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Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19
Open accessAbstract
Coronavirus disease 2019 (COVID-19) is especially severe in aged populations 1. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility 2. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern 2. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D 2 (PGD 2)) and a phospholipase (phospholipase A2 group 2D (PLA 2 G2D)) contributed to poor outcomes in aged mice 3,4. mRNA expression of PLA 2 G2D and prostaglandin D 2 receptor (PTGDR), and production of PGD 2 also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA 2 G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA 2 G2D-PGD 2/PTGDR pathway is a useful target for therapeutic interventions.
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“The levels of PGD2 and related prostaglandins were also found to be increased in older individuals and in individuals infected with SARS-CoV-2 (ref.134).”
From COVID-19 and cellular senescence (2023) · cites this paper as [134]
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Self-citationSmall molecules in the treatment of COVID-19
Lei, S., Chen, X., Wu, J., Duan, X., & Men, K. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01249-8 · Cited by 119
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BackgroundAn aberrant immune–epithelial progenitor niche drives viral lung sequelae
Narasimhan, H., Cheon, I. S., Qian, W., Hu, S. S., Parimon, T., Li, C., Goplen, N. P., Wu, Y., Wei, X., Son, Y. M., et al. (2024) · Nature · doi:10.1038/s41586-024-07926-8 · Cited by 109
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ResultCOVID-19 drug discovery and treatment options
Chan, J. F., Yuan, S., Chu, H., Sridhar, S., & Yuen, K. (2024) · Nature Reviews Microbiology · doi:10.1038/s41579-024-01036-y · Cited by 92
“…such as eicosanoid signalling, sterol regulatory element binding proteins, diglyceride acyltransferase, ATP citrate lyase and phosphatidylinositol 3-kinase catalytic subunit type 3 lead to inhibition of viral replication and/or the formation of these replication organelles 8,46,47,55,153,154 .”
SARS-CoV-2 infection of sustentacular cells disrupts olfactory signaling pathways
Verma, A. K., Zheng, J. H., Meyerholz, D. K., & Perlman, S. M. (2022) · JCI Insight · doi:10.1172/jci.insight.160277 · Cited by 76
“We engineered a virus that expressed N501Y and demonstrated that this mouse-adapted virus caused minimal disease in mice (37).”
MethodSelf-citationModulation of immunity by the secreted phospholipase A2 family
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Self-citationHost Recovery from Respiratory Viral Infection
Wei, X., Narasimhan, H., Zhu, B., & Sun, J. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101921-040450 · Cited by 63
The phospholipase A2 superfamily as a central hub of bioactive lipids and beyond
Murakami, M. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108382 · Cited by 66
Self-citationAlhammad, Y. M. O., Parthasarathy, S., Ghimire, R., Kerr, C. M., O’Connor, J. J., Pfannenstiel, J. J., Chanda, D., Miller, C. A., Baumlin, N., Salathe, M. A., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2302083120 · Cited by 59
“These include the WTSARSCoV2 BAC based off the WuhanHu1 isolate provided by Sonia Zuñiga, Li Wang, Isabel Sola and Luis Enjuanes (CNBCSIC, Madrid, Spain) (67), a MERSCoV BAC based off of the EMC isolate (53), and an MHV BAC based off of the JHMV isolate (26).”
Self-citationFumagalli, V., Ravà, M., Marotta, D., Lucia, P. D., Bono, E. B., Giustini, L., Leo, F. D., Casalgrandi, M., Monteleone, E., Mouro, V., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01787-z · Cited by 61
Self-citationMacrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae
Wei, X., Qian, W., Narasimhan, H., Chan, T., Liu, X., Arish, M., Young, S., Li, C., Cheon, I. S., Yu, Q., et al. (2025) · Science · doi:10.1126/science.adq2509 · Cited by 59
Impaired immune response drives age-dependent severity of COVID-19
Beer, J., Crotta, S., Breithaupt, A., Ohnemus, A., Becker, J., Sachs, B., Kern, L., Llorian, M., Ebert, N., Labroussaa, F., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20220621 · Cited by 52
“All animal work conducted at the University Medical Center Freiburg and the Francis Crick Institute followed the German animal protection law or the Animals (Scientific Procedures) Act 1986, respectively, and was approved by the respective local animal welfare committee ( Regierungspr¨asidium”
Structural basis for mouse receptor recognition by SARS-CoV-2 omicron variant
Zhang, W., Shi, K., Geng, Q., Ye, G., Aihara, H., & Li, F. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2206509119 · Cited by 51
Ying, B., Darling, T. L., Desai, P., Liang, C.-Y., Dmitriev, I. P., Soudani, N., Bricker, T. L., Kashentseva, E. A., Harastani, H., Raju, S., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01743-x · Cited by 49
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Deep phenotyping of the lipidomic response in COVID‐19 and non‐COVID‐19 sepsis
Meng, H., Sengupta, A., Ricciotti, E., Mrčela, A., Mathew, D., Mazaleuskaya, L. L., Ghosh, S., Brooks, T. G., Turner, A. P., Schanoski, A. S., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1440 · Cited by 38
“68 Here, PLA2G2D was not elevated in patients with sepsis compared with healthy controls, suggesting that sPLA 2 is the dominant driver of PGD 2 formation in humans with COVID-19.”
