scholarly journals Autophagy in HCV Replication and Protein Trafficking

2021 ◽  
Vol 22 (3) ◽  
pp. 1089
Author(s):  
Ja Yeon Kim Chu ◽  
Jing-hsiung James Ou
Keyword(s):  
Membrane Trafficking ◽  
Protein Trafficking ◽  
Current Knowledge ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Intracellular Protein ◽  
Cellular Autophagy ◽  
Host Innate Immune Response ◽  
Autophagy Pathway ◽  
Catabolic Process

Autophagy is a catabolic process that is important for maintaining cellular homeostasis. It is also known to possess other functions including protein trafficking and anti-microbial activities. Hepatitis C virus (HCV) is known to co-opt cellular autophagy pathway to promote its own replication. HCV regulates autophagy through multiple mechanisms to control intracellular protein and membrane trafficking to enhance its replication and suppress host innate immune response. In this review, we discuss the current knowledge on the interplay between HCV and autophagy and the crosstalk between HCV-induced autophagy and host innate immune responses.

scholarly journals Canonical and Noncanonical Autophagy as Potential Targets for COVID-19

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1619 ◽  
Author(s):  
Melissa Bello-Perez ◽  
Isabel Sola ◽  
Beatriz Novoa ◽  
Daniel J. Klionsky ◽  
Alberto Falco
Keyword(s):  
Molecular Mechanisms ◽  
Viral Infections ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Innate Immune ◽  
Interacting Proteins ◽  
Innate Immune Responses ◽  
Molecular Machinery ◽  
Autophagy Pathway

The SARS-CoV-2 pandemic necessitates a review of the molecular mechanisms underlying cellular infection by coronaviruses, in order to identify potential therapeutic targets against the associated new disease (COVID-19). Previous studies on its counterparts prove a complex and concomitant interaction between coronaviruses and autophagy. The precise manipulation of this pathway allows these viruses to exploit the autophagy molecular machinery while avoiding its protective apoptotic drift and cellular innate immune responses. In turn, the maneuverability margins of such hijacking appear to be so narrow that the modulation of the autophagy, regardless of whether using inducers or inhibitors (many of which are FDA-approved for the treatment of other diseases), is usually detrimental to viral replication, including SARS-CoV-2. Recent discoveries indicate that these interactions stretch into the still poorly explored noncanonical autophagy pathway, which might play a substantial role in coronavirus replication. Still, some potential therapeutic targets within this pathway, such as RAB9 and its interacting proteins, look promising considering current knowledge. Thus, the combinatory treatment of COVID-19 with drugs affecting both canonical and noncanonical autophagy pathways may be a turning point in the fight against this and other viral infections, which may also imply beneficial prospects of long-term protection.

scholarly journals Hepatitis C virus and autophagy

2015 ◽  
Vol 396 (11) ◽  
pp. 1215-1222 ◽  
Author(s):  
Linya Wang ◽  
Jing-hsiung James Ou
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Current Knowledge ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Innate Immune Responses ◽  
Human Pathogen ◽  
Severe Liver ◽  
Catabolic Process

Abstract Autophagy is a catabolic process by which cells remove protein aggregates and damaged organelles for recycling. It can also be used by cells to remove intracellular microbial pathogens, including viruses, in a process known as xenophagy. However, many viruses have developed mechanisms to subvert this intracellular antiviral response and even use this pathway to support their own replications. Hepatitis C virus (HCV) is one such virus and is an important human pathogen that can cause severe liver diseases. Recent studies indicated that HCV could activate the autophagic pathway to support its replication. This review summarizes the current knowledge on the interplay between HCV and autophagy and how this interplay affects HCV replication and host innate immune responses.

scholarly journals Regulation of dsDNA-induced innate immune responses by membrane trafficking

Autophagy ◽  
2010 ◽  
Vol 6 (3) ◽  
pp. 430-432 ◽  
Author(s):  
Tatsuya Saitoh ◽  
Naonobu Fujita ◽  
Tamotsu Yoshimori ◽  
Shizuo Akira
Keyword(s):  
Immune Responses ◽  
Membrane Trafficking ◽  
Innate Immune ◽  
Innate Immune Responses

scholarly journals Vomocytosis: Too Much Booze, Base, or Calcium?

