Regulation of Viral Restriction by Post-Translational Modifications

Intrinsic immunity is orchestrated by a wide range of host cellular proteins called restriction factors. They have the capacity to interfere with viral replication, and most of them are tightly regulated by interferons (IFNs). In addition, their regulation through post-translational modifications (PTMs) constitutes a major mechanism to shape their action positively or negatively. Following viral infection, restriction factor modification can be decisive. Palmitoylation of IFITM3, SUMOylation of MxA, SAMHD1 and TRIM5α or glycosylation of BST2 are some of those PTMs required for their antiviral activity. Nonetheless, for their benefit and by manipulating the PTMs machinery, viruses have evolved sophisticated mechanisms to counteract restriction factors. Indeed, many viral proteins evade restriction activity by inducing their ubiquitination and subsequent degradation. Studies on PTMs and their substrates are essential for the understanding of the antiviral defense mechanisms and provide a global vision of all possible regulations of the immune response at a given time and under specific infection conditions. Our aim was to provide an overview of current knowledge regarding the role of PTMs on restriction factors with an emphasis on their impact on viral replication.

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RNA Virus-Encoded miRNAs: Current Insights and Future Challenges

Frontiers in Microbiology ◽

10.3389/fmicb.2021.679210 ◽

2021 ◽

Vol 12 ◽

Author(s):

Asuka Nanbo ◽

Wakako Furuyama ◽

Zhen Lin

Keyword(s):

Viral Replication ◽

Rna Viruses ◽

Current Knowledge ◽

Rna Virus ◽

Transcriptional Level ◽

Emerging Viruses ◽

Wide Range ◽

Future Challenges ◽

Eukaryotic Gene ◽

Potential Applications

MicroRNAs are small non-coding RNAs that regulate eukaryotic gene expression at the post-transcriptional level and affect a wide range of biological processes. Over the past two decades, numerous virus-encoded miRNAs have been identified. Some of them are crucial for viral replication, whereas others can help immune evasion. Recent sequencing-based bioinformatics methods have helped identify many novel miRNAs, which are encoded by RNA viruses. Unlike the well-characterized DNA virus-encoded miRNAs, the role of RNA virus-encoded miRNAs remains controversial. In this review, we first describe the current knowledge of miRNAs encoded by various RNA viruses, including newly emerging viruses. Next, we discuss how RNA virus-encoded miRNAs might facilitate viral replication, immunoevasion, and persistence in their hosts. Last, we briefly discuss the challenges in the experimental methodologies and potential applications of miRNAs for diagnosis and therapeutics.

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Structural Insights into APOBEC3-Mediated Lentiviral Restriction

Viruses ◽

10.3390/v12060587 ◽

2020 ◽

Vol 12 (6) ◽

pp. 587 ◽

Cited By ~ 3

Author(s):

Krista A. Delviks-Frankenberry ◽

Belete A. Desimmie ◽

Vinay K. Pathak

Keyword(s):

Defense Mechanisms ◽

Cytidine Deaminase ◽

Immune Defense ◽

Restriction Factors ◽

Intrinsic Immunity ◽

Viral Pathogens ◽

Cytidine Deaminases ◽

Virion Infectivity Factor ◽

Coordinated Expression ◽

Hiv 1

Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is continuously evolving to expand the repertoire of restriction factors and one such family of intrinsic restriction factors is the APOBEC3 (A3) family of cytidine deaminases. The coordinated expression of seven members of the A3 family of cytidine deaminases provides intrinsic immunity against numerous foreign infectious agents and protects the host from exogenous retroviruses and endogenous retroelements. Four members of the A3 proteins—A3G, A3F, A3H, and A3D—restrict HIV-1 in the absence of virion infectivity factor (Vif); their incorporation into progeny virions is a prerequisite for cytidine deaminase-dependent and -independent activities that inhibit viral replication in the host target cell. HIV-1 encodes Vif, an accessory protein that antagonizes A3 proteins by targeting them for polyubiquitination and subsequent proteasomal degradation in the virus producing cells. In this review, we summarize our current understanding of the role of human A3 proteins as barriers against HIV-1 infection, how Vif overcomes their antiviral activity, and highlight recent structural and functional insights into A3-mediated restriction of lentiviruses.