BackgroundSARS-CoV-2 immunity in animal models
Chen, Z., Yuan, Y., Hu, Q., Zhu, A., Chen, F., Li, S., Guan, X., Lv, C., Tang, T., He, Y., et al. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-01122-w · Cited by 39
Self-citationLung Tissue-Resident Memory T cells: The Gatekeeper To Respiratory Viral (Re)-Infection
Tang, J., & Sun, J. (2022) · Current Opinion in Immunology · doi:10.1016/j.coi.2022.102278 · Cited by 39
The consequences of SARS-CoV-2 within-host persistence
Sigal, A., Neher, R. A., & Lessells, R. J. (2024) · Nature Reviews Microbiology · doi:10.1038/s41579-024-01125-y · Cited by 39
“Interestingly, N501Y also evolves during mouse adaptation of SARS-CoV-2, increasing affinity to the mouse ACE2 receptor 136 .”
InfluentialNsp3-N interactions are critical for SARS-CoV-2 fitness and virulence
Li, P., Xue, B., Schnicker, N., Wong, L.-Y. R., Meyerholz, D. K., & Perlman, S. M. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2305674120 · Cited by 34
Self-citationRen, J., Zhou, X., Huang, K. Q., Chen, L., Guo, W., Feng, K., Huang, T., & Cai, Y. (2023) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2023.107883 · Cited by 28
Lei, R., Qing, E., Odle, A. E., Yuan, M., Gunawardene, C. D., Tan, T. J. C., So, N., Ouyang, W. O., Wilson, I. A., Gallagher, T., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48104-8 · Cited by 30
“Based on a BAC-based reverse genetic system of SARS-CoV-2 Wuhan-Hu-1 (pBAC SARS-CoV-2) 37,38 , we constructed a saturation mutagenesis library that contained all possible single amino acid mutations in the bFP and FPPR (residues 816 – 855) of the SARS-CoV-2 S, as well as the eight residues…”
MethodInfluentialSelf-citationDavis, M., Voss, K., Turnbull, J. B., Gustin, A. T., Knoll, M. L., Muruato, A. E., Hsiang, T.-Y., Dinnon, K. H., Leist, S. R., Nickel, K., et al. (2022) · Vaccines · doi:10.3390/vaccines11010047 · Cited by 32
“Compared to the few studies in C57BL/6 mice, the most comprehensive early studies with mouse-adapted strains characterized infection in Balb/c mice [3,7,11,13] which do not permit the vast number of genetic screens that are possible with transgenic and gene knockout lines on the C57BL/6 background.”
MethodResultProstanoids in Cardiac and Vascular Remodeling
Ricciotti, E., Haines, P. G., Chai, W., & FitzGerald, G. A. (2024) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.123.320045 · Cited by 25
Nirmatrelvir treatment of SARS‐CoV‐2‐infected mice blunts antiviral adaptive immune responses
Fumagalli, V., Lucia, P. D., Ravà, M., Marotta, D., Bono, E. B., Grassi, S., Donnici, L., Cannalire, R., Stefanelli, I., Ferraro, A., et al. (2023) · EMBO Molecular Medicine · doi:10.15252/emmm.202317580 · Cited by 22
Self-citationOptimising vaccine immunogenicity in ageing populations: key strategies
Jiang, G., Zou, Y., Zhao, D., & Yu, J. (2024) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(24)00497-3 · Cited by 27
Murakami, M., Takamiya, R., Miki, Y., Sugimoto, N., Nagasaki, Y., Suzuki-Yamamoto, T., & Taketomi, Y. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115176 · Cited by 26
Self-citationHonrubia, J. M., Gutierrez-Alvarez, F. J., Sanz‐Bravo, A., González-Miranda, E., Muñoz‐Santos, D., Castaño-Rodríguez, C., Wang, L., Villarejo-Torres, M., Ripoll-Gómez, J., Esteban, A., et al. (2023) · mBio · doi:10.1128/mbio.03136-22 · Cited by 23
Self-citationSARS-CoV-2-specific immunoglobulin Y antibodies are protective in infected mice
El-Kafrawy, S. A., Odle, A. E., Abbas, A. T., Hassan, A. M., Abdel-dayem, U. A., Qureshi, A. K., Wong, L.-Y. R., Zheng, J. H., Meyerholz, D. K., Perlman, S. M., et al. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010782 · Cited by 22
“Lung homogenates were aliquoted into micro tubes and kept at -80˚C. Infection of BALB/c mice with SARS2-N501YMA30 and anti-RBD IgY treatment Forty-eight male and fifty-four 8–10 week old female BALB/c mice were used in this study.”
