
    Fish &amp Shellfish Immunology 11/2011; 32(2):291-300. DOI:10.1016/j.fsi.2011.11.018 · 2.67 Impact Factor
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    • "This reaction illustrates an efficient way for pathogens to be cleared by the innate immune system and highlights an important possible role for eATP in helping to eliminate latently infected cells [62, 78-80]. Quiescent cells latently infected with HIV, when activated by eATP, are more likely to undergo this host-beneficial process of inflammation that is defensive in nature and protective to the organism in clearing the infectious pathogen [81]. "
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    ABSTRACT: Extracellular adenosine triphosphate (eATP) is a potent molecule that has the capacity to modulate various aspects of cell functions including gene expression. This element of modulation is essential to the role of ATP as a therapeutic agent. The hypothesis presented is that ATP can have an important impact on the treatment of HIV infection. This is supported in part by published research, although a much greater role for ATP is suggested than prior authors ever thought possible. ATP has the ability to enhance the immune system and could thus improve the host's own defense mechanisms to eradicate the virus-infected cells and restore normal immune function. This could provide effective therapy when used in conjunction with highly active antiretroviral therapies (HAART) to eliminate the latently infected cells. The key lies in applying ATP through the methodology described. This article presents a strategy for using ATP therapeutically along with background evidence to substantiate the importance of using ATP in the treatment of HIV infection.
    Current HIV research 06/2011; 9(4):209-22. DOI:10.2174/157016211796320289 · 1.76 Impact Factor
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