Rabies Virus Exploits Cytoskeleton Network to Cause Early Disease Progression and Cellular Dysfunction

Li, Xilin; Nawaz, Zeeshan; Guo, Caixia; Ali, Sultan; Naeem, Muhammad; Jamil, Tariq; Ahmad, Waqas; Siddiq, Muhammad; Ahmed, Sarfraz; Idrees, Muhammad Asif; Ahmad, Ali

doi:10.3389/fvets.2022.889873

Cited by 8 publications

(7 citation statements)

References 59 publications

(131 reference statements)

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“…14, orange arrows), are essential factors regulating central nervous system growth and development and are widely expressed in the brain. Once inside the cell, RABV is readily transported from neuron to neuron, causing dysregulation of the cytoskeleton and neurodegeneration (Liu et al, 2022). All of these receptors had age- and sex-related differential expression and some variation among the brain areas.…”

Section: Resultsmentioning

confidence: 99%

Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

Halabian,

Monteiro,

et al. 2023

Preprint

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Viral infection severity often varies with host factors such as age and sex. The pathogenesis of infections caused by a broad range of viruses, from neurotropic viruses like Rabies and Zika to respiratory viruses such as influenza and SARS-CoV-2, differ between the sexes and across the lifespan. Typically, older males are more susceptible to severe acute outcomes, while females are more vulnerable to the post-acute sequelae of infections. All of these complications can include neuroinflammation, stroke, cognitive dysfunction, and delirium. While these symptoms can be secondary to infection, recent studies suggest that even peripheral infections can lead to neuropathological changes in the brain. However, few studies have characterized the expression of viral receptors in the human brain or examined age- or sex-related differences in such expression. In this study, we used a publicly accessible transcriptomic database to assess the impact of age and sex on the expression of 67 viral host factor genes, associated with ten virus families. Analyzing data from 15 brain areas (n=33, F=14, M=19, age:4 mo-80 yrs), we determined the lifespan trajectory for each gene in each area via LOESS regressions. We used unsupervised hierarchical clustering to determine if a brain-wide pattern or virus family pattern can be detected. Using Dense-tSNE, a dimension-reduction and visualization technique, we discovered four distinct developmental trajectories, clustering the areas into two mixed-sex subcortical clusters and one each of male and female cortical clusters. Applying Differential Expression Sliding Window Analysis (DeSWAN), we identified the genes driving these age- and sex-related differences. Many sex differences were noted in childhood, potentially impacting the brain’s susceptibility to viral infections and underscoring a broader dimorphic organization of male and female brains. These insights contribute to our understanding of sex-specific responses to viral infections, offering the potential for more personalized treatment strategies.

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Section: Resultsmentioning

confidence: 99%

Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

Halabian,

Monteiro,

et al. 2023

Preprint

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“…In addition to being involved in interactions with the RABV L- and N-proteins and viral ribonucleocapsids, the P-protein is known to bind to a multitude of host proteins, such as dynein light-chain 1 and 2 (DYNLL1 (UniProt ID: P63167) and DYNLL2 (UniProt ID: Q96FJ2), respectively) [ 133 ], as well as host signal transducer and activator of transcription 1-alpha/beta and signal transducer and activator of transcription 2 (STAT1 (UniProt ID: P42224) and STAT2 proteins (UniProt ID: P52630), respectively) [ 16 , 17 , 101 , 102 , 103 , 104 ], promyelocytic leukemia (PML) protein (UniProt ID: P29590) [ 110 ], the ribosomal protein L9 (UniProt ID: Q02878) [ 15 ], STAT3 (UniProt ID: P40763), nucleolin (NCL; UniProt ID: P19338), focal adhesion kinase (FAK; UniProt ID: Q05397), Janus kinase 1 (JAK1; UniProt ID: P23458), inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε; UniProt ID: Q14164), Beclin-1 (BECN1; UniProt ID: Q14457), tubulin alpha (TUB-α; UniProt ID: Q71U36 for tubulin alpha-1A chain), tubulin beta (TUB-β; UniProt ID: Q9H4B7 for tubulin beta-1 chain), ATP-binding cassette sub-family E member 1 (ABCE1; UniProt ID: P61221), T-complex protein 1 subunit gamma (CCTγ; UniProt ID: P49368), Hsp90 co-chaperone Cdc37 (CDC37; UniProt ID: Q16543), and heat shock protein HSP 90-alpha (Hsp90AA1; UniProt ID: P07900) [ 71 ]. Furthermore, the P-protein can interact with complex I in mitochondria, leading to mitochondrial dysfunction, the increased generation of reactive oxygen species (ROS), and oxidative stress [ 134 ].…”