MethodInfluentialSelf-citationCOVID-19, Blood Lipid Changes, and Thrombosis
Farooqui, A. A., Farooqui, T., Sun, G. Y., Lin, T., Teh, D. B. L., & Ong, W. (2023) · Biomedicines · doi:10.3390/biomedicines11041181 · Cited by 22
“COVID-19 disease severity was significantly reduced in aged mice that lacked sPLA2-IID or the prostaglandin D2 receptor DP1; treatment with a DP1 antagonist, asapiprant, protected these mice from lethal COVID19 infection [69].”
BackgroundActivated T Cells Break Tumor Immunosuppression by Macrophage Reeducation
Trotta, R., Rivis, S., Zhao, S., Orban, M., Cafarello, S. T., Charatsidou, I., Poźniak, J., Dehairs, J., Vanheer, L., Pulido-Vicuña, C. A., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0415 · Cited by 21
Considering innate immune responses in SARS-CoV-2 infection and COVID-19
Diamond, M., Lambris, J. D., Ting, J. P. ‐., & Tsang, J. S. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00744-x · Cited by 21
Gardinassi, L. G., Servian, C. D. P., Lima, G. D. S., dos Anjos, D. C. C., Gomes, A. R., Guilarde, A. O., Borges, M. A. S. B., dos Santos, G. F., Moraes, B. G. N., Silva, J. M. M., et al. (2023) · Microbiology Spectrum · doi:10.1128/spectrum.02194-22 · Cited by 22
“ical molecules in COVID-19 pathogenesis (63, 64).”
Evidence of antigenic drift in the fusion machinery core of SARS-CoV-2 spike
Tan, T. J. C., Verma, A. K., Odle, A. E., Lei, R., Meyerholz, D. K., Matreyek, K. A., Perlman, S. M., Wong, L.-Y. R., & Wu, N. C. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2317222121 · Cited by 21
Self-citationWang, C., Khatun, M. S., Ellsworth, C. R., Chen, Z., Islamuddin, M., Vidal, A. K. N., Alam, M. A., Liu, S., McCombs, J. E., Maness, N. J., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-06872-5 · Cited by 21
“Mice were infected intranasally with SARS-CoV-2 (2 X 10 5 TCID50 for acute lethal dose infection or 1 X 10 4 TCID50 for sub-lethal dose infection) in an ABSL3 facility.”
InfluentialEmerging role of complement in COVID-19 and other respiratory virus diseases
Xiao, M. T., Ellsworth, C. R., & Qin, X. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05157-8 · Cited by 20
“Among other differences, the MA30 strain showed spike protein mutations, including Q498R, Q493R, and K417M, all of which are suspected to enhance mACE2 binding [131].”
BackgroundInfluentialDynamic behavior and lineage plasticity of the pulmonary venous endothelium
Wong, J., Zhao, G., Adams‐Tzivelekidis, S., Wen, H., Chandrasekaran, P., Michki, S. N., Gentile, M. E., Singh, M., Kass-Gergi, S., Mendoza, M., et al. (2024) · Nature Cardiovascular Research · doi:10.1038/s44161-024-00573-2 · Cited by 18
“Largely pheno-copying our observations in post-infection lungs, TdTomato + ECs exhibited dramatic branching after MA30 SARS-CoV-2 infection (Extended Data Fig.”
