Treatment with the senolytics dasatinib/quercetin reduces SARS‐CoV ‐2‐related mortality in mice
Andrés Pastor‐fernández, Antonio R Bertos, Arantzazu Sierra‐ramírez, Javier Del Moral‐salmoral, Javier Merino, Ana I De Ávila, Cristina Olagüe, Ricardo Villares, Gloria González‐aseguinolaza, María Ángeles Rodríguez, Manuel Fresno, Nuria Gironés, Matilde Bustos, Cristian Smerdou, Pablo Jose Fernandez‐marcos, Cayetano Von Kobbe
Aging Cell, doi:10.1111/acel.13771
The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the proinflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases. Using the established COVID-19 murine model K18-hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS-CoV-2-related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS-CoV-2 may be related to the post-COVID-19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID-19, and make D/Q a new and promising therapeutic tool.
| Histological processing The samples fixed in 10% neutral buffered formalin solution (Panreac Química, SLU) were mounted in synthetic paraffin with a melting point of 56 °C (Casa Álvarez Material Científico), using a Citadel 2000 Tissue Processor (Thermo Fisher Scientific), with an automatic program applying alcohols of increasing concentration and xylene substitute (Citrus Clearing Solvent, Thermo Fisher Scientific). Blocks were made in a cold plate block forming unit (Histo Star Embedding Workstation, Thermo Fisher Scientific) . Histological sections were obtained with a rotary microtome (Finesse Me+ Microtome, Thermo Fisher Scientific) at 3-4 μm thickness. A Gemini AS Automated Slide Stainer (Thermo Fisher Scientific) was used to stain the sections with hematoxylin-eosin and finally mounted using a CTM6 Coverslipper (Thermo Fisher Scientific), with a xylene-based mounting medium (ClearVue Mountant, Thermo Fisher Scientific).
| Immunohistochemistry (IHC) Tissue samples were cut at 3 μm thickness, mounted on superfrost®plus slides and dried overnight. For IHC, an automated immunostaining platform was used (Autostainer Link, Dako or Ventana Discovery ULTRA; Roche). Antigen retrieval was performed with CC1 32 min, only for p21 and High pH buffer, Dako, Agilent (p19 and SARS-CoV-2 nucleocapsid); endogenous peroxidase was blocked (hydrogen peroxide at 3%) and slides were then incubated with the appropriate primary antibody as detailed: rat monoclonal anti-p21 CIP1 (291H;..
References
Blagosklonny, From causes of aging to death from COVID-19, Aging
Boumaza, Gay, Mezouar, Bestion, Diallo et al., Monocytes and macrophages, targets of severe acute respiratory syndrome coronavirus 2: The clue for coronavirus disease 2019 immunoparalysis, The Journal of Infectious Diseases,
doi:10.1093/infdis/jiab044Camell, Yousefzadeh, Zhu, Prata, Huggins et al., Senolytics reduce coronavirus-related mortality in old mice, Science,
doi:10.1126/science.abe4832Cayetano Von Kobbe, None
Chen, Lau, Lamirande, Paddock, Bartlett et al., Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4 + T cells are important in control of SARS-CoV infection, Journal of Virology,
doi:10.1128/jvi.01281-09Daamen, Bachali, Owen, Kingsmore, Hubbard et al., Comprehensive transcriptomic analysis of COVID-19 blood, lung, and airway, Scientific Reports,
doi:10.1038/s41598-021-86002-xEvangelou, Veroutis, Paschalaki, Foukas, Lagopati et al., Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: Possible implications for viral mutagenesis, The European Respiratory Journal,
doi:10.1183/13993003.02951-2021Golden, Cline, Zeng, Garrison, Carey et al., Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease, JCI Insight,
doi:10.1172/jci.insight.142032Idda, Mcclusky, Lodde, Munk, Abdelmohsen et al., Survey of senescent cell markers with age in human tissues, Aging,
doi:10.18632/aging.102903Islam, Chamberlain, Mui, Little, Elevated Interleukin-10 levels in COVID-19: Potentiation of proinflammatory responses or impaired anti-inflammatory action?, Frontiers in Immunology,
doi:10.3389/fimmu.2021.677008Kirkland, Tchkonia, Senolytic drugs: From discovery to translation (review), Journal of Internal Medicine,
doi:10.1111/joim.13141Lee, Peng, Yang, Liou, Liao et al., C-C chemokine Ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury, Scientific Reports,
