Cytopathogenesis and Inhibition of Host Gene Expression by RNA Viruses

SUMMARY Many viruses interfere with host cell function in ways that are harmful or pathological. This often results in changes in cell morphology referred to as cytopathic effects. However, pathogenesis of virus infections also involves inhibition of host cell gene expression. Thus the term “cytopathogenesis,” or pathogenesis at the cellular level, is meant to be broader than the term “cytopathic effects” and includes other cellular changes that contribute to viral pathogenesis in addition to those changes that are visible at the microscopic level. The goal of this review is to place recent work on the inhibition of host gene expression by RNA viruses in the context of the pathogenesis of virus infections. Three different RNA virus families, picornaviruses, influenza viruses, and rhabdoviruses, are used to illustrate common principles involved in cytopathogenesis. These examples were chosen because viral gene products responsible for inhibiting host gene expression have been identified, as have some of the molecular targets of the host. The argument is made that the role of the virus-induced inhibition of host gene expression is to inhibit the host antiviral response, such as the response to double-stranded RNA. Viral cytopathogenesis is presented as a balance between the host antiviral response and the ability of viruses to inhibit that response through the overall inhibition of host gene expression. This balance is a major determinant of viral tissue tropism in infections of intact animals.

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Genome Wide Host Gene Expression Analysis in Chicken Lungs Infected with Avian Influenza Viruses

PLoS ONE ◽

10.1371/journal.pone.0153671 ◽

2016 ◽

Vol 11 (4) ◽

pp. e0153671 ◽

Cited By ~ 37

Author(s):

Pradip B. Ranaware ◽

Anamika Mishra ◽

Periyasamy Vijayakumar ◽

Pradeep N. Gandhale ◽

Himanshu Kumar ◽

...

Keyword(s):

Gene Expression ◽

Avian Influenza ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Influenza Viruses ◽

Host Gene ◽

Host Gene Expression ◽

Avian Influenza Viruses ◽

Genome Wide

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Identification of amino acid residues required for inhibition of host gene expression by influenza A/Viet Nam/1203/2004 H5N1 PA-X

Journal of Virology ◽

10.1128/jvi.00408-21 ◽

2021 ◽

Cited By ~ 1

Author(s):

Kevin Chiem ◽

Darío López-García ◽

Javier Ortego ◽

Luis Martinez-Sobrido ◽

Marta L. DeDiego ◽

...

Keyword(s):

Gene Expression ◽

Amino Acid ◽

Influenza A ◽

Influenza Viruses ◽

Host Gene ◽

Viet Nam ◽

Amino Acid Residues ◽

Host Gene Expression ◽

X Protein ◽

Identify Amino Acid

PA-X is a non-structural protein of influenza A virus (IAV), which is encoded by the polymerase acidic (PA) N-terminal region that contains a C-terminal +1 frameshifted sequence. IAV PA-X protein modulates virus-induced host innate immune responses and viral pathogenicity via suppression of host gene expression or cellular shutoff, through cellular mRNA cleavage. Highly pathogenic avian influenza viruses (HPAIV) of the H5N1 subtype naturally infect different avian species, they have an enormous economic impact in the poultry farming, and they also have zoonotic and pandemic potential, representing a risk to human public health. In the present study, we describe a novel bacteria-based approach to identify amino acid residues in the PA-X protein of the HPAIV A/Viet Nam/1203/2004 H5N1 that are important for its ability to inhibit host protein expression or cellular shutoff activity. Identified PA-X mutants displayed a reduced shutoff activity as compared to that of the wild-type (WT) A/Viet Nam/1203/2004 H5N1 PA-X protein. Notably, this new bacteria-based screening allowed us to identify amino acid residues widely distributed over the entire N-terminal region of PA-X. Furthermore, we found that some of the residues affecting A/Viet Nam/1203/2004 H5N1 PA-X host shutoff activity also affect PA polymerase activity in a minigenome assay. This information could be used for the rational design of new and more effective compounds with antiviral activity against IAV. Moreover, our results demonstrate the feasibility of using this bacteria-based approach to identify amino acid residues important for the activity of viral proteins to inhibit host gene expression. IMPORTANCE Highly pathogenic avian influenza viruses (HPAIV) continue to pose a huge threat to global animal and human health. Despite of the limited genome size of Influenza A virus (IAV), the virus encodes eight main viral structural proteins and multiple accessory non-structural proteins, depending on the IAV type, subtype or strain. One of the IAV accessory proteins, PA-X, is encoded by the polymerase acidic (PA) protein and is involved in pathogenicity through the modulation of IAV-induced host inflammatory and innate immune responses. However, the molecular mechanism(s) of IAV PA-X regulation of the host immune response is not well understood. In this work, we used, for the first time, a bacteria-based approach for the identification of amino acids important for the ability of IAV PA-X to induce host shutoff activity and describe novel residues relevant for its ability to inhibit host gene expression, and their contribution in PA polymerase activity.

