SARS-CoV-2 RNA elements share human sequence identity and upregulate hyaluronan via NamiRNA-enhancer network

Wei Li, Shuai Yang, Peng Xu, Dapeng Zhang, Ying Tong, Lu Chen, Ben Jia, Ang Li, Cheng Lian, Daoping Ru, Baolong Zhang, Mengxing Liu, Cancan Chen, Weihui Fu, Songhua Yuan, Chenjian Gu, Lu Wang, Wenxuan Li, Ying Liang, Zhicong Yang, Xiaoguang Ren, Shaoxuan Wang, Xiaoyan Zhang, Yuanlin Song, Youhua Xie, Hongzhou Lu, Jianqing Xu, Hailin Wang, Wenqiang Yu, Wei Li, Shuai Yang, Peng Xu, Dapeng Zhang, Ying Tong, Lu Chen, Ben Jia, Ang Li, Cheng Lian, Daoping Ru, Baolong Zhang, Mengxing Liu, Cancan Chen, Weihui Fu, Songhua Yuan, Chenjian Gu, Lu Wang, Wenxuan Li, Ying Liang, Zhicong Yang, Xiaoguang Ren, Shaoxuan Wang, Xiaoyan Zhang, Yuanlin Song, Youhua Xie, Hongzhou Lu, Jianqing Xu, Hailin Wang, Wenqiang Yu

Abstract

Background: Since late 2019, SARS-CoV-2 infection has resulted in COVID-19 accompanied by diverse clinical manifestations. However, the underlying mechanism of how SARS-CoV-2 interacts with host and develops multiple symptoms is largely unexplored.

Methods: Bioinformatics analysis determined the sequence similarity between SARS-CoV-2 and human genomes. Diverse fragments of SARS-CoV-2 genome containing Human Identical Sequences (HIS) were cloned into the lentiviral vector. HEK293T, MRC5 and HUVEC were infected with laboratory-packaged lentivirus or transfected with plasmids or antagomirs for HIS. Quantitative RT-PCR and chromatin immunoprecipitation assay detected gene expression and H3K27ac enrichment, respectively. UV-Vis spectroscopy assessed the interaction between HIS and their target locus. Enzyme-linked immunosorbent assay evaluated the hyaluronan (HA) levels of culture supernatant and plasma of COVID-19 patients.

Findings: Five short sequences (24-27 nt length) sharing identity between SARS-CoV-2 and human genome were identified. These RNA elements were highly conserved in primates. The genomic fragments containing HIS were predicted to form hairpin structures in silico similar to miRNA precursors. HIS may function through direct genomic interaction leading to activation of host enhancers, and upregulation of adjacent and distant genes, including cytokine genes and hyaluronan synthase 2 (HAS2). HIS antagomirs and Cas13d-mediated HIS degradation reduced HAS2 expression. Severe COVID-19 patients displayed decreased lymphocytes and elevated D-dimer, and C-reactive proteins, as well as increased plasma hyaluronan. Hymecromone inhibited hyaluronan production in vitro, and thus could be further investigated as a therapeutic option for preventing severe outcome in COVID-19 patients.

Interpretation: HIS of SARS-CoV-2 could promote COVID-19 progression by upregulating hyaluronan, providing novel targets for treatment.

Funding: The National Key R&D Program of China (2018YFC1005004), Major Special Projects of Basic Research of Shanghai Science and Technology Commission (18JC1411101), and the National Natural Science Foundation of China (31872814, 32000505).

Keywords: Human Identical Sequences; Hyaluronan; NamiRNA-enhancer network; SARS-CoV-2.

Conflict of interest statement

Declaration of interests Wenqiang Yu, Wei Li, Jianqing Xu, Hailin Wang, Cheng Lian, Peng Xu, Shuai Yang, and Daoping Ru are listed as inventors on patents' application related to this work; no other relationships or activities that could appear to have influenced the submitted work.