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Human APOBEC3 Variations and Viral Infection

Viruses ◽

10.3390/v13071366 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1366

Author(s):

Shiva Sadeghpour ◽

Saeideh Khodaee ◽

Mostafa Rahnama ◽

Hamzeh Rahimi ◽

Diako Ebrahimi

Keyword(s):

Defense Mechanisms ◽

Splice Variants ◽

Current Knowledge ◽

Nucleotide Polymorphisms ◽

Mrna Editing ◽

Single Nucleotide ◽

Essential Components ◽

Wide Range ◽

Natural Variations ◽

Hiv 1

Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using deaminase and deaminase-independent mechanisms. These enzymes are essential components of our innate immune system, as evidenced by (a) their strong positive selection and expansion in primates, (b) the evolution of viral counter-defense mechanisms, such as proteasomal degradation mediated by HIV Vif, and (c) hypermutation and inactivation of a large number of integrated HIV-1 proviruses. Numerous APOBEC3 single nucleotide polymorphisms, haplotypes, and splice variants have been identified in humans. Several of these variants have been reported to be associated with differential antiviral immunity. This review focuses on the current knowledge in the field about these natural variations and their roles in infectious diseases.

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Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

International Journal of Molecular Sciences ◽

10.3390/ijms20071636 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1636 ◽

Cited By ~ 11

Author(s):

Tanja Becker ◽

Vu Le-Trilling ◽

Mirko Trilling

Keyword(s):

Drug Targets ◽

Current Knowledge ◽

Antiviral Treatment ◽

Term Therapy ◽

Restriction Factors ◽

Intrinsic Immunity ◽

Host Restriction ◽

Host Restriction Factors ◽

Inhibitory Compound ◽

Long Term Therapy

Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise in patients receiving long-term therapy. Additionally, side effects and the risk to cause birth defects limit the use of currently approved antivirals against HCMV. Therefore, the identification of new drug targets is of clinical relevance. Recent work identified DNA-damage binding protein 1 (DDB1) and the family of the cellular cullin (Cul) RING ubiquitin (Ub) ligases (CRLs) as host-derived factors that are relevant for the replication of human and mouse cytomegaloviruses. The first-in-class CRL inhibitory compound Pevonedistat (also called MLN4924) is currently under investigation as an anti-tumor drug in several clinical trials. Cytomegaloviruses exploit CRLs to regulate the abundance of viral proteins, and to induce the proteasomal degradation of host restriction factors involved in innate and intrinsic immunity. Accordingly, pharmacological blockade of CRL activity diminishes viral replication in cell culture. In this review, we summarize the current knowledge concerning the relevance of DDB1 and CRLs during cytomegalovirus replication and discuss chances and drawbacks of CRL inhibitory drugs as potential antiviral treatment against HCMV.

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Fitness of Herbicide-Resistant Weeds: Current Knowledge and Implications for Management

Plants ◽

10.3390/plants8110469 ◽

2019 ◽

Vol 8 (11) ◽

pp. 469 ◽

Cited By ~ 5

Author(s):

Vila-Aiub

Keyword(s):

Life History ◽

Herbicide Resistance ◽

Management Practices ◽

Current Knowledge ◽

Resistance Management ◽

Fitness Cost ◽

Plant Fitness ◽

Resistance Mutations ◽

Fitness Costs ◽

Wide Range

Herbicide resistance is the ultimate evidence of the extraordinary capacity of weeds to evolve under stressful conditions. Despite the extraordinary plant fitness advantage endowed by herbicide resistance mutations in agroecosystems under herbicide selection, resistance mutations are predicted to exhibit an adaptation cost (i.e., fitness cost), relative to the susceptible wild-type, in herbicide untreated conditions. Fitness costs associated with herbicide resistance mutations are not universal and their expression depends on the particular mutation, genetic background, dominance of the fitness cost, and environmental conditions. The detrimental effects of herbicide resistance mutations on plant fitness may arise as a direct impact on fitness-related traits and/or coevolution with changes in other life history traits that ultimately may lead to fitness costs under particular ecological conditions. This brings the idea that a “lower adaptive value” of herbicide resistance mutations represents an opportunity for the design of resistance management practices that could minimize the evolution of herbicide resistance. It is evident that the challenge for weed management practices aiming to control, minimize, or even reverse the frequency of resistance mutations in the agricultural landscape is to “create” those agroecological conditions that could expose, exploit, and exacerbate those life history and/or fitness traits affecting the evolution of herbicide resistance mutations. Ideally, resistance management should implement a wide range of cultural practices leading to environmentally mediated fitness costs associated with herbicide resistance mutations.