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Differential host gene expression in cells infected with highly pathogenic H5N1 avian influenza viruses

Veterinary Immunology and Immunopathology ◽

10.1016/j.vetimm.2008.05.021 ◽

2008 ◽

Vol 125 (3-4) ◽

pp. 291-302 ◽

Cited By ~ 28

Author(s):

Luciana Sarmento ◽

Claudio L. Afonso ◽

Carlos Estevez ◽

Jamie Wasilenko ◽

Mary Pantin-Jackwood

Keyword(s):

Gene Expression ◽

Avian Influenza ◽

Influenza Viruses ◽

Host Gene ◽

Host Gene Expression ◽

Avian Influenza Viruses ◽

Highly Pathogenic ◽

Differential Host ◽

H5n1 Avian Influenza ◽

Pathogenic H5n1

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The K186E Amino Acid Substitution in the Canine Influenza Virus H3N8 NS1 Protein Restores Its Ability To Inhibit Host Gene Expression

Journal of Virology ◽

10.1128/jvi.00877-17 ◽

2017 ◽

Vol 91 (22) ◽

Cited By ~ 9

Author(s):

Aitor Nogales ◽

Caroline Chauché ◽

Marta L. DeDiego ◽

David J. Topham ◽

Colin R. Parrish ◽

...

Keyword(s):

Gene Expression ◽

Amino Acid ◽

Immune Responses ◽

Influenza Viruses ◽

Innate Immune ◽

Host Gene ◽

Innate Immune Responses ◽

Host Gene Expression ◽

Avian Origin ◽

Canine Influenza

ABSTRACT Canine influenza viruses (CIVs) are the causative agents of canine influenza, a contagious respiratory disease in dogs, and include the equine-origin H3N8 and the avian-origin H3N2 viruses. Influenza A virus (IAV) nonstructural protein 1 (NS1) is a virulence factor essential for counteracting the innate immune response. Here, we evaluated the ability of H3N8 CIV NS1 to inhibit host innate immune responses. We found that H3N8 CIV NS1 was able to efficiently counteract interferon (IFN) responses but was unable to block general gene expression in human or canine cells. Such ability was restored by a single amino acid substitution in position 186 (K186E) that resulted in NS1 binding to the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), a cellular protein involved in pre-mRNA processing. We also examined the frequency distribution of K186 and E186 among H3N8 CIVs and equine influenza viruses (EIVs), the ancestors of H3N8 CIV, and experimentally determined the impact of amino acid 186 in the ability of different CIV and EIV NS1s to inhibit general gene expression. In all cases, the presence of E186 was responsible for the control of host gene expression. In contrast, the NS1 protein of H3N2 CIV harbors E186 and blocks general gene expression in canine cells. Altogether, our results confirm previous studies on the strain-dependent ability of NS1 to block general gene expression. Moreover, the observed polymorphism on amino acid 186 between H3N8 and H3N2 CIVs might be the result of adaptive changes acquired during long-term circulation of avian-origin IAVs in mammals. IMPORTANCE Canine influenza is a respiratory disease of dogs caused by two CIV subtypes, the H3N8 and H3N2 viruses, of equine and avian origins, respectively. Influenza NS1 is the main viral factor responsible for the control of host innate immune responses, and changes in NS1 can play an important role in host adaptation. Here we assessed the ability of H3N8 CIV NS1 to inhibit host innate immune responses and gene expression. The H3N8 CIV NS1 did not block host gene expression, but this activity was restored by a single amino acid substitution (K186E), which was responsible for NS1 binding to the host factor CPSF30. In contrast, the H3N2 CIV NS1, which contains E186, blocks general gene expression. Our results suggest that the ability to block host gene expression is not required for influenza virus replication in mammals but might be important in the long-term adaptation of avian-origin influenza viruses to mammals.