InfluentialGoepp, M., Milburn, J. V., Zhang, B., Dong, Y., Tyrrell, V. J., Zheng, X., Marshall, J. M., Bolsega, S., Basic, M., Glendinning, L., et al. (2025) · Cell Host & Microbe · doi:10.1016/j.chom.2025.04.014 · Cited by 18
Self-citationHu, B., Chan, J. F., Liu, Y., Liu, H., Chen, Y., Shuai, H., Hu, Y., Hartnoll, M., Chen, L., Xia, Y., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104916 · Cited by 19
Shi, J., Zheng, J. H., Zhang, X., Tai, W., Odle, A. E., Perlman, S. M., & Du, L. (2022) · Translational research · doi:10.1016/j.trsl.2022.04.007 · Cited by 18
“At 70 days post-2nd immunization, the vaccinated mice were intranasally challenged with SARS2-N501YMA30 (a virulent mouseadapted strain of SARS-CoV-2, 5£103 PFU/mouse, in 50 mL DMEM), and observed for 2 weeks for survival and body weight changes.(27,29,30) Mouse sera collected at 10 days post-last immunization or befo…”
MethodSelf-citationPlatelet-derived integrin- and tetraspanin-enriched tethers exacerbate severe inflammation
Kusch, C., Stegner, D., Weiss, L. J., Nurden, P., Burkard, P., Johnson, D., Bergmeier, W., Onursal, C., Navarro, S., Hackenbroch, C., et al. (2026) · Science · doi:10.1126/science.adu2825 · Cited by 17
“The mouse-adapted SARS-CoV-2 strain rSARS-CoV-2-N501YMA30 (51) was propagated in Vero E6-TMPRSS2 cells for 48–73 hours and titrated by plaque assay under biosafety level 3 (BSL-3) conditions.”
The nervous system during COVID ‐19: Caught in the crossfire
Natale, N. R., Lukens, J. R., & Petri, W. A. (2022) · Immunological Reviews · doi:10.1111/imr.13114 · Cited by 19
Lu, H., Liu, Z., Deng, X., Chen, S., Zhou, R., Zhao, R., Parandaman, R., Thind, A., Henley, J. E., Tian, L., et al. (2023) · PLoS Pathogens · doi:10.1371/journal.ppat.1011240 · Cited by 17
“Consistent with the report with another mouse-adapted virus strain generated independently [79], the CMAp20 mouse-adapted virus demonstrated stronger pathogenicity in Balb/c mice than that in C57BL/6 mice (Fig 11A and 11B).”
ResultAdaptive variations in SARS-CoV-2 spike proteins: effects on distinct virus-cell entry stages
Qing, E., & Gallagher, T. (2023) · mBio · doi:10.1128/mbio.00171-23 · Cited by 17
COVID-19 and influenza infections mediate distinct pulmonary cellular and transcriptomic changes
Wang, C., Khatun, M. S., Zhang, Z., Allen, M. J., Chen, Z., Ellsworth, C. R., Currey, J. M., Dai, G., Tian, D., Bach, K., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-05626-z · Cited by 16
“The dissection of the questions requires the use of multiple approaches including in vitro cell culture system 54 , human organoid method 58,59 , our model reported here, other mouse-adapted SARS-CoV2 strains such as MA10 or MA30, and human Flu and COVID patient samples 56,60,61 .”
Pan-beta-coronavirus subunit vaccine prevents SARS-CoV-2 Omicron, SARS-CoV, and MERS-CoV challenge
Wang, G., Verma, A. K., Guan, X., Bu, F., Odle, A. E., Li, F., Liu, B., Perlman, S. M., & Du, L. (2024) · Journal of Virology · doi:10.1128/jvi.00376-24 · Cited by 17
Self-citationTissue-resident memory T cells contribute to protection against heterologous SARS-CoV-2 challenge
Odle, A. E., Kar, M., Verma, A. K., Sariol, A., Meyerholz, D. K., Suthar, M. S., Wong, L.-Y. R., & Perlman, S. M. (2024) · JCI Insight · doi:10.1172/jci.insight.184074 · Cited by 15
“Consequently, the ancestral S protein was removed from the latest vaccine formulations, which express a single Omicron S protein (XBB.1.5 JN.1 or KP.2).”
InfluentialSelf-citationdos Reis, L. M., Berçot, M. R., Castelucci, B. G., Martins, A. J. E., Castro, G., & Moraes‐Vieira, P. M. (2023) · Viruses · doi:10.3390/v15020525 · Cited by 17
“worsened in aged individuals [59] and associated with high expression of PGD2 receptor 1 (DP1) by cDCs in mice [60,61].”
BackgroundEwart, G. D., Bobardt, M. D., Bentzen, B. H., Yan, Y., Thomson, A., Klumpp, K., Becker, S. L., ROSENKILDE, M. M., Miller, M., & Gallay, P. A. (2023) · PLoS Pathogens · doi:10.1371/journal.ppat.1011328 · Cited by 15
Self-citationLacasse, É., Dubuc, I., Gudimard, L., Andrade, A. C. D. S. P., Gravel, A., Greffard, K., Chamberland, A., Oger, C., Galano, J., Durand, T., et al. (2025) · Immunity & Ageing · doi:10.1186/s12979-025-00503-1 · Cited by 14
Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality
Albert, M., Uranga-Murillo, I., Arias, M. A., de Miguel, D., Peña, N., Montinaro, A., Varanda, A. B., Theobald, S. J., Zubiaur, I. A., Saggau, J., et al. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01278-6 · Cited by 15
Remuzzi, G., Schiaffino, S., Santoro, M. G., FitzGerald, G. A., Melino, G., & Patrono, C. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.987816 · Cited by 16
Feng, Q., Li, G., Xia, W., Dai, G., Zhou, J., Xu, Y., Liu, D., & Zhang, G. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.983501 · Cited by 13
“Drugs or nutrients that can enhance the resilience are particularly beneficial to the health of aging people, especially in the current COVID-19 epidemic (5, 6).”
