Identification of Genes Involved in the Host Response to Neurovirulent Alphavirus Infection

ABSTRACT Single-amino-acid mutations in Sindbis virus proteins can convert clinically silent encephalitis into uniformly lethal disease. However, little is known about the host gene response during avirulent and virulent central nervous system (CNS) infections. To identify candidate host genes that modulate alphavirus neurovirulence, we utilized GeneChip Expression analysis to compare CNS gene expression in mice infected with two strains of Sindbis virus that differ by one amino acid in the E2 envelope glycoprotein. Infection with Sindbis virus, dsTE12H (E2-55 HIS), resulted in 100% mortality in 10-day-old mice, whereas no disease was observed in mice infected with dsTE12Q (E2-55 GLN). dsTE12H, compared with dsTE12Q, replicated to higher titers in mouse brain and induced more CNS apoptosis. Infection with the neurovirulent dsTE12H strain was associated with both a greater number of host genes with increased expression and greater changes in levels of host gene expression than was infection with the nonvirulent dsTE12Q strain. In particular, dsTE12H infection resulted in greater increases in the levels of mRNAs encoding chemokines, proteins involved in antigen presentation and protein degradation, complement proteins, interferon-regulated proteins, and mitochondrial proteins. At least some of these increases may be beneficial for the host, as evidenced by the demonstration that enforced expression of the antiapoptotic mitochondrial protein peripheral benzodiazepine receptor (PBR) protects neonatal mice against lethal Sindbis virus infection. Thus, our findings identify specific host genes that may play a role in the host protective or pathologic response to neurovirulent Sindbis virus infection.

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Faculty Opinions recommendation of Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718116186.793484231 ◽

2014 ◽

Author(s):

Lars Malmstroem

Keyword(s):

Gene Expression ◽

Amino Acid ◽

Regulatory Protein ◽

Single Amino Acid ◽

Naturally Occurring

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Genetic Variation and Evolution of the 2019 Novel Coronavirus

Public Health Genomics ◽

10.1159/000513530 ◽

2021 ◽

pp. 1-13

Author(s):

Salvatore Dimonte ◽

Muhammed Babakir-Mina ◽

Taib Hama-Soor ◽

Salar Ali

Keyword(s):

Amino Acid ◽

Receptor Binding ◽

Rapid Evolution ◽

Single Amino Acid ◽

Angiotensin Converting Enzyme 2 ◽

New Type ◽

Amino Acid Mutations ◽

Host Infection ◽

Human Coronaviruses ◽

Novel Coronavirus

Introduction: SARS-CoV-2 is a new type of coronavirus causing a pandemic severe acute respiratory syndrome (SARS-2). Coronaviruses are very diverting genetically and mutate so often periodically. The natural selection of viral mutations may cause host infection selectivity and infectivity. Methods: This study was aimed to indicate the diversity between human and animal coronaviruses through finding the rate of mutation in each of the spike, nucleocapsid, envelope, and membrane proteins. Results: The mutation rate is abundant in all 4 structural proteins. The most number of statistically significant amino acid mutations were found in spike receptor-binding domain (RBD) which may be because it is responsible for a corresponding receptor binding in a broad range of hosts and host selectivity to infect. Among 17 previously known amino acids which are important for binding of spike to angiotensin-converting enzyme 2 (ACE2) receptor, all of them are conservative among human coronaviruses, but only 3 of them significantly are mutated in animal coronaviruses. A single amino acid aspartate-454, that causes dissociation of the RBD of the spike and ACE2, and F486 which gives the strength of binding with ACE2 remain intact in all coronaviruses. Discussion/Conclusion: Observations of this study provided evidence of the genetic diversity and rapid evolution of SARS-CoV-2 as well as other human and animal coronaviruses.

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Structural assessment of single amino acid mutations: application to TP53 function

Human Mutation ◽

10.1002/humu.20379 ◽

2006 ◽

Vol 27 (9) ◽

pp. 926-937 ◽

Cited By ~ 11

Author(s):

Yum L. Yip ◽

Vincent Zoete ◽

Holger Scheib ◽

Olivier Michielin

Keyword(s):

Amino Acid ◽

Single Amino Acid ◽

Structural Assessment ◽

Amino Acid Mutations

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Age-Dependent Resistance to Lethal Alphavirus Encephalitis in Mice: Analysis of Gene Expression in the Central Nervous System and Identification of a Novel Interferon-Inducible Protective Gene, Mouse ISG12