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Melissa Cruz-Acuña ◽  
Noah Pacifici ◽  
Jamal S. Lewis
Keyword(s):  
Current Knowledge ◽  
Innate Immune ◽  
Macrophage Phenotype ◽  
Innate Immune Responses ◽  
Content Type ◽  
Phagosomal Maturation ◽  
Immunodeficiency Virus ◽  
Cellular Pathways ◽  
The Individual ◽  
Pathogenic Agents

ABSTRACT Macrophages are well known for their phagocytic activity and their role in innate immune responses. Macrophages eat non-self particles, via a variety of mechanisms, and typically break down internalized cargo into small macromolecules. However, some pathogenic agents have the ability to evade this endosomal degradation through a nonlytic exocytosis process termed vomocytosis. This phenomenon has been most often studied for Cryptococcus neoformans, a yeast that causes roughly 180,000 deaths per year, primarily in immunocompromised (e.g., human immunodeficiency virus [HIV]) patients. Existing dogma purports that vomocytosis involves distinctive cellular pathways and intracellular physicochemical cues in the host cell during phagosomal maturation. Moreover, it has been observed that the immunological state of the individual and macrophage phenotype affect vomocytosis outcomes. Here we compile the current knowledge on the factors (with respect to the phagocytic cell) that promote vomocytosis of C. neoformans from macrophages.

scholarly journals Inhibition of Cellular Autophagy Deranges Dengue Virion Maturation

2012 ◽  
Vol 87 (3) ◽  
pp. 1312-1321 ◽  
Author(s):  
Roberto Mateo ◽  
Claude M. Nagamine ◽  
Jeannie Spagnolo ◽  
Ernesto Méndez ◽  
Michael Rahe ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Virus Production ◽  
Innate Immune ◽  
Viral Rna ◽  
Virus Particles ◽  
Cellular Autophagy ◽  
Autophagy Pathway ◽  
Viral Maturation ◽  
Rna Accumulation ◽  
Selection Of

ABSTRACTAutophagy is an important component of the innate immune response, directly destroying many intracellular pathogens. However, some pathogens, including several RNA viruses, subvert the autophagy pathway, or components of the pathway, to facilitate their replication. In the present study, the effect of inhibiting autophagy on the growth of dengue virus was tested using a novel inhibitor, spautin-1 (specific andpotentautophagyinhibitor 1). Inhibition of autophagy by spautin-1 generated heat-sensitive, noninfectious dengue virus particles, revealing a large effect of components of the autophagy pathway on viral maturation. A smaller effect on viral RNA accumulation was also observed. Conversely, stimulation of autophagy resulted in increased viral titers and pathogenicity in the mouse. We conclude that the presence of functional autophagy components facilitates viral RNA replication and, more importantly, is required for infectious dengue virus production. Pharmacological inhibition of host processes is an attractive antiviral strategy to avoid selection of treatment-resistant variants, and inhibitors of autophagy may prove to be valuable therapeutics against dengue virus infection and pathogenesis.

scholarly journals Effect of Protein O-Mannosyltransferase (MSMEG_5447) on M. smegmatis and Its Survival in Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Liqiu Jia ◽  
Shanshan Sha ◽  
Shufeng Yang ◽  
Ayaz Taj ◽  
Yufang Ma
Keyword(s):  
Gene Knockout ◽  
Initial Step ◽  
Mycobacterial Infection ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Macrophage Infection ◽  
Host Interaction ◽  
Activation Of Transcription ◽  
Host Innate Immune Response

Protein O-mannosyltransferase (PMT) catalyzes an initial step of protein O-mannosylation of Mycobacterium tuberculosis (Mtb) and plays a crucial role for Mtb survival in the host. To better understand the role of PMT in the host innate immune response during mycobacterial infection, in this study, we utilized Mycobacterium smegmatis pmt (MSMEG_5447) gene knockout strain, ΔM5447, to infect THP-1 cells. Our results revealed that the lack of MSMEG_5447 not only impaired the growth of M. smegmatis in 7H9 medium but also reduced the resistance of M. smegmatis against lysozyme and acidic stress in vitro. Macrophage infection assay showed that ΔM5447 displayed attenuated growth in macrophages at 24 h post-infection. The production of TNF-α and IL-6 and the activation of transcription factor NF-κB were decreased in ΔM5447-infected macrophages, which were further confirmed by transcriptomic analysis. Moreover, ΔM5447 failed to inhibit phagosome–lysosome fusion in macrophages. These findings revealed that PMT played a role in modulating the innate immune responses of the host, which broaden our understanding for functions of protein O-mannosylation in mycobacterium–host interaction.