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Transfer of Plasmid DNA to Clinical Coagulase-Negative Staphylococcal Pathogens by Using a Unique Bacteriophage

Applied and Environmental Microbiology ◽

10.1128/aem.04190-14 ◽

2015 ◽

Vol 81 (7) ◽

pp. 2481-2488 ◽

Cited By ~ 19

Author(s):

Volker Winstel ◽

Petra Kühner ◽

Bernhard Krismer ◽

Andreas Peschel ◽

Holger Rohde

Keyword(s):

Plasmid Dna ◽

Genetic Manipulation ◽

Current Knowledge ◽

Virulence Determinants ◽

Coagulase Negative Staphylococci ◽

Reliable Technique ◽

Content Type ◽

Research Activities ◽

Wide Range ◽

Genetic Barriers

ABSTRACTGenetic manipulation of emerging bacterial pathogens, such as coagulase-negative staphylococci (CoNS), is a major hurdle in clinical and basic microbiological research. Strong genetic barriers, such as restriction modification systems or clustered regularly interspaced short palindromic repeats (CRISPR), usually interfere with available techniques for DNA transformation and therefore complicate manipulation of CoNS or render it impossible. Thus, current knowledge of pathogenicity and virulence determinants of CoNS is very limited. Here, a rapid, efficient, and highly reliable technique is presented to transfer plasmid DNA essential for genetic engineering to important CoNS pathogens from a uniqueStaphylococcus aureusstrain via a specificS. aureusbacteriophage, Φ187. Even strains refractory to electroporation can be transduced by this technique once donor and recipient strains share similar Φ187 receptor properties. As a proof of principle, this technique was used to delete the alternative transcription factor sigma B (SigB) via allelic replacement in nasal and clinicalStaphylococcus epidermidisisolates at high efficiencies. The described approach will allow the genetic manipulation of a wide range of CoNS pathogens and might inspire research activities to manipulate other important pathogens in a similar fashion.

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Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

Viruses ◽

10.3390/v13050784 ◽

2021 ◽

Vol 13 (5) ◽

pp. 784

Author(s):

Solène Lerolle ◽

Natalia Freitas ◽

François-Loïc Cosset ◽

Vincent Legros

Keyword(s):

Host Cell ◽

Viral Entry ◽

Current Knowledge ◽

Restriction Factors ◽

Antiviral State ◽

Cellular Factors ◽

Pathogenic Viruses ◽

Genome Transcription ◽

Infected Cells ◽

Molecular Patterns

The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.

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Molecular Subtyping of Blastocystis sp. Isolated from Farmed Animals in Southern Italy

Microorganisms ◽

10.3390/microorganisms9081656 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1656

Author(s):

Simona Gabrielli ◽

Marialetizia Palomba ◽

Federica Furzi ◽

Emanuele Brianti ◽

Gabriella Gaglio ◽

...

Keyword(s):

Current Knowledge ◽

Pcr Amplification ◽

Epidemiological Studies ◽

Fallow Deer ◽

Small Subunit ◽

Zoonotic Transmission ◽

Ssu Rrna ◽

Molecular Approaches ◽

Wide Range ◽

Blastocystis Sp

Blastocystis is a common intestinal protist distributed worldwide, infecting humans and a wide range of domestic and wild animals. It exhibits an extensive genetic diversity and, so far, 25 distinct small subunit ribosomal RNA (SSU rRNA) lineages termed subtypes (STs)) have been characterized; among them, 12 have thus far been reported in humans. The aims of the present study were to detect and genetically characterize Blastocystis sp. in synantropic animals to improve our current knowledge on the distribution and zoonotic transmission of Blastocystis STs in Italy. Samples were collected from N = 193 farmed animals and submitted to DNA extraction and PCR amplification of the SSU rRNA. Blastocystis was detected in 60 samples (31.08%) and successfully subtyped. Phylogenetic analysis evidenced that the isolates from fallow deer, goats, and pigs (N = 9) clustered within the ST5; those from pheasants (N = 2) in the ST6; those from chickens (N = 8) in the ST7; those from sheep (N = 6) in the ST10; and those from water buffaloes (N = 9) in the ST14 clade. The comparison between the present isolates from animals and those previously detected in humans in Italy suggested the animal-to-human spillover for ST6 and ST7. The present study represents the widest Blastocystis survey performed thus far in farmed animals in Italy. Further epidemiological studies using molecular approaches are required to determine the occurrence and distribution of Blastocystis STs in other potential animal reservoirs in Italy and to define the pathways of zoonotic transmission.