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Figure 1
Figure 1
Identification of human identical sequences in SARS-CoV-2. (a) The sequences of five HIS identified in SARS-CoV-2. Numbers in parentheses indicate the location of HIS in the corresponding genomes. (b) The location of the identical sequence of HIS-SARS2-1 and HIS-SARS2-2 in human chromosome 3 and their surrounding genes. All genes within ± 500 kb of these loci are listed. Among them, inflammation- or immunity- related genes are written in red, which are defined by text mining (search combining keywords "gene name + inflammation" or "gene name + immunity") in PubMed and Google Scholar. (c) The distribution of enhancer marker H3K27 acetylation (H3K27ac) across the identical sequence of HIS-SARS2-1 in human genome in seven human cell lines. The location of the identical sequence of HIS-SARS2-1 is marked in red line and black block, respectively. (d) KEGG pathway enrichment analysis of genes within ± 500 kb of the identical sequences of HIS-SARS2 in human genomes.
Figure 2
Figure 2
The distribution and conservation of HIS. (a) Number of HIS identified in seven known HCoVs. (b) The sequence conservation of HIS-SARS2-1 in 19 species. The color of bases represents the conservation degree, dark blue represents the fully conserved, while light blue represents the mismatched base, single line (-) indicates no bases in the aligned species. (c) The predicted RNA secondary structures of HIS-SARS2-1 and its adjunct bases (defined as pre-HIS-SARS2-1) by the algorithm of minimum free energy. The sequence in red represents HIS-SARS2-1 RNA.
Figure 3
Figure 3
HIS-SARS2 activates genes related to COVID-19 pathology. (a–c) The relative mRNA expression of the neighboring genes FBXO15, TIMM21, and CYB5A after HIS-SARS2-4 vector transfected in HEK293T cells (a), MRC5 cells (b), and HUVEC cells (c). (d–f) The relative mRNA expression of the distant gene EPN1, MYL9, and ISOC2 after HIS-SARS2-3 vector transfected in HEK293T cells (d), MRC5 cells (e), and HUVEC cells (f). (g–i) The relative mRNA expression of HSA2 after five HIS-SARS2 vectors transfected in HEK293T cells, MRC5 cells, and HUVEC cells. (k) The enrichment of enhancer marker H3K27ac after HIS-SARS-1, HIS-SARS2-1, HIS-SARS2-3, and HIS-SARS2-4 transfection. Data are represented as mean ± SEM (n = 3). P-values were calculated using the unpaired, two-tailed Student's t test by GraphPad Prism 7.0. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant.
Figure 4
Figure 4