scholarly journals Great balls of fire: activation and signalling of inflammatory caspases

2021 ◽  
Author(s):  
Georgia Bateman ◽  
Benjamin Hill ◽  
Ryan Knight ◽  
Dave Boucher
Keyword(s):  
Immune Responses ◽  
Inflammatory Cell ◽  
Current Knowledge ◽  
Cysteine Proteases ◽  
Innate Immune ◽  
Caspase Activity ◽  
Innate Immune Responses ◽  
Caspase Activation ◽  
Biochemical Processes ◽  
Inflammatory Caspases

Innate immune responses are tightly regulated by various pathways to control infections and maintain homeostasis. One of these pathways, the inflammasome pathway, activates a family of cysteine proteases called inflammatory caspases. They orchestrate an immune response by cleaving specific cellular substrates. Canonical inflammasomes activate caspase-1, whereas non-canonical inflammasomes activate caspase-4 and -5 in humans and caspase-11 in mice. Caspases are highly specific enzymes that select their substrates through diverse mechanisms. During inflammation, caspase activity is responsible for the secretion of inflammatory cytokines and the execution of a form of lytic and inflammatory cell death called pyroptosis. This review aims to bring together our current knowledge of the biochemical processes behind inflammatory caspase activation, substrate specificity, and substrate signalling.

scholarly journals Innate Immune Responses to Herpesvirus Infection

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2122
Author(s):  
Christine M. O’Connor ◽  
Ganes C. Sen
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Defense Mechanisms ◽  
Innate Immune ◽  
Host Cells ◽  
Innate Immune Responses ◽  
Viral Pathogen ◽  
Dna Viruses ◽  
Host Innate Immune Response ◽  
Human Herpesviruses

Infection of a host cell by an invading viral pathogen triggers a multifaceted antiviral response. One of the most potent defense mechanisms host cells possess is the interferon (IFN) system, which initiates a targeted, coordinated attack against various stages of viral infection. This immediate innate immune response provides the most proximal defense and includes the accumulation of antiviral proteins, such as IFN-stimulated genes (ISGs), as well as a variety of protective cytokines. However, viruses have co-evolved with their hosts, and as such, have devised distinct mechanisms to undermine host innate responses. As large, double-stranded DNA viruses, herpesviruses rely on a multitude of means by which to counter the antiviral attack. Herein, we review the various approaches the human herpesviruses employ as countermeasures to the host innate immune response.

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

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.

scholarly journals Nidovirus papain-like proteases antagonize the host innate immune response

2014 ◽  
Vol 70 (a1) ◽  
pp. C1598-C1598
Author(s):  
Ben Bailey-Elkin ◽  
Puck van Kasteren ◽  
Eric Snijder ◽  
Marjolein Kikkert ◽  
Brian Mark
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Cellular Proteins ◽  
Common Mechanism ◽  
Innate Immune Responses ◽  
Protein Ubiquitination ◽  
Binding Interface ◽  
Host Innate Immune Response

Protein ubiquitination regulates important innate immune responses. Ubiquitin (Ub) can be attached to lysine residues on cellular proteins to promote, among other activities, the innate immune responses of the cell. These pathways can in turn be downregulated by the removal of Ub from cellular proteins by deubiquitinases (DUBs). Viruses of the order Nidovirales have positive-sense, single stranded RNA genomes. Within this order are the families Coronaviridae and Arteriviridae, which include viruses known to cause severe disease in humans and animals, respectively. Members of the families Coronaviridae and Arteriviridae share a common mechanism of gene expression, whereby the viral nonstructural proteins (nsps) are initially expressed as a single polyprotein, which is then cleaved into functional units by papain-like protease (PLP) domains encoded within. Interestingly, while also being necessary for viral replication, a number of Nidovirus PLPs have been shown to remove Ub from host proteins, in order to down-regulate the host innate immune response. Here we present the crystal structure of a Nidovirus PLP in complex with Ub. The structure allowed for the characterization of a Ub-binding interface, and identification of specific residues involved in Ub recognition that are distant from the enzyme active site.  The selective inactivation of DUB activity of viral PLP enzymes verses their polyprotein cleavage activity by site directed mutagenesis is allowing us to understand the role of DUB activity in evading innate immune responses of the host, and opens the door for the development of improved live attenuated vaccines against Nidoviruses and other viruses encoding similar dual specificity proteases.

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