doi:10.1038/s41598-017-03956-7Lee, Yu, Trimpert, Benthani, Mairhofer et al., Virus-induced senescence is a driver and therapeutic target in COVID-19, Nature,
doi:10.1038/s41586-021-03995-1Li, Jiang, Li, Lin, Wang et al., Clinical and pathological investigation of patients with severe COVID-19, JCI Insight,
doi:10.1172/jci.insight.138070Ling, Chen, Lui, Wong, Wong et al., Longitudinal cytokine profile in patients with mild to critical COVID-19, Frontiers in Immunology,
doi:10.3389/fimmu.2021.763292Maghazachi, Al-Aoukaty, Schall, C-C chemokines induce the chemotaxis of NK and IL-2-activated NK cells: Role for G proteins, Journal of Immunology
Malavolta, Giacconi, Brunetti, Provinciali, Maggi, Exploring the relevance of senotherapeutics for the current SARS-CoV-2 emergency and similar future global health threats, Cell,
doi:10.3390/cells9040909Mccray, Jr, Pewe, Wohlford-Lenane, Hickey et al., Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus, Journal of Virology,
doi:10.1128/JVI.02012-06Mchugh, Gil, Senescence and aging: Causes, consequences, and therapeutic avenues, Journal of Cell Biology,
doi:10.1083/jcb.201708092Mohiuddin, Kasahara, The emerging role of cellular senescence in complications of COVID-19, Cancer Treatment and Research Communications,
doi:10.1016/j.ctarc.2021.100399Nehme, Borghesan, Mackedenski, Bird, Demaria, Cellular senescence as a potential mediator of COVID-19 severity in the elderly, Aging Cell,
doi:10.1111/acel.13237Oladunni, Park, Pino, Gonzalez, Akhter et al., Lethality of SARS-CoV-2 infection in K18 human angiotensinconverting enzyme 2 transgenic mice, Nature Communications,
doi:10.1038/s41467-020-19891-7Ovadya, Krizhanovsky, Li, Karamanis, Ognibene et al., Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, The Journal of Clinical Investigation,
doi:10.1016/j.metabol.2020.154262Palmer, Xu, Zhu, Pirtskhalava, Weivoda et al., Targeting senescent cells alleviates obesityinduced metabolic dysfunction, Aging Cell,
doi:10.1111/acel.12950Rathnasinghe, Strohmeier, Amanat, Gillespie, Krammer et al., Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection, Emerging Microbes & Infections,
doi:10.1080/22221751.2020.1838955Ruan, Yang, Wang, Jiang, Song, Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China, Intensive Care Medicine,
doi:10.1007/s00134-020-05991-xSchafer, White, Iijima, Haak, Ligresti et al., Cellular senescence mediates fibrotic pulmonary disease, Nature Communications,
doi:10.1038/ncomms14532Schall, Bacon, Toy, Goeddel, Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES, Nature,
doi:10.1038/347669a0Sierra-Ramirez, López-Aceituno, Costa-Machado, Plaza, Barradas et al., Transient metabolic improvement in obese mice treated with navitoclax or dasatinib/ quercetin, Aging,
doi:10.18632/aging.103607Tsuji, Minami, Hashimoto, Konishi, Suzuki et al., SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response, Nature Aging,
doi:10.1038/s43587-022-00170-7Vaz De Paula, De Azevedo, Nagashima, Martins, Malaquias et al., SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function, Scientific Reports,
doi:10.1038/s41590-020-0778-2Yang, Shen, Li, Yuan, Wei et al., Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19, The Journal of Allergy and Clinical Immunology,
doi:10.1016/j.jaci.2020.04.027Yinda, Port, Bushmaker, Offei Owusu, Purushotham et al., K18-hACE2 mice develop respiratory disease resembling severe COVID-19, PLoS Pathogens,
doi:10.1371/journal.ppat.1009195Zhang, Kishimoto, Grammatikakis, Gottimukkala, Cutler et al., Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model, Nature Neuroscience,
doi:10.1038/s41593-019-0372-9Zhao, Qin, Zhang, Li, Liang et al., Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease, JCI Insight,
doi:10.1172/jci.insight.139834Zheng, Wong, Li, Verma, Ortiz et al., Treatment with the senolytics dasatinib/quercetin reduces SARS-CoV-2-related mortality in mice, The New England Journal of Medicine
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'order': 2,
'name': 'published',
'label': 'Published',
'group': {'name': 'publication_history', 'label': 'Publication History'}}]}