Loss-of-function of HIS abolishes the upregulation of their targeted genes. (a) The relative mRNA expression of HIS-SARS2-1 targeted gene KALRN in HEK293T cells after Cas13d knocked down HIS-SARS2-1. (b) The relative mRNA expression of HIS-SARS2-3 targeted genes HAS2 and MYL9 in HEK293T cells after Cas13d knocked down HIS-SARS2-3. (c) The relative mRNA expression of HIS-SARS2-4 targeted genes HAS2, FBXO15, and TIMM21 in HEK293T cells after Cas13d knocked down HIS-SARS2-4. (d–f) The relative mRNA expression of the targeted gene KALRN (d), MYL9 (e), HAS2, FBXO15, and TIMM21 (f) after transfection of antagomirs of HIS-SARS2-1, HIS-SARS2-3, and HIS-SARS2-4, respectively. Data are represented as mean ± SEM (n = 3). In all figures, P-values were calculated using the unpaired, two-tailed Student's t test by GraphPad Prism 7.0. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant.
Figure 5
Figure 5
HIS-SARS2 RNA binds to homologous sequence of human genome for gene activation. (a) The UV absorption spectra of 2 μM HIS-SARS2-1 DNA (red curve a), 2 μM HIS-SARS2-1 RNA (blue curve b), mixed HIS-SARS2-1 DNA and RNA (dark cyan curve), hybridized mixture of HIS-SARS2-1 (magenta curve), and the simple sum of curve a and b (dark yellow dotted curve). (b) The relative absorbance changes of 2 μM hybridized mixture of HIS-SARS2-1 and the complementary RNA-HIS-SARS2-1(black square) or HIS-SARS2-1 and the complementary ssDNA (red circle) at 260 nm versus temperature. (c) Gel showing of 25 nM 5′Cy5-HIS-SARS2-1 in the presence of increasing concentrations of hAGO2. (d) Gel showing of 25 nM 5′Cy5-HIS-SARS2-1 DNA duplex in the presence of increasing concentrations of hAGO2. (e) Gel showing of 25 nM 5′Cy5-HIS-SARS2-1 DNA-RNA hybrid in the presence of increasing concentrations of hAGO2. (f) Gel showing 25 nM 5′Cy5-HIS-SARS2-1 (lane 1, 2), 5′Cy5-HIS-SARS2-1 DNA-RNA hybrid (lane 3, 4), 5′Cy5-HIS-SARS2-1 DNA duplex (lane 5, 6) in the absence and presence of 100 nM hAGO2. (g) The bound fraction of 5′Cy5-HIS-SARS2-1 (blue triangle), 5′Cy5-HIS-SARS2-1 DNA-RNA hybrid (black square) and 5′Cy5-HIS-SARS2-1 DNA duplex (red circle) probes in the presence of different concentration of hAGO2.
Figure 6
Figure 6
Hyaluronan can serve as a potential therapeutic target for COVID-19. (a) Hyaluronan released in cell culture supernatants of Mock, HIS-SARS-1, HIS-SARS2-3, and HIS-SARS2-4 overexpressed in HEK293T cell. (b) Hyaluronan in mild patients (n = 37) and severe patients (n = 100). (c-e) HA level (10 ng/mL) functions as a discriminator for patients’ lymphocytes number (c), D-Dimer level (d), and CRP level (e). (f) Represented CT images of pulmonary lesions in mice treated with hyaluronan were presented (n = 5 / group). (g) HA released in cell culture supernatants of Mock, HIS-SARS-1, HIS-SARS2-3, or HIS-SARS2-4 overexpressed in HEK293T after treated with 500 µM 4-MU and DMSO as control. (h) HA released in cell culture supernatants of Mock, HIS-SARS-1, HIS-SARS2-3, and HIS-SARS2-4 overexpressed in HEK293T after treated with 200 µg/ml hymecromone and DMSO as control. Data are represented as mean ± SEM (n = 3). In (a, g-h), P-values were calculated using the unpaired, two-tailed Student's t-test; in (b–e), P-values were calculated using the two-tailed nonparametric Mann–Whitney test by GraphPad Prism 7.0. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.

