Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells

Chaudhry, M. Zeeshan; Casalegno-Garduño, Rosaely; Sitnik, Katarzyna; Kasmapour, Bahram; Pulm, Ann-Kathrin; Brizić, Ilija; Moosmann, Andreas; Jonjić, Stipan; Mocarski, Edward S.; Čičin‐Šain, Luka

doi:10.1073/pnas.1914667117

Cited by 32 publications

(33 citation statements)

References 51 publications

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“…Apoptosis can be initiated through one of two alternative convergent pathways. The intrinsic pathway is mediated by mitochondria, and the extrinsic pathway is mediated by cell surface death receptors [ 50 , 51 , 52 ]. Furthermore, perturbations in mitochondria morphology and function in human lung epithelial cells have been documented following SARS-CoV-2 infection [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Cell-Type Apoptosis in Lung during SARS-CoV-2 Infection

et al. 2021

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The SARS-CoV-2 pandemic has inspired renewed interest in understanding the fundamental pathology of acute respiratory distress syndrome (ARDS) following infection. However, the pathogenesis of ARDS following SRAS-CoV-2 infection remains largely unknown. In the present study, we examined apoptosis in postmortem lung sections from COVID-19 patients and in lung tissues from a non-human primate model of SARS-CoV-2 infection, in a cell-type manner, including type 1 and 2 alveolar cells and vascular endothelial cells (ECs), macrophages, and T cells. Multiple-target immunofluorescence assays and Western blotting suggest both intrinsic and extrinsic apoptotic pathways are activated during SARS-CoV-2 infection. Furthermore, we observed that SARS-CoV-2 fails to induce apoptosis in human bronchial epithelial cells (i.e., BEAS2B cells) and primary human umbilical vein endothelial cells (HUVECs), which are refractory to SARS-CoV-2 infection. However, infection of co-cultured Vero cells and HUVECs or Vero cells and BEAS2B cells with SARS-CoV-2 induced apoptosis in both Vero cells and HUVECs/BEAS2B cells but did not alter the permissiveness of HUVECs or BEAS2B cells to the virus. Post-exposure treatment of the co-culture of Vero cells and HUVECs with a novel non-cyclic nucleotide small molecule EPAC1-specific activator reduced apoptosis in HUVECs. These findings may help to delineate a novel insight into the pathogenesis of ARDS following SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 99%

Cell-Type Apoptosis in Lung during SARS-CoV-2 Infection

et al. 2021

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“…Many viruses encode proteins that inhibit apoptosis, one of the main function of the innate defence mechanism against viral infection. It is known that HCMV encodes several cell death inhibitors (e.g., vMIA, vICA) that overcome mitochondrion-mediated apoptosis [ 24 , 25 , 26 ]. vMIA inactivates Bax by direct binding causing changes of Bax as well as mitochondrial translocation [ 24 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Both proteins are localized at the mitochondria outer membrane and induce permeabilization of this membrane during apoptosis [ 24 , 25 ]. HCMV pUL36 known as the viral inhibitor of caspase-8 activation (vICA) prevents proapoptotic signaling by binding to caspase-8 [ 26 ]. Another protein that blocks apoptosis is pUL38 that antagonizes cellular stress responses [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

HCMV-Mediated Interference of Bortezomib-Induced Apoptosis in Colon Carcinoma Cell Line Caco-2

Härtel

Theiß

Abdelaziz

et al. 2021

Viruses

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Human cytomegalovirus (HCMV) has been implicated in the development of human malignancies, for instance in colon cancer. Proteasome inhibitors were developed for cancer therapy and have also been shown to influence HCMV infection. The aim of this study was to investigate if proteasome inhibitors have therapeutic potential for colon carcinoma and how this is influenced by HCMV infection. We show by immunofluorescence and flow cytometry that the colon carcinoma cell line Caco-2 is susceptible to HCMV infection. Growth curve analysis as well as protein expression kinetics and quantitative genome analysis further confirm these results. HCMV has an anti-apoptotic effect on Caco-2 cells by inhibiting very early events of the apoptosis cascade. Further investigations showed that HCMV stabilizes the membrane potential of the mitochondria, which is typically lost very early during apoptosis. This stabilization is resistant to proteasome inhibitor Bortezomib treatment, allowing HCMV-infected cells to survive apoptotic signals. Our findings indicate a possible role of proteasome inhibitors in colon carcinoma therapy.

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“…HCMV pp65 495-503 epitope (NLVPMVATV) was preceded by two alanine residues that enhance peptide processing and presentation (66). The peptide was inserted at the ie2 C-terminus position 187,296 (NCBI accession: NC_004065) using en passant mutagenesis as described before (66, 67).…”

Section: Methodsmentioning

confidence: 99%

Targeted T cell receptor gene editing provides predictable T cell product function for immunotherapy

Müller

Jarosch

Hammel

et al. 2020

Preprint

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Adoptive transfer of T cells expressing a transgenic T cell receptor (TCR) has the potential to revolutionize immunotherapy of infectious diseases and cancer. However, the generation of defined TCR-transgenic T cell medicinal products with predictable in vivo function still poses a major challenge and limits broader and more successful application of this ‘living drug’. Here, by studying 51 different TCRs, we show that conventional genetic engineering by viral transduction leads to variable TCR expression and T cell product functionality as a result of interference with the endogenous TCR, variable transgene copy numbers, and un-targeted transgene integration. In contrast, CRISPR/Cas9-mediated TCR gene editing enables defined, targeted TCR insertion with concomitant knock-out of the endogenous receptor. Thereby, T cell products display more homogenous and physiological TCR expression which results in increased functionality and – importantly – less variable in vivo T cell responses in comparison to conventionally generated T cells. Hence, targeted TCR gene editing increases the predictability of TCR-transgenic T cell product function, which represents a crucial aspect for clinical application in adoptive T cell immunotherapy.BRIEF SUMMARYSafer, more functional and predictable transgenic T cell products for immunotherapy can be generated via CRISPR/Cas9-mediated targeted TCR engineering

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Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells

Cited by 32 publications

References 51 publications

Cell-Type Apoptosis in Lung during SARS-CoV-2 Infection

Cell-Type Apoptosis in Lung during SARS-CoV-2 Infection

HCMV-Mediated Interference of Bortezomib-Induced Apoptosis in Colon Carcinoma Cell Line Caco-2

Targeted T cell receptor gene editing provides predictable T cell product function for immunotherapy

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