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

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

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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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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Pathogenic Biohacking: Induction, Modulation and Subversion of Host Transcriptional Responses by Listeria monocytogenes

Toxins ◽

10.3390/toxins12050294 ◽

2020 ◽

Vol 12 (5) ◽

pp. 294

Author(s):

Matthew J. G. Eldridge ◽

Pascale Cossart ◽

Mélanie A. Hamon

Keyword(s):

Gene Expression ◽

Listeria Monocytogenes ◽

Virulence Factors ◽

Bacterial Pathogen ◽

Typical Feature ◽

Host Gene ◽

Host Cells ◽

Host Gene Expression ◽

Transcriptional Responses ◽

The Impact

During infection, the foodborne bacterial pathogen Listeria monocytogenes dynamically influences the gene expression profile of host cells. Infection-induced transcriptional changes are a typical feature of the host-response to bacteria and contribute to the activation of protective genes such as inflammatory cytokines. However, by using specialized virulence factors, bacterial pathogens can target signaling pathways, transcription factors, and epigenetic mechanisms to alter host gene expression, thereby reprogramming the response to infection. Therefore, the transcriptional profile that is established in the host is delicately balanced between antibacterial responses and pathogenesis, where any change in host gene expression might significantly influence the outcome of infection. In this review, we discuss the known transcriptional and epigenetic processes that are engaged during Listeria monocytogenes infection, the virulence factors that can remodel them, and the impact these processes have on the outcome of infection.

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Serum Response Factor Regulates Immediate Early Host Gene Expression in Toxoplasma gondii-Infected Host Cells

PLoS ONE ◽

10.1371/journal.pone.0018335 ◽

2011 ◽

Vol 6 (3) ◽

pp. e18335 ◽

Cited By ~ 11

Author(s):

Mandi Wiley ◽

Crystal Teygong ◽

Eric Phelps ◽

Jay Radke ◽

Ira J. Blader

Keyword(s):

Gene Expression ◽

Toxoplasma Gondii ◽

Serum Response Factor ◽

Host Gene ◽

Host Cells ◽

Immediate Early ◽

Infected Host ◽

Response Factor ◽

Host Gene Expression ◽

Serum Response

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Host Gene Expression of Macrophages in Response to Feline Coronavirus Infection

Cells ◽

10.3390/cells9061431 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1431 ◽

Cited By ~ 1

Author(s):

Yvonne Drechsler ◽

Elton J. R. Vasconcelos ◽

Lisa M. Griggs ◽

Pedro P. P. V. Diniz ◽

Ellen Collisson

Keyword(s):

Gene Expression ◽

Viral Infections ◽

Ex Vivo ◽

Host Gene ◽

Host Responses ◽

Host Gene Expression ◽

Feline Infectious Peritonitis ◽

Host Immune Responses ◽

Individual Host ◽

Feline Coronavirus

Feline coronavirus is a highly contagious virus potentially resulting in feline infectious peritonitis (FIP), while the pathogenesis of FIP remains not well understood, particularly in the events leading to the disease. A predominant theory is that the pathogenic FIPV arises from a mutation, so that it could replicate not only in enterocytes of the intestines but also in monocytes, subsequently systemically transporting the virus. The immune status and genetics of affected cats certainly play an important role in the pathogenesis. Considering the importance of genetics and host immune responses in viral infections, the goal of this study was to elucidate host gene expression in macrophages using RNA sequencing. Macrophages from healthy male cats infected with FIPV 79-1146 ex vivo displayed a differential host gene expression. Despite the virus uptake, aligned viral reads did not increase from 2 to 17 h. The overlap of host gene expression among macrophages from different cats was limited, even though viral transcripts were detected in the cells. Interestingly, some of the downregulated genes in all macrophages were involved in immune signaling, while some upregulated genes common for all cats were found to be inhibiting immune activation. Our results highlight individual host responses playing an important role, consistent with the fact that few cats develop feline infectious peritonitis despite a common presence of enteric FCoV.

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Cytopathogenesis and Inhibition of Host Gene Expression by RNA Viruses

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.64.4.709-724.2000 ◽

2000 ◽

Vol 64 (4) ◽

pp. 709-724 ◽

Cited By ~ 119

Author(s):

Douglas S. Lyles

Keyword(s):

Gene Expression ◽

Host Cell ◽

Rna Viruses ◽

Antiviral Response ◽

Influenza Viruses ◽

Host Gene ◽

Host Gene Expression ◽

Virus Infections ◽

Cytopathic Effects ◽

Host Antiviral Response

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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Gut Microbiota Has a Widespread and Modifiable Effect on Host Gene Regulation

mSystems ◽

10.1128/msystems.00323-18 ◽

2019 ◽

Vol 4 (5) ◽

Cited By ~ 18

Author(s):

Allison L. Richards ◽

Amanda L. Muehlbauer ◽

Adnan Alazizi ◽

Michael B. Burns ◽

Anthony Findley ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Gut Microbiota ◽

Complex Traits ◽

Chromatin Accessibility ◽

Host Gene ◽

Host Cells ◽

Host Gene Expression ◽

Host Genes

ABSTRACT Variation in gut microbiome is associated with wellness and disease in humans, and yet the molecular mechanisms by which this variation affects the host are not well understood. A likely mechanism is that of changing gene regulation in interfacing host epithelial cells. Here, we treated colonic epithelial cells with live microbiota from five healthy individuals and quantified induced changes in transcriptional regulation and chromatin accessibility in host cells. We identified over 5,000 host genes that change expression, including 588 distinct associations between specific taxa and host genes. The taxa with the strongest influence on gene expression alter the response of genes associated with complex traits. Using ATAC-seq, we showed that a subset of these changes in gene expression are associated with changes in host chromatin accessibility and transcription factor binding induced by exposure to gut microbiota. We then created a manipulated microbial community with titrated doses of Collinsella, demonstrating that manipulation of the composition of the microbiome under both natural and controlled conditions leads to distinct and predictable gene expression profiles in host cells. Taken together, our results suggest that specific microbes play an important role in regulating expression of individual host genes involved in human complex traits. The ability to fine-tune the expression of host genes by manipulating the microbiome suggests future therapeutic routes. IMPORTANCE The composition of the gut microbiome has been associated with various aspects of human health, but the mechanism of this interaction is still unclear. We utilized a cellular system to characterize the effect of the microbiome on human gene expression. We showed that some of these changes in expression may be mediated by changes in chromatin accessibility. Furthermore, we validate the role of a specific microbe and show that changes in its abundance can modify the host gene expression response. These results show an important role of gut microbiota in regulating host gene expression and suggest that manipulation of microbiome composition could be useful in future therapies.

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