References

    1. Guan W.J., Ni Z.Y., Hu Y., et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–1720.
    1. Mao R., Qiu Y., He J.S., et al. Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5(7):667–678.
    1. Wiersinga W.J., Rhodes A., Cheng A.C., Peacock S.J., Prescott H.C. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324(8):782–793.
    1. Zhang B., Zhou X., Qiu Y., et al. Clinical characteristics of 82 cases of death from COVID-19. PLoS One. 2020;15(7)
    1. Hassan A.O., Case J.B., Winkler E.S., et al. A SARS-CoV-2 infection model in mice demonstrates protection by neutralizing antibodies. Cell. 2020;182(3):744-53 e4.
    1. Zhou P., Yang X.L., Wang X.G., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273.
    1. Hoffmann M., Kleine-Weber H., Schroeder S., Krüger N., Herrler T., Erichsen S., et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271. 80.e8.
    1. Blanco-Melo D., Nilsson-Payant B.E., Liu W.C., et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181(5):1036-45 e9.
    1. Chen G., Wu D., Guo W., et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620–2629.
    1. Diao B.W., Tan C., Chen Y., et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19) Front Immunol. 2020;11:827.
    1. Levi M., Thachil J., Iba T., Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020;7(6):e438–ee40.
    1. Weng K.F., Hsieh P.T., Huang H.I., Shih SR. Mammalian RNA virus-derived small RNA: biogenesis and functional activity. Microbes Infect. 2015;17(8):557–563.
    1. Shapiro J.S. Processing of virus-derived cytoplasmic primary-microRNAs. Wiley Interdiscip Rev RNA. 2013;4(4):463–471.
    1. Mishra R., Kumar A., Ingle H., Kumar H. The interplay between viral-derived miRNAs and host immunity during infection. Front Immunol. 2019;10:3079.
    1. Weng K.F., Hung C.T., Hsieh P.T., et al. A cytoplasmic RNA virus generates functional viral small RNAs and regulates viral IRES activity in mammalian cells. Nucleic Acids Res. 2014;42(20):12789–12805.
    1. Perez J.T., Varble A., Sachidanandam R., et al. Influenza A virus-generated small RNAs regulate the switch from transcription to replication. Proc Natl Acad Sci U S A. 2010;107(25):11525–11530.
    1. Lung R.W., Tong J.H., To KF. Emerging roles of small Epstein-Barr virus derived non-coding RNAs in epithelial malignancy. Int J Mol Sci. 2013;14(9):17378–17409.
    1. Guo X., Li W.X., Lu R. Silencing of host genes directed by virus-derived short interfering RNAs in caenorhabditis elegans. J Virol. 2012;86(21):11645–11653.
    1. Morales L., Oliveros J.C., Fernandez-Delgado R., tenOever B.R., Enjuanes L., Sola I. SARS-CoV-encoded small RNAs contribute to infection-associated lung pathology. Cell Host Microbe. 2017;21(3):344–355.
    1. Arisan E.D., Dart A., Grant G.H., et al. The prediction of miRNAs in SARS-CoV-2 genomes: hsa-miR databases identify 7 key miRs linked to host responses and virus pathogenicity-related KEGG pathways significant for comorbidities. Viruses. 2020;12(6)
    1. Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012;13(4):271–282.
    1. Xiao M., Li J., Li W., et al. MicroRNAs activate gene transcription epigenetically as an enhancer trigger. RNA Biol. 2017;14(10):1326–1334.
    1. Liang Y., Lu Q., Li W., et al. Reactivation of tumour suppressor in breast cancer by enhancer switching through NamiRNA network. Nucleic Acids Res. 2021;49(15):8556–8572.
    1. Suzuki H.I., Young R.A., Sharp PA. Super-enhancer-mediated RNA processing revealed by integrative MicroRNA network analysis. Cell. 2017;168(6):1000–1014. e15.
    1. Wu K.E., Fazal F.M., Parker K.R., Zou J., Chang HY. RNA-GPS predicts SARS-CoV-2 RNA residency to host mitochondria and nucleolus. Cell Syst. 2020;11(1):102. 8.e3.
    1. Kim D., Lee J.Y., Yang J.S., Kim J.W., Kim V.N., Chang H. The architecture of SARS-CoV-2 transcriptome. Cell. 2020;181(4):914-21 e10.
    1. Chen Y., Ye W., Zhang Y., Xu Y. High speed BLASTN: an accelerated MegaBLAST search tool. Nucleic Acids Res. 2015;43(16):7762–7768.
    1. Bernhart S.H., Hofacker I.L., Will S., Gruber A.R., Stadler PF. RNAalifold: improved consensus structure prediction for RNA alignments. BMC Bioinf. 2008;9:474.
    1. Huang da W., Sherman B.T., Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.