BackgroundDavis, M., Voss, K., Turnbull, J. B., Gustin, A. T., Knoll, M. L., Muruato, A. E., Hsiang, T.-Y., Dinnon, K. H., Leist, S. R., Nickel, K., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-2194450/v1 · Cited by 13
Respiratory viral infections prime accelerated lung cancer growth
Qian, W. G., Wei, X., Barros, A., Ye, X., Zhang, H., Yu, Q., Young, S. P., Yeatts, E. V., Park, Y. J., Li, C., et al. (2026) · Cell · doi:10.1016/j.cell.2026.02.013 · Cited by 12
Untangle the mystery behind DS-associated AD – Is APP the main protagonist?
Elangovan, A., Babu, H. W. S., Iyer, M., Gopalakrishnan, A. V., & Vellingiri, B. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101930 · Cited by 12
The Roles of sPLA2s in Skin Homeostasis and Disease
Yamamoto, K., Hakoi, H., Nomura, S., & Murakami, M. (2023) · Biomolecules · doi:10.3390/biom13040668 · Cited by 11
Self-citationChanges in the innate immune response to SARS-CoV-2 with advancing age in humans
Agrawal, S., Tran, M., Jennings, T. S. K., Soliman, M. M. H., Heo, S., Sasson, B., Rahmatpanah, F. B., & Agrawal, A. (2024) · Immunity & Ageing · doi:10.1186/s12979-024-00426-3 · Cited by 12
“Moreover, increased levels of eicosanoid prostaglandin D 2 and phospholipase PLA 2 G2D were linked with poor outcomes in aged mice [65].”
BackgroundMontoya, B., Melo‐Silva, C. R., Tang, L., Kafle, S., Lidskiy, P., Bajusz, C., Vadovics, M., Muramatsu, H., Ábrahám, E., Lipinszki, Z., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.04.019 · Cited by 14
Enhanced complement activation and MAC formation accelerates severe COVID-19
Ellsworth, C. R., Chen, Z., Xiao, M. T., Qian, C., Wang, C., Khatun, M. S., Liu, S., Islamuddin, M., Maness, N. J., Halperin, J. A., et al. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05430-w · Cited by 12
Ghimire, R., Shrestha, R., Amaradhi, R., Patton, T., Whitley, C., Chanda, D., Liu, L., Ganesh, T., More, S., & Channappanavar, R. (2025) · Journal of Virology · doi:10.1128/jvi.01668-24 · Cited by 13
SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19
Barthez, M., Xue, B., Zheng, J., Wang, Y., Song, Z., Mu, W., Wang, C.-L., Guo, J., Yang, F., Ma, Y., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115562 · Cited by 14
Self-citationZhang, L., Li, Y., Kibler, K. V., Kraberger, S. J., Varsani, A., Turk, J., Elmadbouly, N., Aliskevich, E., Spaccarelli, L., Estifanos, B., et al. (2023) · EMBO Molecular Medicine · doi:10.15252/emmm.202317376 · Cited by 13
CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection
Zheng, J. H., Dhakal, H., Qing, E., Shrestha, R., Geller, A. E., Morrissey, S. M., Saxena, D., Hu, X., Li, H., Li, H., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188222 · Cited by 11
“To generate a virulent mouse-adapted SARS-CoV-2, we inserted the N501Y mutation into the SARS-CoV-2 genome using reverse genetics and passaged this mutant virus through mouse lungs (32).”