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Recent Development on Plant Aldehyde Dehydrogenase Enzymes and Their Functions in Plant Development and Stress Signaling

Genes ◽

10.3390/genes12010051 ◽

2020 ◽

Vol 12 (1) ◽

pp. 51

Author(s):

Adesola J. Tola ◽

Amal Jaballi ◽

Hugo Germain ◽

Tagnon D. Missihoun

Keyword(s):

Plant Development ◽

Critical Analysis ◽

Current Knowledge ◽

Stress Signaling ◽

Oxygen Species ◽

Abiotic And Biotic Stresses ◽

Aldehyde Dehydrogenases ◽

Biotic Stresses ◽

Wide Range ◽

Excessive Accumulation

Abiotic and biotic stresses induce the formation of reactive oxygen species (ROS), which subsequently causes the excessive accumulation of aldehydes in cells. Stress-derived aldehydes are commonly designated as reactive electrophile species (RES) as a result of the presence of an electrophilic α, β-unsaturated carbonyl group. Aldehyde dehydrogenases (ALDHs) are NAD(P)+-dependent enzymes that metabolize a wide range of endogenous and exogenous aliphatic and aromatic aldehyde molecules by oxidizing them to their corresponding carboxylic acids. The ALDH enzymes are found in nearly all organisms, and plants contain fourteen ALDH protein families. In this review, we performed a critical analysis of the research reports over the last decade on plant ALDHs. Newly discovered roles for these enzymes in metabolism, signaling and development have been highlighted and discussed. We concluded with suggestions for future investigations to exploit the potential of these enzymes in biotechnology and to improve our current knowledge about these enzymes in gene signaling and plant development.

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Sporulation in solventogenic and acetogenic clostridia

Applied Microbiology and Biotechnology ◽

10.1007/s00253-021-11289-9 ◽

2021 ◽

Author(s):

Mamou Diallo ◽

Servé W. M. Kengen ◽

Ana M. López-Contreras

Keyword(s):

Current Knowledge ◽

Carbon Sources ◽

Cost Effective ◽

Biotechnological Production ◽

Key Points ◽

Wide Range ◽

Potential Applications ◽

A Cell ◽

Sporulation Initiation ◽

Solventogenic Clostridia

AbstractThe Clostridium genus harbors compelling organisms for biotechnological production processes; while acetogenic clostridia can fix C1-compounds to produce acetate and ethanol, solventogenic clostridia can utilize a wide range of carbon sources to produce commercially valuable carboxylic acids, alcohols, and ketones by fermentation. Despite their potential, the conversion by these bacteria of carbohydrates or C1 compounds to alcohols is not cost-effective enough to result in economically viable processes. Engineering solventogenic clostridia by impairing sporulation is one of the investigated approaches to improve solvent productivity. Sporulation is a cell differentiation process triggered in bacteria in response to exposure to environmental stressors. The generated spores are metabolically inactive but resistant to harsh conditions (UV, chemicals, heat, oxygen). In Firmicutes, sporulation has been mainly studied in bacilli and pathogenic clostridia, and our knowledge of sporulation in solvent-producing or acetogenic clostridia is limited. Still, sporulation is an integral part of the cellular physiology of clostridia; thus, understanding the regulation of sporulation and its connection to solvent production may give clues to improve the performance of solventogenic clostridia. This review aims to provide an overview of the triggers, characteristics, and regulatory mechanism of sporulation in solventogenic clostridia. Those are further compared to the current knowledge on sporulation in the industrially relevant acetogenic clostridia. Finally, the potential applications of spores for process improvement are discussed.Key Points• The regulatory network governing sporulation initiation varies in solventogenic clostridia.• Media composition and cell density are the main triggers of sporulation.• Spores can be used to improve the fermentation process.

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