    1. Gao T., Qian J. EnhancerAtlas 2.0: an updated resource with enhancer annotation in 586 tissue/cell types across nine species. Nucleic Acids Res. 2020;48(D1):D58–D64.
    1. Zou Q., Xiao X., Liang Y., et al. miR-19a-mediated downregulation of RhoB inhibits the dephosphorylation of AKT1 and induces osteosarcoma cell metastasis. Cancer Lett. 2018;428:147–159.
    1. Chen T., Chen X., Zhang S., et al. The genome sequence archive family: toward explosive data growth and diverse data types. Genom Proteom Bioinform. 2021 In press.
    1. Members C-N, Partners Database resources of the national genomics data center, China national center for bioinformation in 2021. Nucleic Acids Res. 2021;49(D1):D18–D28.
    1. Green M.R., Hughes H., Sambrook J., MacCallum P. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press; 2012. Molecular cloning: a laboratory manual; p. 1890.
    1. Bernard H.U. Regulatory elements in the viral genome. Virology. 2013;445(1-2):197–204.
    1. Fan P.C., Chen C.C., Chen Y.C., Chang Y.S., Chu PH. MicroRNAs in acute kidney injury. Hum Genom. 2016;10(1):29.
    1. Mathews D.H., Disney M.D., Childs J.L., Schroeder S.J., Zuker M., Turner D.H. Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. Proc Natl Acad Sci U S A. 2004;101(19):7287–7292.
    1. Besnard V., Calender A., Bouvry D., et al. G908R NOD2 variant in a family with sarcoidosis. Respir Res. 2018;19(1):44.
    1. Chen B.B., Coon T.A., Glasser J.R., et al. E3 ligase subunit Fbxo15 and PINK1 kinase regulate cardiolipin synthase 1 stability and mitochondrial function in pneumonia. Cell Rep. 2014;7(2):476–487.
    1. Mick D.U., Dennerlein S., Wiese H., et al. MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation. Cell. 2012;151(7):1528–1541.
    1. Plitzko B., Ott G., Reichmann D., et al. The involvement of mitochondrial amidoxime reducing components 1 and 2 and mitochondrial cytochrome b5 in N-reductive metabolism in human cells. J Biol Chem. 2013;288(28):20228–20237.
    1. Hayashizaki K., Kimura M.Y., Tokoyoda K., et al. Myosin light chains 9 and 12 are functional ligands for CD69 that regulate airway inflammation. Sci Immunol. 2016;1(3):eaaf9154.
    1. Brophy M.L., Dong Y., Tao H., et al. Myeloid-specific deletion of epsins 1 and 2 reduces atherosclerosis by preventing LRP-1 downregulation. Circ Res. 2019;124(4):e6–e19.
    1. Hällgren R., Samuelsson T., Laurent T.C., Modig J. Accumulation of hyaluronan (hyaluronic acid) in the lung in adult respiratory distress syndrome. Am Rev Respir Dis. 1989;139(3):682–687.
    1. Wu C., Chen X., Cai Y., et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934–943.
    1. Xiong Y., Liu Y., Cao L., et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerg Microbes Infect. 2020;9(1):761–770.
    1. Zhang X., Tan Y., Ling Y., et al. Viral and host factors related to the clinical outcome of COVID-19. Nature. 2020;583(7816):437–440.
    1. Banerjee A.K., Blanco M.R., Bruce E.A., et al. SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses. Cell. 2020;183(5):1325–1339. e21.
    1. Ravindra N.G., Alfajaro M.M., Gasque V., et al. Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes. PLoS Biol. 2021;19(3)
    1. Robinot R., Hubert M., de Melo G.D., et al. SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance. Nat Commun. 2021;12(1):4354.
    1. Victor J., Deutsch J., Whitaker A., et al. SARS-CoV-2 triggers DNA damage response in Vero E6 cells. Biochem Biophys Res Commun. 2021;579:141–145.
    1. Zou Q., Liang Y., Luo H., Yu W. miRNA-mediated RNAa by targeting enhancers. Adv Exp Med Biol. 2017;983:113–125.
    1. Liang Y., Xu P., Zou Q., Luo H., Yu W. An epigenetic perspective on tumorigenesis: loss of cell identity, enhancer switching, and NamiRNA network. Semin Cancer Biol. 2019;57:1–9.
    1. Wang D., Li R., Wang J., et al. Correlation analysis between disease severity and clinical and biochemical characteristics of 143 cases of COVID-19 in Wuhan, China: a descriptive study. BMC Infect Dis. 2020;20(1):519.
    1. Xie X., Zhong Z., Zhao W., Zheng C., Wang F., Liu J. Chest CT for typical coronavirus disease 2019 (COVID-19) pneumonia: relationship to negative RT-PCR testing. Radiology. 2020;296(2):E41–EE5.
    1. Nagy N., Kuipers H.F., Frymoyer A.R., et al. 4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer. Front Immunol. 2015;6:123.