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Genome wide host gene expression analysis in chicken lungs infected with avian influenza viruses

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2016.02.218 ◽

2016 ◽

Vol 45 ◽

pp. 78

Author(s):

P.B. Ranaware ◽

A. Mishra ◽

P. vijayakumar ◽

P.N. Gandhale ◽

S.B. Sudhakar ◽

...

Keyword(s):

Gene Expression ◽

Avian Influenza ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Influenza Viruses ◽

Host Gene ◽

Host Gene Expression ◽

Avian Influenza Viruses ◽

Genome Wide

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Simultaneous ribosome profiling of human host cells infected with Toxoplasma gondii

10.1101/619916 ◽

2019 ◽

Author(s):

Michael J. Holmes ◽

Premal Shah ◽

Ronald C. Wek ◽

William J. Sullivan

Keyword(s):

Gene Expression ◽

Toxoplasma Gondii ◽

Host Cell ◽

Translational Control ◽

Ribosome Profiling ◽

Host Gene ◽

Host Cells ◽

Host Gene Expression ◽

Quiescent Cells ◽

Study Gene Expression

AbstractToxoplasma gondii is a ubiquitous obligate intracellular parasite that infects the nucleated cells of warm-blooded animals. From within the parasitophorous vacuole in which they reside, Toxoplasma tachyzoites secrete an arsenal of effector proteins that can reprogram host gene expression to facilitate parasite survival and replication. Gaining a better understanding of how host gene expression is altered upon infection is central for understanding parasite strategies for host invasion and for developing new parasite therapies. Here, we applied ribosome profiling coupled with mRNA measurements to concurrently study gene expression in the parasite and in host human foreskin fibroblasts. By examining the parasite transcriptome and translatome, we identified potential upstream open reading frames that may permit the stress-induced preferential translation of parasite mRNAs. We also determined that tachyzoites reduce host death-associated pathways and increase survival, proliferation, and motility in both quiescent and proliferative host cell models of infection. Additionally, proliferative cells alter their gene expression in ways consistent with massive transcriptional rewiring while quiescent cells were best characterized by re-entry into the cell cycle. We also identified a translational control regimen consistent with mTOR activation in quiescent cells, and to a lesser degree in proliferative cells. This study illustrates the utility of the method for dissection of gene expression programs simultaneously in parasite and host.ImportanceToxoplasma gondii is a single-celled parasite that has infected up to one-third of the world’s population. Significant overhauls in gene expression in both the parasite and the host cell accompany parasite invasion, and a better understanding of these changes may lead to the development of new therapeutic agents. In this study, we employed ribosome profiling to determine the changes that occur at the levels of transcription and translation in both the parasite and the infected host cell at the same time. We discovered features of Toxoplasma mRNAs that suggest a means for controlling parasite gene expression under stressful conditions. We also show that differences in host gene expression occur depending on whether they are confluent or not. Our findings demonstrate the feasibility of using ribosomal profiling to interrogate the host-parasite dynamic under a variety of conditions.