Journal of Virology ◽

10.1128/jvi.76.22.11688-11703.2002 ◽

2002 ◽

Vol 76 (22) ◽

pp. 11688-11703 ◽

Cited By ~ 82

Author(s):

Lucia Labrada ◽

Xiao Huan Liang ◽

Wei Zheng ◽

Christine Johnston ◽

Beth Levine

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

Virus Infection ◽

Sindbis Virus ◽

Expressed Sequence Tag ◽

Severe Disease ◽

Altered Expression ◽

Age Dependent ◽

Old Mice

ABSTRACT Several different mammalian neurotropic viruses produce an age-dependent encephalitis characterized by more severe disease in younger hosts. To elucidate potential factors that contribute to age-dependent resistance to lethal viral encephalitis, we compared central nervous system (CNS) gene expression in neonatal and weanling mice that were either mock infected or infected intracerebrally with a recombinant strain, dsTE12Q, of the prototype alphavirus Sindbis virus. In 1-day-old mice, infection with dsTE12Q resulted in rapidly fatal disease associated with high CNS viral titers and extensive CNS apoptosis, whereas in 4-week-old mice, dsTE12Q infection resulted in asymptomatic infection with lower CNS virus titers and undetectable CNS apoptosis. GeneChip expression comparisons of mock-infected neonatal and weanling mouse brains revealed developmental regulation of the mRNA expression of numerous genes, including some apoptosis regulatory genes, such as the proapoptotic molecules caspase-3 and TRAF4, which are downregulated during development, and the neuroprotective chemokine, fractalkine, which is upregulated during postnatal development. In parallel with increased neurovirulence and increased viral replication, Sindbis virus infection in 1-day-old mice resulted in both a greater number of host inflammatory genes with altered expression and greater changes in levels of host inflammatory gene expression than infection in 4-week-old mice. Only one inflammatory response gene, an expressed sequence tag similar to human ISG12, increased by a greater magnitude in infected 4-week-old mouse brains than in infected 1-day-old mouse brains. Furthermore, we found that enforced neuronal ISG12 expression results in a significant delay in Sindbis virus-induced death in neonatal mice. Together, our data identify genes that are developmentally regulated in the CNS and genes that are differentially regulated in the brains of different aged mice in response to Sindbis virus infection.

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Host Gene Regulation by Transposable Elements: The New, the Old and the Ugly

Viruses ◽

10.3390/v12101089 ◽

2020 ◽

Vol 12 (10) ◽

pp. 1089 ◽

Cited By ~ 2

Author(s):

Rocio Enriquez-Gasca ◽

Poppy A. Gould ◽

Helen M. Rowe

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Transposable Elements ◽

Essential Gene ◽

Expression Patterns ◽

Genetic Material ◽

Endogenous Retroviruses ◽

Host Gene ◽

New Genes ◽

Host Genes

The human genome has been under selective pressure to evolve in response to emerging pathogens and other environmental challenges. Genome evolution includes the acquisition of new genes or new isoforms of genes and changes to gene expression patterns. One source of genome innovation is from transposable elements (TEs), which carry their own promoters, enhancers and open reading frames and can act as ‘controlling elements’ for our own genes. TEs include LINE-1 elements, which can retrotranspose intracellularly and endogenous retroviruses (ERVs) that represent remnants of past retroviral germline infections. Although once pathogens, ERVs also represent an enticing source of incoming genetic material that the host can then repurpose. ERVs and other TEs have coevolved with host genes for millions of years, which has allowed them to become embedded within essential gene expression programmes. Intriguingly, these host genes are often subject to the same epigenetic control mechanisms that evolved to combat the TEs that now regulate them. Here, we illustrate the breadth of host gene regulation through TEs by focusing on examples of young (The New), ancient (The Old), and disease-causing (The Ugly) TE integrants.

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Mutations in Plasmodium falciparumCytochrome b That Are Associated with Atovaquone Resistance Are Located at a Putative Drug-Binding Site

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.8.2100-2108.2000 ◽

2000 ◽

Vol 44 (8) ◽

pp. 2100-2108 ◽

Cited By ~ 232

Author(s):

Michael Korsinczky ◽

Nanhua Chen ◽

Barbara Kotecka ◽

Allan Saul ◽

Karl Rieckmann ◽

...

