Inhibitors of One or More Cellular Aurora Kinases Impair the Replication of Herpes Simplex Virus 1 and Other DNA and RNA Viruses with Diverse Genomes and Life Cycles

Ly, Cindy Y; Pfannenstiel, Jessica; Pant, Anil; Yang, Zhilong; Rodzkin, Maxim S; Davido, David J.

doi:10.1128/spectrum.01943-22

Cited by 3 publications

(3 citation statements)

References 55 publications

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“…In both these cases, there was no evidence of AurA-HDAC6 pathway involvement, or that primary cilia loss was beneficial to the microbe. AurA kinase activity has not been linked with bacterial infection, but appears to promote replication of several viruses [ 42 , 43 ]. In addition, the E6 ligase of human papillomavirus (HPV) interacts with AurA to promote HPV-mediated carcinogenesis [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Chlamydia trachomatis induces disassembly of the primary cilium to promote the intracellular infection

Ekka,

Gutierrez,

Johnson

et al. 2024

PLoS Pathog

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Chlamydia trachomatis is a clinically important bacterium that infects epithelial cells of the genitourinary and respiratory tracts and the eye. These differentiated cells are in a quiescent growth state and have a surface organelle called a primary cilium, but the standard Chlamydia cell culture infection model uses cycling cells that lack primary cilia. To investigate if these differences are relevant, we performed infections with host cells that have a primary cilium. We found that C. trachomatis caused progressive loss of the primary cilium that was prevented by disrupting Aurora A (AurA), HDAC6 or calmodulin, which are components of the cellular cilia disassembly pathway. Stabilization of the primary cilium by targeting this pathway caused a large reduction in infectious progeny although there were no changes in chlamydial inclusion growth, chlamydial replication or the ultrastructural appearance of dividing and infectious forms (RBs and EBs, respectively). Thus, the presence of a primary cilium interfered with the production of infectious EBs at a late step in the developmental cycle. C. trachomatis infection also induced quiescent cells to re-enter the cell cycle, as detected by EdU incorporation in S-phase, and Chlamydia-induced cilia disassembly was necessary for cell cycle re-entry. This study therefore describes a novel host-pathogen interaction in which the primary cilium limits a productive Chlamydia infection, and the bacterium counteracts this host cell defense by activating the cellular cilia disassembly pathway.

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Section: Discussionmentioning

confidence: 99%

Chlamydia trachomatis induces disassembly of the primary cilium to promote the intracellular infection

Ekka,

Gutierrez,

Johnson

et al. 2024

PLoS Pathog

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“…(iv) PHA-793887: Few experimental studies have been conducted to certify its activity, but it was demonstrated in vitro that PHA-793887 was able to interfere with the viability of osteosarcoma cells [76]. (v) JNJ-7706621: a potent inhibitor of CDKs and Aurora kinase (AURKA) demonstrated effectiveness in dealing with the herpes simplex virus 1 [77].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Profiling and Therapeutic Insights into Differentially Expressed Genes in Hepatocellular Carcinoma

Caputo,

de Souza,

Basso

et al. 2023

Cancers

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Background: Drug repurposing is a strategy that complements the conventional approach of developing new drugs. Hepatocellular carcinoma (HCC) is a highly prevalent type of liver cancer, necessitating an in-depth understanding of the underlying molecular alterations for improved treatment. Methods: We searched for a vast array of microarray experiments in addition to RNA-seq data. Through rigorous filtering processes, we have identified highly representative differentially expressed genes (DEGs) between tumor and non-tumor liver tissues and identified a distinct class of possible new candidate drugs. Results: Functional enrichment analysis revealed distinct biological processes associated with metal ions, including zinc, cadmium, and copper, potentially implicating chronic metal ion exposure in tumorigenesis. Conversely, up-regulated genes are associated with mitotic events and kinase activities, aligning with the relevance of kinases in HCC. To unravel the regulatory networks governing these DEGs, we employed topological analysis methods, identifying 25 hub genes and their regulatory transcription factors. In the pursuit of potential therapeutic options, we explored drug repurposing strategies based on computational approaches, analyzing their potential to reverse the expression patterns of key genes, including AURKA, CCNB1, CDK1, RRM2, and TOP2A. Potential therapeutic chemicals are alvocidib, AT-7519, kenpaullone, PHA-793887, JNJ-7706621, danusertibe, doxorubicin and analogues, mitoxantrone, podofilox, teniposide, and amonafide. Conclusion: This multi-omic study offers a comprehensive view of DEGs in HCC, shedding light on potential therapeutic targets and drug repurposing opportunities.

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“…RNA was isolated according to manufacturer’s protocol and reverse transcribed as published (ref). cDNAs of viral and cellular transcripts were amplified using primers for ICP0, ICP4, ICP27, and 18S rRNA as previously described (36).…”

Section: Methodsmentioning

confidence: 99%

PARP14 is pro- and anti-viral host factor that promotes IFN production and affects the replication of multiple viruses

Parthasarathy,

Saenjamsai,

Hao

et al. 2024

Preprint

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PARP14 is a 203 kDa multi-domain protein that is primarily known as an ADP-ribosyltransferase, and is involved in a variety of cellular functions including DNA damage, microglial activation, inflammation, and cancer progression. In addition, PARP14 is upregulated by interferon (IFN), indicating a role in the antiviral response. Furthermore, PARP14 has evolved under positive selection, again indicating that it is involved in host-pathogen conflict. We found that PARP14 is required for increased IFN-I production in response to coronavirus infection lacking ADP-ribosylhydrolase (ARH) activity and poly(I:C), however, whether it has direct antiviral function remains unclear. Here we demonstrate that the catalytic activity of PARP14 enhances IFN-I and IFN-III responses and restricts ARH-deficient murine hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. To determine if PARP14 antiviral functions extended beyond CoVs, we tested the ability of herpes simplex virus 1 (HSV-1) and several negative-sense RNA viruses, including vesicular stomatitis virus (VSV), Ebola virus (EBOV), and Nipah virus (NiV), to infect A549 PARP14 knockout (KO) cells. HSV-1 had increased replication in PARP14 KO cells, indicating that PARP14 restricts HSV-1 replication. In contrast, PARP14 was critical for the efficient infection of VSV, EBOV, and NiV, with EBOV infectivity at less than 1% of WT cells. A PARP14 active site inhibitor had no impact on HSV-1 or EBOV infection, indicating that its effect on these viruses was independent of its catalytic activity. These data demonstrate that PARP14 promotes IFN production and has both pro- and anti-viral functions targeting multiple viruses.

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Inhibitors of One or More Cellular Aurora Kinases Impair the Replication of Herpes Simplex Virus 1 and Other DNA and RNA Viruses with Diverse Genomes and Life Cycles

Abstract: We have demonstrated that aurora kinases play a role during HSV-1 lytic infection. Three aurora kinase inhibitors significantly impaired HSV-1 immediate-early gene expression.

Cited by 3 publications

References 55 publications

Chlamydia trachomatis induces disassembly of the primary cilium to promote the intracellular infection

Chlamydia trachomatis induces disassembly of the primary cilium to promote the intracellular infection

Comprehensive Profiling and Therapeutic Insights into Differentially Expressed Genes in Hepatocellular Carcinoma

PARP14 is pro- and anti-viral host factor that promotes IFN production and affects the replication of multiple viruses

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