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From Gene to Protein—How Bacterial Virulence Factors Manipulate Host Gene Expression During Infection

International Journal of Molecular Sciences ◽

10.3390/ijms21103730 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3730 ◽

Cited By ~ 1

Author(s):

Lea Denzer ◽

Horst Schroten ◽

Christian Schwerk

Keyword(s):

Gene Expression ◽

Host Cell ◽

Host Gene ◽

Host Cells ◽

Host Gene Expression ◽

Protein Activation ◽

Virulence Proteins ◽

Mrna Stabilization ◽

Host Immune Responses ◽

Bacterial Effectors

Bacteria evolved many strategies to survive and persist within host cells. Secretion of bacterial effectors enables bacteria not only to enter the host cell but also to manipulate host gene expression to circumvent clearance by the host immune response. Some effectors were also shown to evade the nucleus to manipulate epigenetic processes as well as transcription and mRNA procession and are therefore classified as nucleomodulins. Others were shown to interfere downstream with gene expression at the level of mRNA stability, favoring either mRNA stabilization or mRNA degradation, translation or protein stability, including mechanisms of protein activation and degradation. Finally, manipulation of innate immune signaling and nutrient supply creates a replicative niche that enables bacterial intracellular persistence and survival. In this review, we want to highlight the divergent strategies applied by intracellular bacteria to evade host immune responses through subversion of host gene expression via bacterial effectors. Since these virulence proteins mimic host cell enzymes or own novel enzymatic functions, characterizing their properties could help to understand the complex interactions between host and pathogen during infections. Additionally, these insights could propose potential targets for medical therapy.

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Simultaneous Ribosome Profiling of Human Host Cells Infected with Toxoplasma gondii

mSphere ◽

10.1128/msphere.00292-19 ◽

2019 ◽

Vol 4 (3) ◽

Cited By ~ 6

Author(s):

Michael J. Holmes ◽

Premal Shah ◽

Ronald C. Wek ◽

William J. Sullivan

Keyword(s):

Gene Expression ◽

Toxoplasma Gondii ◽

Host Cell ◽

Ribosome Profiling ◽

Host Gene ◽

Host Cells ◽

Host Gene Expression ◽

Content Type ◽

Quiescent Cells ◽

Study Gene Expression

ABSTRACT Toxoplasma gondii is a ubiquitous obligate intracellular parasite that infects the nucleated cells of warm-blooded animals. From within the parasitophorous vacuole in which they reside, Toxoplasma tachyzoites secrete an arsenal of effector proteins that can reprogram host gene expression to facilitate parasite survival and replication. Gaining a better understanding of how host gene expression is altered upon infection is central for understanding parasite strategies for host invasion and for developing new parasite therapies. Here, we applied ribosome profiling coupled with mRNA measurements to concurrently study gene expression in the parasite and in host human foreskin fibroblasts. By examining the parasite transcriptome and translatome, we identified potential upstream open reading frames that may permit the stress-induced preferential translation of parasite mRNAs. We also determined that tachyzoites reduce host death-associated pathways and increase survival, proliferation, and motility in both quiescent and proliferative host cell models of infection. Additionally, proliferative cells alter their gene expression in ways that are consistent with massive transcriptional rewiring, while quiescent cells were best characterized by reentry into the cell cycle. We also identified a translational control regimen consistent with mechanistic target of rapamycin (mTOR) activation in quiescent cells and, to a lesser degree, in proliferative cells. This study illustrates the utility of the method for dissection of gene expression programs simultaneously in the parasite and host. IMPORTANCE Toxoplasma gondii is a single-celled parasite that has infected up to one-third of the world’s population. Significant overhauls in gene expression in both the parasite and the host cell accompany parasite invasion, and a better understanding of these changes may lead to the development of new therapeutic agents. In this study, we employed ribosome profiling to determine the changes that occur at the levels of transcription and translation in both the parasite and the infected host cell at the same time. We discovered features of Toxoplasma mRNAs that suggest a means for controlling parasite gene expression under stressful conditions. We also show that differences in host gene expression occur depending on whether they are confluent or not. Our findings demonstrate the feasibility of using ribosomal profiling to interrogate the host-parasite dynamic under a variety of conditions.

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