Section: Resultsmentioning

confidence: 99%

Looking at the Pathogenesis of the Rabies Lyssavirus Strain Pasteur Vaccins through a Prism of the Disorder-Based Bioinformatics

Dhulipala

Uversky

2022

Biomolecules

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Rabies is a neurological disease that causes between 40,000 and 70,000 deaths every year. Once a rabies patient has become symptomatic, there is no effective treatment for the illness, and in unvaccinated individuals, the case-fatality rate of rabies is close to 100%. French scientists Louis Pasteur and Émile Roux developed the first vaccine for rabies in 1885. If administered before the virus reaches the brain, the modern rabies vaccine imparts long-lasting immunity to the virus and saves more than 250,000 people every year. However, the rabies virus can suppress the host’s immune response once it has entered the cells of the brain, making death likely. This study aimed to make use of disorder-based proteomics and bioinformatics to determine the potential impact that intrinsically disordered protein regions (IDPRs) in the proteome of the rabies virus might have on the infectivity and lethality of the disease. This study used the proteome of the Rabies lyssavirus (RABV) strain Pasteur Vaccins (PV), one of the best-understood strains due to its use in the first rabies vaccine, as a model. The data reported in this study are in line with the hypothesis that high levels of intrinsic disorder in the phosphoprotein (P-protein) and nucleoprotein (N-protein) allow them to participate in the creation of Negri bodies and might help this virus to suppress the antiviral immune response in the host cells. Additionally, the study suggests that there could be a link between disorder in the matrix (M) protein and the modulation of viral transcription. The disordered regions in the M-protein might have a possible role in initiating viral budding within the cell. Furthermore, we checked the prevalence of functional disorder in a set of 37 host proteins directly involved in the interaction with the RABV proteins. The hope is that these new insights will aid in the development of treatments for rabies that are effective after infection.

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“…First, the internalization and uptake of RABV requires an intact actin network, and the depolymerization of actin filaments inhibits the virus infection. Next, RABV utilizes the microtubules and the motor protein dynein/kinesin for intracellular transport [ 18 , 19 , 20 , 29 , 30 ]. During this stage, the M protein enhances the expression of cellular histone deacetylase 6 (HDAC6) to depolymerize the microtubules and facilitate viral RNA synthesis [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…As the major structural components of IFs in skeletal, cardiac, and some smooth muscle cells, desmin is important for the maintenance and integrity of the cytoskeleton [ 17 ]. Our identification of desmin as a novel host interactor with RABV-M is particularly intriguing since RABV exploits the cytoskeleton network to facilitate different stages of its lifecycle and the development of pathological processes [ 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Host Desmin Interacts with RABV Matrix Protein and Facilitates Virus Propagation

Wen

Liu

et al. 2023

Viruses

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Microfilaments and microtubules, two crucial structures of cytoskeletal networks, are usurped by various viruses for their entry, egress, and/or intracellular trafficking, including the Rabies virus (RABV). Intermediate filaments (IFs) are the third major component of cytoskeletal filaments; however, little is known about the role of IFs during the RABV infection. Here, we identified the IF protein desmin as a novel host interactor with the RABV matrix protein, and we show that this physical interaction has a functional impact on the virus lifecycle. We found that the overexpression of desmin facilitates the RABV infection by increasing the progeny virus yield, and the suppression of endogenous desmin inhibits virus replication. Furthermore, we used confocal microscopy to observe that the RABV-M co-localizes with desmin in IF bundles in the BHK-21 cells. Lastly, we found that mice challenged with RABV displayed an enhanced expression of desmin in the brains of infected animals. These findings reveal a desmin/RABV-M interaction that positively regulates the virus infection and suggests that the RABV may utilize cellular IFs as tracks for the intracellular transport of viral components and efficient budding.

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Rabies Virus Exploits Cytoskeleton Network to Cause Early Disease Progression and Cellular Dysfunction

Cited by 8 publications

References 59 publications

Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

Looking at the Pathogenesis of the Rabies Lyssavirus Strain Pasteur Vaccins through a Prism of the Disorder-Based Bioinformatics

Host Desmin Interacts with RABV Matrix Protein and Facilitates Virus Propagation

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