InfluentialSelf-citationMurthy, A., Rodríguez, L. R., Dimopoulos, T. T., Bui, S., Iyer, S., Chavez, K., Tomer, Y., Abraham, V., Cooper, C., Renner, D. M., et al. (2024) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00324.2023 · Cited by 11
Upregulation of inflammatory genes and pathways links obesity to severe COVID-19
Currey, J. M., Ellsworth, C. R., Khatun, M. S., Wang, C., Chen, Z., Liu, S., Midkiff, C. C., Xiao, M. T., Ren, M., Liu, F., et al. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167322 · Cited by 12
Wang, L., Guzman, M., Muñoz‐Santos, D., Honrubia, J. M., Ripoll-Gómez, J., Delgado, R. B., Sola, I., Enjuanes, L., & Zúñiga, S. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1268227 · Cited by 11
Self-citationCell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection
Tang, A. T., Buchholz, D. W., Szigety, K. M., Imbiakha, B., Gao, S., Frankfurter, M., Wang, M., Yang, J., Hewins, P., Mericko-Ishizuka, P., et al. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3001989 · Cited by 13
“Similarly, wild-type mice infected with a SARS-CoV-2 virus in which a single amino acid change mutation in the spike protein (D614G) enables efficient infection and transmission do not exhibit severe disease [73], but severe disease and lethality is conferred by a more heavily mutated virus generated by multiple round…”
BackgroundUniversal subunit vaccine protects against multiple SARS-CoV-2 variants and SARS-CoV
Wang, G., Verma, A. K., Shi, J., Guan, X., Meyerholz, D. K., Bu, F., Wen, W., Liu, B., Li, F., Perlman, S. M., et al. (2024) · npj Vaccines · doi:10.1038/s41541-024-00922-z · Cited by 11
Self-citationXia, L., Yuan, L., Hu, Y.-H., Liu, J., Hu, G.-S., Qi, R., Zhang, T.-Y., Xiong, H., Zheng, Z., Lin, H.-W., et al. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-00985-3 · Cited by 10
“For instance, the prototype virus [55] and early variants such as D614G [66], N501Y [67], and Delta [68] are likely to induce robust cytokine storm.”
BackgroundSARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in micePreprint
Alhammad, Y. M. O., Parthasarathy, S., Ghimire, R., O’Connor, J. J., Kerr, C. M., Pfannenstiel, J. J., Chanda, D., Miller, C. A., Unckless, R. L., Zúñiga, S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.06.535927 · Cited by 10
“These include the WT-SARS-CoV-2 BAC based off the Wuhan-Hu-1 isolate provided by Sonia Zuñiga, Li Wang, Isabel Sola and Luis Enjuanes (CNB-CSIC, Madrid, Spain) (59), a MERS-CoV BAC based of the EMC isolate (48), and an MHV BAC based on the JHMV isolate (26).”
MethodSelf-citationReview of impaired immune parameters in RSV infections in the elderly
Miller, J. L., & Niewiesk, S. (2025) · Virology · doi:10.1016/j.virol.2025.110395 · Cited by 9
Andrade, A. C. D. S. P., Lacasse, É., Dubuc, I., Gudimard, L., Gravel, A., Puhm, F., Campolina-Silva, G. H., Queiroz‐Junior, C. M., Allaeys, I., Prunier, J., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2420441122 · Cited by 8
“Our study revealed an increase in prostaglandin production throughout the infection, with PGE 2 and TXA 2 (assessed by quantitating TXB 2 ) showing a positive correlation with lung inflammation, as demonstrated in other studies ( 17 , 18 , 54 ).”
Murakami, M. (2025) · International Immunology · doi:10.1093/intimm/dxaf027 · Cited by 11
“…mediators from EVs or through other mechanisms. sPLA 2 -IID-deficient mice are protected against lung injury caused by infection with influenza or coronavirus (CoV), including severe acute respiratory syndrome (SARS)- CoV, Middle East respiratory syndrome -CoV, and pandemic SARS-CoV-2 (42, 43).”
Self-citationMarjaneh, M. M., Challenger, J. D., Salas, A., Gómez‐Carballa, A., Sivananthan, A., Calle, I. R., Barbeito‐Castiñeiras, G., Foo, C. Y., Wu, Y., Liew, F., et al. (2023) · Journal of Infection · doi:10.1016/j.jinf.2023.10.009 · Cited by 9
The Metabolic Signature of AML Cells Treated With Homoharringtonine
Zhang, Y., Li, N., Chang, Z., Wang, H., Pei, H., Zhang, D., Zhang, Q., Huang, J., Guo, Y., Zhao, Y., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.931527 · Cited by 9
DeDiego, M. L., Portilla, Y., Daviu, N., López-García, D., Villamayor, L., Vázquez-Utrilla, P., Mulens‐Arias, V., Pérez-Yagüe, S., Nogales, A., Ovejero, J. G., et al. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s475323 · Cited by 8
Self-citationRavindran, R. K., O’Connor, E., Gupta, A., Luciw, P. A., Khan, A. I., Dorreh, N., Chiang, K. C., Ikram, A., & Reddy, S. T. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713054 · Cited by 8
“With regards to COVID-19 pathophysiology, blockage of eicosanoid signaling protects mice from severe disease, and apoA-I mimetics attenuate replication of the virus, apoptosis, inflammation, and oxidative stress in vitro [33,34].”
