Battle Royale: Innate Recognition of Poxviruses and Viral Immune Evasion

Host pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs), which are molecular signatures shared by different pathogens. Recognition of PAMPs by PRRs initiate innate immune responses via diverse signaling pathways. Over recent decades, advances in our knowledge of innate immune sensing have enhanced our understanding of the host immune response to poxviruses. Multiple PRR families have been implicated in poxvirus detection, mediating the initiation of signaling cascades, activation of transcription factors, and, ultimately, the expression of antiviral effectors. To counteract the host immune defense, poxviruses have evolved a variety of immunomodulators that have diverse strategies to disrupt or circumvent host antiviral responses triggered by PRRs. These interactions influence the outcomes of poxvirus infections. This review focuses on our current knowledge of the roles of PRRs in the recognition of poxviruses, their elicited antiviral effector functions, and how poxviral immunomodulators antagonize PRR-mediated host immune responses.

Download Full-text

The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype

10.1101/466755 ◽

2018 ◽

Author(s):

Priya Hari ◽

Fraser R. Millar ◽

Nuria Tarrats ◽

Jodie Birch ◽

Curtis J. Rink ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Innate Immune ◽

Toll Like Receptor ◽

Cycle Arrest ◽

Secretory Phenotype ◽

Immune Sensing ◽

Molecular Patterns ◽

Innate Immune Sensing

ABSTRACTCellular senescence is a stress response program characterised by a robust cell cycle arrest and the induction of a pro-inflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that during oncogene-induced senescence (OIS), the Toll-like receptor TLR2 and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumour suppressors p53-p21CIP1, p16INK4a and p15INK4b, and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAA) that, in turn, function as the damage associated molecular patterns (DAMPs) signalling through TLR2 in OIS. Finally, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAA expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.

Download Full-text

Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS

Journal of Experimental Medicine ◽

10.1084/jem.20181329 ◽

2019 ◽

Vol 216 (5) ◽

pp. 1199-1213 ◽

Cited By ~ 19

Author(s):

Matthieu Gratia ◽

Mathieu P. Rodero ◽

Cécile Conrad ◽

Elias Bou Samra ◽

Mathieu Maurin ◽

...

Keyword(s):

Dna Damage ◽

Immune Responses ◽

Genome Instability ◽

Bloom Syndrome ◽

Innate Immune ◽

Genome Integrity ◽

Immune Sensing ◽

Syndrome Protein ◽

Innate Immune Sensing ◽

Exonuclease Trex1

Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-DNA inside cells poses a risk of triggering unchecked immune responses. The mechanisms limiting induction of inflammation by self-DNA are poorly understood. BLM RecQ–like helicase is essential for genome integrity and is deficient in Bloom syndrome (BS), a rare genetic disease characterized by genome instability, accumulation of micronuclei, susceptibility to cancer, and immunodeficiency. Here, we show that BLM-deficient fibroblasts show constitutive up-regulation of inflammatory interferon-stimulated gene (ISG) expression, which is mediated by the cGAS–STING–IRF3 cytosolic DNA–sensing pathway. Increased DNA damage or down-regulation of the cytoplasmic exonuclease TREX1 enhances ISG expression in BLM-deficient fibroblasts. cGAS-containing cytoplasmic micronuclei are increased in BS cells. Finally, BS patients demonstrate elevated ISG expression in peripheral blood. These results reveal that BLM limits ISG induction, thus connecting DNA damage to cellular innate immune response, which may contribute to human pathogenesis.

Download Full-text

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

10.1101/2020.02.22.960757 ◽

2020 ◽

Cited By ~ 1

Author(s):

Hataf Khan ◽

Rebecca P. Sumner ◽

Jane Rasaiyaah ◽

Choon Ping Tan ◽

Maria Teresa Rodriguez-Plata ◽

...

Keyword(s):

Immune Activation ◽

Nuclear Import ◽

Nuclear Transport ◽

Innate Immune ◽

Human Macrophages ◽

Innate Immune Activation ◽

Immune Sensing ◽

Molecular Patterns ◽

Innate Immune Sensing ◽

Hiv 1

AbstractHIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.

Download Full-text

Innate immunology in COVID-19—a living review. Part II: dysregulated inflammation drives immunopathology

Oxford Open Immunology ◽

10.1093/oxfimm/iqaa005 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Patrícia R S Rodrigues ◽

Aljawharah Alrubayyi ◽

Ellie Pring ◽

Valentina M T Bart ◽

Ruth Jones ◽

...