Keyword(s):

Amino Acid ◽

Binding Site ◽

Point Mutations ◽

Drug Binding ◽

Single Amino Acid ◽

Malaria Parasites ◽

Drug Binding Site ◽

Sole Agent ◽

Amino Acid Mutations

ABSTRACT Atovaquone is the major active component of the new antimalarial drug Malarone. Considerable evidence suggests that malaria parasites become resistant to atovaquone quickly if atovaquone is used as a sole agent. The mechanism by which the parasite develops resistance to atovaquone is not yet fully understood. Atovaquone has been shown to inhibit the cytochrome bc 1 (CYTbc 1) complex of the electron transport chain of malaria parasites. Here we report point mutations in Plasmodium falciparum CYT b that are associated with atovaquone resistance. Single or double amino acid mutations were detected from parasites that originated from a cloned line and survived various concentrations of atovaquone in vitro. A single amino acid mutation was detected in parasites isolated from a recrudescent patient following atovaquone treatment. These mutations are associated with a 25- to 9,354-fold range reduction in parasite susceptibility to atovaquone. Molecular modeling showed that amino acid mutations associated with atovaquone resistance are clustered around a putative atovaquone-binding site. Mutations in these positions are consistent with a reduced binding affinity of atovaquone for malaria parasite CYTb.

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Specificity of amino acid regulated gene expression: analysis of genes subjected to either complete or single amino acid deprivation

Amino Acids ◽

10.1007/s00726-008-0199-2 ◽

2008 ◽

Vol 37 (1) ◽

pp. 79-88 ◽

Cited By ~ 74

Author(s):

S. S. Palii ◽

C. E. Kays ◽

C. Deval ◽

A. Bruhat ◽

P. Fafournoux ◽

...

Keyword(s):

Gene Expression ◽

Amino Acid ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Single Amino Acid ◽

Amino Acid Deprivation ◽

Regulated Gene Expression

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Single amino acid mutations ofMedicagoglycosyltransferase UGT85H2 enhance activity and impart reversibility

FEBS Letters ◽

10.1016/j.febslet.2009.05.046 ◽

2009 ◽

Vol 583 (12) ◽

pp. 2131-2135 ◽

Cited By ~ 30

Author(s):

Luzia V. Modolo ◽

Luis L. Escamilla-Treviño ◽

Richard A. Dixon ◽

Xiaoqiang Wang

Keyword(s):

Amino Acid ◽

Single Amino Acid ◽

Amino Acid Mutations ◽

Enhance Activity

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Infection of Human Dendritic Cells by a Sindbis Virus Replicon Vector Is Determined by a Single Amino Acid Substitution in the E2 Glycoprotein

Journal of Virology ◽

10.1128/jvi.74.24.11849-11857.2000 ◽

2000 ◽

Vol 74 (24) ◽

pp. 11849-11857 ◽

Cited By ~ 92

Author(s):

Jason P. Gardner ◽

Ilya Frolov ◽

Silvia Perri ◽

Yaying Ji ◽

Mary Lee MacKichan ◽

...

Keyword(s):

Dendritic Cells ◽

Amino Acid ◽

Amino Acid Substitution ◽

Sindbis Virus ◽

Single Amino Acid Substitution ◽

Single Amino Acid ◽

E2 Glycoprotein ◽

Human Dendritic Cells ◽

Antigen Presenting

ABSTRACT The ability to target antigen-presenting cells with vectors encoding desired antigens holds the promise of potent prophylactic and therapeutic vaccines for infectious diseases and cancer. Toward this goal, we derived variants of the prototype alphavirus, Sindbis virus (SIN), with differential abilities to infect human dendritic cells. Cloning and sequencing of the SIN variant genomes revealed that the genetic determinant for human dendritic cell (DC) tropism mapped to a single amino acid substitution at residue 160 of the envelope glycoprotein E2. Packaging of SIN replicon vectors with the E2 glycoprotein from a DC-tropic variant conferred a similar ability to efficiently infect immature human DC, whereupon those DC were observed to undergo rapid activation and maturation. The SIN replicon particles infected skin-resident mouse DC in vivo, which subsequently migrated to the draining lymph nodes and upregulated cell surface expression of major histocompatibility complex and costimulatory molecules. Furthermore, SIN replicon particles encoding human immunodeficiency virus type 1 p55Gag elicited robust Gag-specific T-cell responses in vitro and in vivo, demonstrating that infected DC maintained their ability to process and present replicon-encoded antigen. Interestingly, human and mouse DC were differentially infected by selected SIN variants, suggesting differences in receptor expression between human and murine DC. Taken together, these data illustrate the tremendous potential of using a directed approach in generating alphavirus vaccine vectors that target and activate antigen-presenting cells, resulting in robust antigen-specific immune responses.

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