BackgroundJing, H. C., Cao, X., LI, K., Liu, Y., Meng, M., Liu, S., Ye, M., Zhang, J., & Wu, Y. (2024) · Scandinavian Journal of Immunology · doi:10.1111/sji.13393 · Cited by 8
“33 The involvement of PLA2G2D in inflammation and immune responses was mentioned in numerous studies.”
Self-citationDmytrenko, O., Das, S., Kovács, A. D., Cicka, M., Liu, M., Scheaffer, S. M., Bredemeyer, A. L., Mack, M., Diamond, M., & Lavine, K. J. (2024) · Journal of Virology · doi:10.1128/jvi.01179-24 · Cited by 8
Contrasting roles of MERS-CoV and SARS-CoV-2 internal proteins in pathogenesis in mice
Wong, L.-Y. R., Odle, A. E., Luhmann, E. K., Wu, D. C., Wang, Y., Teo, Q. W., Ptak, C. C., Sariol, A., Lowery, S. A., Mack, M., et al. (2023) · mBio · doi:10.1128/mbio.02476-23 · Cited by 9
Self-citationLi, P.-F., Kim, Y., Dampalla, C. S., Nguyen, H. N., Meyerholz, D., Johnson, D. K., Lovell, S., Groutas, W., Perlman, S., & Chang, K.-O. (2023) · mBio · doi:10.1128/mbio.02878-23 · Cited by 7
Self-citationDisruption of immune responses by type 1 diabetes exacerbates SARS-CoV-2 mediated lung injury
Kass-Gergi, S., Gan, Z., Wong, J., Weiner, A. I., Adams‐Tzivelekidis, S., Gentile, M. E., Mendoza, M., Holcomb, N. P., Li, X., Singh, M., et al. (2024) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00250.2024 · Cited by 7
Pan, R., Meyerholz, D. K., & Perlman, S. M. (2023) · Journal of Clinical Investigation · doi:10.1172/jci172659 · Cited by 7
“V2C was inserted into ancestral SARS-CoV-2 (Wuhan-Hu-1; rSARS2-WH-V2C), which cannot infect laboratory mice but can infect hACE2 transgenic (K18-hACE2) mice (4), and into mouse-adapted SARS2-N501Y MA30 (rSARS2-MA30-V2C), which infects all strains of laboratory mice (5).”
BackgroundSelf-citationNatural Killer Cells Do Not Attenuate a Mouse-Adapted SARS-CoV-2-Induced Disease in Rag2−/− Mice
Ellsworth, C. R., Wang, C., Katz, A. R., Chen, Z., Islamuddin, M., Yang, H., Scheuermann, S. E., Goff, K. A., Maness, N. J., Blair, R. V., et al. (2024) · Viruses · doi:10.3390/v16040611 · Cited by 7
“They reported MA30 as highly virulent such that 5000 PFUs caused a lethal disease in young (6–10 week) BALB/c mice and aged (24 weeks old) B6 mice, but not in 6–10-week-old B6 mice [22].”
BackgroundMethodInfluentialPersistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug LimitationsPreprint
Verma, A. K., Lowery, S. A., Lin, L.-C., Duraisami, E., Abrahante, J. E., Qiu, Q., Hefti, M. M., Yu, C. R., Albers, M. W., & Perlman, S. M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.02.596989 · Cited by 7
Self-citationT-cell-derived IFN-γ suppresses T follicular helper cell differentiation and antibody responses
Sala, E., Nelli, M., Laura, C., Lucia, P. D., Beccaría, C. G., Bono, E. B., Mangione, M., Marotta, D., Sperto, V., Grillo, M., et al. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00414-3 · Cited by 6
“To this end we used a mouse-adapted SARS-CoV-2 strain, rSARS-N501YMA30 (Wong et al, 2022) which was administrated to WT mice via aerosol (Fumagalli et al, 2021, 2024) (Fig.”
Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models
Zheng, H., 中国科学院昆明动物研究所遗传资源与进化国家重点实验室, 生., Song, T., Zheng, Y., & 中国科学院昆明动物研究所模式动物表型与遗传研究国家重大科技基础设施(灵长类设施), 国. (2024) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2024.062 · Cited by 6
Effects of sEH inhibition on the eicosanoid and cytokine storms in SARS‐CoV ‐2‐infected mice
Edin, M. L., Gruzdev, A., Graves, J. P., Lih, F. B., Morisseau, C. H. P., Ward, J. M., Hammock, B. D., Bosio, C. M., & Zeldin, D. C. (2024) · The FASEB Journal · doi:10.1096/fj.202302202rr · Cited by 7
“6,13,15 P450-derived EETs have largely beneficial cardiovascular actions.”