    1. Rothenburg S., Brennan G. Species-specific host-virus interactions: implications for viral host range and virulence. Trends Microbiol. 2020;28(1):46–56.
    1. De Meyer S., Gong Z.J., Suwandhi W., van Pelt J., Soumillion A., Yap S.H. Organ and species specificity of hepatitis B virus (HBV) infection: a review of literature with a special reference to preferential attachment of HBV to human hepatocytes. J Viral Hepat. 1997;4(3):145–153.
    1. Iwamoto T., Okinaka Y., Mise K., et al. Identification of host-specificity determinants in betanodaviruses by using reassortants between striped jack nervous necrosis virus and sevenband grouper nervous necrosis virus. J Virol. 2004;78(3):1256–1262.
    1. Ohlund P., Lunden H., Blomstrom AL. Insect-specific virus evolution and potential effects on vector competence. Virus Genes. 2019;55(2):127–137.
    1. Levy JA. HIV and the pathogenesis of AIDS. American Society for Microbiology; 1994.
    1. Beeching NJ, Fenech M, Houlihan CF. Ebola virus disease. BMJ. 2014;349:g7348.
    1. Petersen L.R., Jamieson D.J., Powers A.M. Honein MAJNEJoM. Zika Virus. 2016;374(16):1552–1563.
    1. Zhou P., Yang X.L., Wang X.G., Hu B., Zhang L., Zhang W., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273.
    1. Lam T.T., Jia N., Zhang Y.W., et al. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Nature. 2020;583(7815):282–285.
    1. Xiao K., Zhai J., Feng Y., et al. Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins. Nature. 2020;583(7815):286–289.
    1. Shi J., Wen Z., Zhong G., et al. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science. 2020;368(6494):1016–1020.
    1. Huang C., Wang Y., Li X., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.
    1. Giorgi M., Cardarelli S., Ragusa F., et al. Phosphodiesterase inhibitors: could they be beneficial for the treatment of COVID-19? Int J Mol Sci. 2020;21(15)
    1. Saleh J., Peyssonnaux C., Singh K.K., Edeas M. Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion. 2020;54:1–7.
    1. Csoka A.B., Frost G.I., Stern R. The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol. 2001;20(8):499–508.
    1. Ding M., Zhang Q., Li Q., Wu T., Huang YZ. Correlation analysis of the severity and clinical prognosis of 32 cases of patients with COVID-19. Respir Med. 2020;167
    1. Turino G.M., Cantor JO. Hyaluronan in respiratory injury and repair. Am J Respir Crit Care Med. 2003;167(9):1169–1175.
    1. Bhattacharya J., Cruz T., Bhattacharya S., Bray BA. Hyaluronan affects extravascular water in lungs of unanesthetized rabbits. J Appl Physiol. 1989;66(6):2595–2599. (1985)
    1. Qin C., Zhou L., Hu Z., et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762–768.
    1. McKallip R.J., Do Y., Fisher M.T., Robertson J.L., Nagarkatti P.S., Nagarkatti M. Role of CD44 in activation-induced cell death: CD44-deficient mice exhibit enhanced T cell response to conventional and superantigens. Int Immunol. 2002;14(9):1015–1026.
    1. Kanse S.M., Parahuleva M., Muhl L., Kemkes-Matthes B., Sedding D., Preissner K.T. Factor VII-activating protease (FSAP): vascular functions and role in atherosclerosis. Thromb Haemost. 2008;99(2):286–289.
    1. Mambetsariev N., Mirzapoiazova T., Mambetsariev B., et al. Hyaluronic acid binding protein 2 is a novel regulator of vascular integrity. Arterioscler Thromb Vasc Biol. 2010;30(3):483–490.
    1. Barrios-Lopez J.M., Rego-Garcia I., Munoz Martinez C., et al. Ischaemic stroke and SARS-CoV-2 infection: a causal or incidental association? Neurologia. 2020;35(5):295–302.
    1. Klein S., Cortese M., Winter S.L., et al. SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography. Nat Commun. 2020;11(1):5885.
    1. Burke J.M., St Clair L.A., Perera R., Parker R. SARS-CoV-2 infection triggers widespread host mRNA decay leading to an mRNA export block. RNA. 2021;27(11):1318–1329.
    1. Mine S., Okada Y., Kawahara C., Tabata T., Tanaka Y. Serum hyaluronan concentration as a marker of angiopathy in patients with diabetes mellitus. Endocr J. 2006;53(6):761–766. advpub:0609110032
    1. Kalay N., Elcik D., Canatan H., et al. Elevated plasma hyaluronan levels in pulmonary hypertension. Tohoku J Exp Med. 2013;230(1):7–11.

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