Viruses as ‘Truffle Hounds’: Molecular Tools for Untangling Brain Cellular Pathology

Müller‐Schiffmann, Andreas; Trossbach, Svenja V.; Lingappa, Vishwanath R.; Korth, Carsten

doi:10.1016/j.tins.2020.11.004

Cited by 7 publications

(16 citation statements)

References 118 publications

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“…In accord with recent suggestions about the importance of understanding genetic variability at the systems level rather than in individual genes (Li et al 2019) this study indicates that the interaction between host genotype and EBV (including other Herpesviruses) is relevant for MS etiology, reinforcing the rationale for future studies that attempt to decipher disease mechanisms by looking at virus-mediated pathology (Müller-Schiffmann et al 2021). It also strengthens the rationale for experimental medicine approaches aimed at advancing therapies while proving the causality of viral agents in MS.…”

Section: Discussionsupporting

confidence: 82%

Enrichment analysis of GWAS data in autoimmunity delineates the multiple sclerosis-Epstein Barr virus association

Mechelli

Umeton

Rinaldi

et al. 2021

Preprint

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We exploited genetic information to assess non-genetic influences in autoimmunity. We isolated gene modules whose products physically interact with environmental exposures related to autoimmunity, and analyzed their nominal statistical evidence of association with autoimmune and non-autoimmune diseases in genome-wide association studies (GWAS) data. Epstein Barr virus (EBV) and other Herpesviruses interactomes emerged as specifically associated with multiple sclerosis (MS), possibly under common regulatory mechanisms. Analyses of MS blood and brain transcriptomes, cytofluorimetric studies of endogenous EBV-infected lymphoblastoid lines, and lesion immunohistochemistry, confirmed a dysregulation of MS-associated EBV interactors, suggesting their contribution to CD40 signaling alterations in MS. These interactors resulted enriched in modules from inherited axonopathies-causing genes, supporting a link between EBV and neurodegeneration in MS, in accord with the observed transcriptomic dysregulations in MS brains. They were also enriched with top-ranked pharmaceutical targets prioritized on a genetic basis. This study delineates a disease-specific influence of herpesviruses on MS biology.

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Section: Discussionsupporting

confidence: 82%

Enrichment analysis of GWAS data in autoimmunity delineates the multiple sclerosis-Epstein Barr virus association

Mechelli

Umeton

Rinaldi

et al. 2021

Preprint

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“…Protein aggregation is a major pathological hallmark in many neurodegenerative disorders. [ 38 , 51 ] Interestingly, several studies have hinted at possible connections between viral infections and the onset of diseases such as Parkinson's disease [ 11 , 52 ] or Alzheimer's disease. [ 12 , [53] , [54] , [55] ] Therefore, it is of great interest to investigate whether this connection results from direct interactions between host and viral aggregation-prone proteins, or from a more general effect at the level of the proteostasis network.…”

Section: Discussionmentioning

confidence: 99%

In silico analysis of the aggregation propensity of the SARS-CoV-2 proteome: Insight into possible cellular pathologies

Flores-León

Lázaro

Shvachiy

et al. 2021

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The coronavirus disease 19 emerged in 2020 is caused by the SARS-CoV-2 virus. The pandemic triggered a turmoil in public health and is having a tremendous social and economic impact around the globe. Upon entry into host cells, the SARS-CoV-2 virus hijacks cellular machineries to produce and maintain its own proteins, spreading the infection. Although the disease is known for prominent respiratory symptoms, accumulating evidence is also demonstrating the involvement of the central nervous system, with possible mid- and long-term neurological consequences. In this study, we conducted a detailed bioinformatic analysis of the SARS-CoV-2 proteome aggregation propensity by using several complementary computational tools. Our study identified 10 aggregation prone proteins in the reference SARS-CoV-2 strain: the non-structural proteins Nsp4, Nsp6 and Nsp7 as well as ORF3a, ORF6, ORF7a, ORF7b, ORF10, CovE and CovM. By searching for the available mutants of each protein, we have found that most proteins are conserved, while ORF3a and ORF7b are variable and characterized by the occurrence of a large number of mutants with increased aggregation propensity. The geographical distribution of the mutants revealed interesting differences in the localization of aggregation-prone mutants of each protein. Aggregation-prone mutants of ORF7b were found in 7 European countries, whereas those of ORF3a in only 2. Aggregation-prone sequences of ORF7b, but not of ORF3a, were identified in Australia, India, Nepal, China, and Thailand. Our results are important for future analysis of a possible correlation between higher transmissibility and infection, as well as the presence of neurological symptoms with aggregation propensity of SARS-CoV-2 proteins.

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“…First, they might identify small molecules that inhibit replication of unrelated viruses if those viruses use common host machinery during assembly [15]. Secondly, the multiprotein complexes involved in virus assembly could play important roles in non-viral diseases that result from disordered protein homeostasis [87,88], thereby leading to small molecule therapeutics effective against chronic degenerative diseases. For example, studies suggest that the neuronal protein ARC, which is found in synapses and is critical for learning and memory, evolved from an ancient retroelement Gag protein [89][90][91]; thus, the host machinery involved in Gag assembly could easily be critical for assembly of multiprotein complexes that are critical for neuronal function.…”

Section: Host-targeted Assembly Inhibitors-challenges and Future Directionsmentioning

confidence: 99%

“…Hence the importance of further understanding the host-targeting assembly inhibitor PAV-206. Diseases that result from disordered homeostasis and aggregation of neuronal multiprotein complexes include degenerative neurologic diseases for which few drug treatments exist [88]. Thus, from many perspectives, a better understanding of hostcatalyzed assembly pathways and screens that result from them offers new and exciting avenues for combatting disease.…”

Section: Host-targeted Assembly Inhibitors-challenges and Future Directionsmentioning

confidence: 99%

Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs—First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor

Lingappa

Lingappa²,

Reed

2021

Viruses

Self Cite

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The concerning increase in HIV-1 resistance argues for prioritizing the development of host-targeting antiviral drugs because such drugs can offer high genetic barriers to the selection of drug-resistant viral variants. Targeting host proteins could also yield drugs that act on viral life cycle events that have proven elusive to inhibition, such as intracellular events of HIV-1 immature capsid assembly. Here, we review small molecule inhibitors identified primarily through HIV-1 self-assembly screens and describe how all act either narrowly post-entry or broadly on early and late events of the HIV-1 life cycle. We propose that a different screening approach could identify compounds that specifically inhibit HIV-1 Gag assembly, as was observed when a potent rabies virus inhibitor was identified using a host-catalyzed rabies assembly screen. As an example of this possibility, we discuss an antiretroviral small molecule recently identified using a screen that recapitulates the host-catalyzed HIV-1 capsid assembly pathway. This chemotype potently blocks HIV-1 replication in T cells by specifically inhibiting immature HIV-1 capsid assembly but fails to select for resistant viral variants over 37 passages, suggesting a host protein target. Development of such small molecules could yield novel host-targeting antiretroviral drugs and provide insight into chronic diseases resulting from dysregulation of host machinery targeted by these drugs.

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Viruses as ‘Truffle Hounds’: Molecular Tools for Untangling Brain Cellular Pathology

Cited by 7 publications

References 118 publications

Enrichment analysis of GWAS data in autoimmunity delineates the multiple sclerosis-Epstein Barr virus association

Enrichment analysis of GWAS data in autoimmunity delineates the multiple sclerosis-Epstein Barr virus association

In silico analysis of the aggregation propensity of the SARS-CoV-2 proteome: Insight into possible cellular pathologies

Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs—First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor

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