Keyword(s):

Immune Responses ◽

Current Knowledge ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Innate Immunology ◽

Viral Pathogen ◽

Health Crisis ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Abstract The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dysregulated immune responses may contribute to disease progression. Here we have reviewed current knowledge of cellular innate immune responses to SARS-CoV-2 infection, highlighting areas for further investigation and suggesting potential strategies for intervention. We conclude that in severe COVID-19 initial innate responses, primarily type I interferon, are suppressed or sabotaged which results in an early interleukin (IL)-6, IL-10 and IL-1β-enhanced hyperinflammation. This inflammatory environment is driven by aberrant function of innate immune cells: monocytes, macrophages and natural killer cells dispersing viral pathogen-associated molecular patterns and damage-associated molecular patterns into tissues. This results in primarily neutrophil-driven pathology including fibrosis that causes acute respiratory distress syndrome. Activated leukocytes and neutrophil extracellular traps also promote immunothrombotic clots that embed into the lungs and kidneys of severe COVID-19 patients, are worsened by immobility in the intensive care unit and are perhaps responsible for the high mortality. Therefore, treatments that target inflammation and coagulation are promising strategies for reducing mortality in COVID-19.

Download Full-text

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

eLife ◽

10.7554/elife.60821 ◽

2020 ◽

Vol 9 ◽

Author(s):

Hataf Khan ◽

Rebecca P Sumner ◽

Jane Rasaiyaah ◽

Choon Ping Tan ◽

Maria Teresa Rodriguez-Plata ◽

...

Keyword(s):

Immune Activation ◽

Nuclear Import ◽

Nuclear Transport ◽

Innate Immune ◽

Human Macrophages ◽

Innate Immune Activation ◽

Immune Sensing ◽

Molecular Patterns ◽

Innate Immune Sensing ◽

Hiv 1

HIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here, we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr-dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.

Download Full-text

Innate Immune Activation and Subversion of Mammalian Functions byLeishmaniaLipophosphoglycan

Journal of Parasitology Research ◽

10.1155/2012/165126 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 17

Author(s):

Luis H. Franco ◽

Stephen M. Beverley ◽

Dario S. Zamboni

Keyword(s):

Immune Responses ◽

Current Knowledge ◽

Innate Immune ◽

Sand Fly ◽

Mammalian Host ◽

Innate Immune Cells ◽

Host Immune Responses ◽

Parasite Survival ◽

Mammalian Infection

Leishmaniapromastigotes express several prominent glycoconjugates, either secreted or anchored to the parasite surface. Of these lipophosphoglycan (LPG) is the most abundant, and along with other phosphoglycan-bearing molecules, plays important roles in parasite infectivity and pathogenesis in both the sand fly and the mammalian host. Besides its contribution for parasite survival in the sand fly vector, LPG is important for modulation the host immune responses to favor the establishment of mammalian infection. This review will summarize the current knowledge regarding the role of LPG inLeishmaniainfectivity, focusing on the interaction of LPG and innate immune cells and in the subversion of mammalian functions by this molecule.

Download Full-text

Viral Evasion of RIG-I-Like Receptor-Mediated Immunity through Dysregulation of Ubiquitination and ISGylation

Viruses ◽

10.3390/v13020182 ◽

2021 ◽

Vol 13 (2) ◽

pp. 182

Author(s):

Cindy Chiang ◽

Guanqun Liu ◽

Michaela U. Gack

Keyword(s):

Immune Responses ◽

Current Knowledge ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Deubiquitinating Enzymes ◽

Viral Pathogens ◽

Dna Viruses ◽

E3 Ligases ◽

Antiviral Responses

Viral dysregulation or suppression of innate immune responses is a key determinant of virus-induced pathogenesis. Important sensors for the detection of virus infection are the RIG-I-like receptors (RLRs), which, in turn, are antagonized by many RNA viruses and DNA viruses. Among the different escape strategies are viral mechanisms to dysregulate the post-translational modifications (PTMs) that play pivotal roles in RLR regulation. In this review, we present the current knowledge of immune evasion by viral pathogens that manipulate ubiquitin- or ISG15-dependent mechanisms of RLR activation. Key viral strategies to evade RLR signaling include direct targeting of ubiquitin E3 ligases, active deubiquitination using viral deubiquitinating enzymes (DUBs), and the upregulation of cellular DUBs that regulate RLR signaling. Additionally, we summarize emerging new evidence that shows that enzymes of certain coronaviruses such as SARS-CoV-2, the causative agent of the current COVID-19 pandemic, actively deISGylate key molecules in the RLR pathway to escape type I interferon (IFN)-mediated antiviral responses. Finally, we discuss the possibility of targeting virally-encoded proteins that manipulate ubiquitin- or ISG15-mediated innate immune responses for the development of new antivirals and vaccines.

Download Full-text