BackgroundViral syncytia evolve to resist interferon
Li, T., Kang, I., Ye, J., Hu, Z., Gibbs, J. S., Ye, C., Takeda, K., Košík, I., Shi, G., Hollý, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-74676-8 · Cited by 6
Optimal diagnostic fever thresholds using non-contact infrared thermometers under COVID-19
Lai, F., Li, X., Liu, T., Wang, X., Wang, Q., Chen, S., Wei, S., Xiong, Y., Hou, Q., Zeng, X., et al. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2022.985553 · Cited by 6
A complex immune communication between eicosanoids and pulmonary macrophages
Pernet, E., Poschmann, J., & Divangahi, M. (2024) · Current Opinion in Virology · doi:10.1016/j.coviro.2024.101399 · Cited by 6
Dual-role epitope on SARS-CoV-2 spike enhances and neutralizes viral entry across different variants
Ye, G., Bu, F., Pan, R., Mendoza, A., Saxena, D., Zheng, J., Perlman, S. M., Liu, B., & Li, F. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012493 · Cited by 6
Self-citationXu, Y., Wu, C., Cao, X., Gu, C., Liu, H., Jiang, M., Wang, X., Yuan, Q., Wu, K., Liu, J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.12.488075 · Cited by 6
TNF-α exacerbates SARS-CoV-2 infection by stimulating CXCL1 production from macrophages
Kobayashi, M., Kobayashi, N., Deguchi, K., Omori, S., Nagai, M., Fukui, R., Song, I., Fukuda, S., Miyake, K., & Ichinohe, T. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012776 · Cited by 5
Airway immunometabolic responses during pulmonary bacterial and viral infections
Wadhwa, R., Tang, E. W., Wong, L. Y. R., & Lung, T. W. F. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116614 · Cited by 5
“99,100 This drives the increased production of the lipid mediator prostaglandin D 2 (PGD 2 ) in the airway during CoV infection.”
Self-citation
Metadata
- Authors
- Wong, L.-Y. R., Zheng, J., Wilhelmsen, K., Li, K., Ortiz, M. E., Schnicker, N. J., Thurman, A., Pezzulo, A. A., Szachowicz, P. J., Li, P., Pan, R., Klumpp, K., Aswad, F., Rebo, J., Narumiya, S., Murakami, M., Zuniga, S., Sola, I., Enjuanes, L., Meyerholz, D. K., Fortney, K., McCray, P. B., & Perlman, S.
- Affiliations
- University of Iowa (US)
- Kyoto University (JP)
- Center for Disease Biology and Integrative Medicine, The University of Tokyo (JP)
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- McCray, Paul B.
- Perlman, Stanley
- ORCID
- Wong, Lok-Yin Roy
- Zheng, Jian
- Wilhelmsen, Kevin
- Li, Kun
- Ortiz, Miguel E.
- Schnicker, Nicholas J.
- Thurman, Andrew
- Pezzulo, Alejandro A.
- Szachowicz, Peter J.
- Li, Pengfei
- Pan, Ruangang
- Klumpp, Klaus
- Aswad, Fred
- Narumiya, Shuh
- Murakami, Makoto
- Zuniga, Sonia
- Sola, Isabel
- Enjuanes, Luis
- Meyerholz, David K.
- Fortney, Kristen
- McCray, Paul B.
- Perlman, Stanley
- Venue
- Nature
- Published
- 2022-03-21
- Volume
- 605
- Issue
- 7908
- Pages
- 146-151
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9783543
- OpenAlex
- W4221027163
- Semantic Scholar
- 1b2a5f58f143f03b3e8a769283ac4c513f4b72f8
- Cited by
- 178
- References
- 49
- Citations by year
- 2026: 21 · 2025: 34 · 2024: 59 · 2023: 43 · 2022: 21
- FWCI
- 19.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Cystic Fibrosis Foundation
- Roy J. Carver Charitable Trust
- University of Washington
- National Institutes of Health (P30 DK, T32 AI007511, AI060699, P30 DK-54759, AI007511)
- National Heart, Lung, and Blood Institute (K01HL140261, R01HL163024)
- National Institute of Allergy and Infectious Diseases (T32 AI007511, P01AI060699, R01AI129269)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK054759)
- National Institute of Environmental Health Sciences (P30ES005605)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Asthma and respiratory diseases
- Keywords
- COVID-19 pandemic, SARS-CoV-2, prostaglandin D2, prostaglandin D2 receptor, aging, aged mice, SARS-CoV-2 variants, spike protein mutations, dendritic cells, disease severity
- MeSH terms
- COVID-19, SARS-CoV-2, Animals, Leukocytes, Mononuclear, Organic Chemicals, Oxazoles, Piperazines, Polyesters, Prostaglandins, Sulfonamides, Eicosanoids, Mice, Spike Glycoprotein, Coronavirus
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