{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T18:49:15Z","timestamp":1760986155241,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T00:00:00Z","timestamp":1667865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development (CNPq)","doi-asserted-by":"publisher","award":["304356\/2018-2"],"award-info":[{"award-number":["304356\/2018-2"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"name":"BRDE-PUCPR (Banco Regional de Desenvolvimento do Extremo Sul)","award":["304356\/2018-2"],"award-info":[{"award-number":["304356\/2018-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The COVID-19 pandemic, promoted by the SARS-CoV-2 respiratory virus, has resulted in widespread global morbidity and mortality. The immune response against this pathogen has shown a thin line between protective effects and pathological reactions resulting from the massive release of cytokines and poor viral clearance. The latter is possibly caused by exhaustion, senescence, or both of TCD8+ cells and reduced activity of natural killer (NK) cells. The imbalance between innate and adaptive responses during the early stages of infection caused by SARS-CoV-2 contributes to the ineffective control of viral spread. The present study evaluated the tissue immunoexpression of the tissue biomarkers (Arginase-1, CCR4, CD3, CD4, CD8, CD20, CD57, CD68, CD138, IL-4, INF-\u03b1, INF-\u03b3, iNOS, PD-1, Perforin and Sphingosine-1) to understand the cellular immune response triggered in patients who died of COVID-19. We evaluated twenty-four paraffin-embedded lung tissue samples from patients who died of COVID-19 (COVID-19 group) and compared them with ten lung tissue samples from patients who died of H1N1pdm09 (H1N1 group) with the immunohistochemical markers mentioned above. In addition, polymorphisms in the Perforin gene were genotyped through Real-Time PCR. Significantly increased tissue immunoexpression of Arginase, CD4, CD68, CD138, Perforin, Sphingosine-1, and IL-4 markers were observed in the COVID-19 group. A significantly lower immunoexpression of CD8 and CD57 was also found in this group. It is suggested that patients who died from COVID-19 had a poor cellular response concerning viral clearance and adaptive response going through tissue repair.<\/jats:p>","DOI":"10.3390\/ijms232213734","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T02:34:52Z","timestamp":1667961292000},"page":"13734","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Immune Response Gaps Linked to SARS-CoV-2 Infection: Cellular Exhaustion, Senescence, or Both?"],"prefix":"10.3390","volume":"23","author":[{"given":"Leonardo Vinicius","family":"Barbosa","sequence":"first","affiliation":[{"name":"Postgraduate in Biotechnology Applied in Health of Children and Adolescent, Faculdades Pequeno Pr\u00edncipe (FPP), Instituto de Pesquisa Pel\u00e9 Pequeno Pr\u00edncipe (IPPPP), R. Silva Jardim, 1632 \u00c1gua Verde, Curitiba 80250-060, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele Margarita Marani","family":"Pr\u00e1","sequence":"additional","affiliation":[{"name":"Postgraduate Program of Health Sciences, School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Paran\u00e1 (PUCPR), R. Imaculada Concei\u00e7\u00e3o, 1155 Prado Velho, Curitiba 80215-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0069-3823","authenticated-orcid":false,"given":"Seigo","family":"Nagashima","sequence":"additional","affiliation":[{"name":"Postgraduate Program of Health Sciences, School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Paran\u00e1 (PUCPR), R. Imaculada Concei\u00e7\u00e3o, 1155 Prado Velho, Curitiba 80215-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2637-8856","authenticated-orcid":false,"given":"Marcos Roberto Curcio","family":"Pereira","sequence":"additional","affiliation":[{"name":"Postgraduate Program of Health Sciences, School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Paran\u00e1 (PUCPR), R. Imaculada Concei\u00e7\u00e3o, 1155 Prado Velho, Curitiba 80215-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-3583","authenticated-orcid":false,"given":"Rebecca Benicio","family":"Stocco","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Pathology, School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Paran\u00e1 (PUCPR), R. Imaculada Concei\u00e7\u00e3o, 1155 Prado Velho, Curitiba 80215-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francys de Luca Fernandes","family":"da Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Pathology, School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Paran\u00e1 (PUCPR), R. Imaculada Concei\u00e7\u00e3o, 1155 Prado Velho, Curitiba 80215-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milena Rueda","family":"Cruz","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Pathology, School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Paran\u00e1 (PUCPR), R. Imaculada Concei\u00e7\u00e3o, 1155 Prado Velho, Curitiba 80215-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Djessyka","family":"Dallagassa","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Pathology, School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Paran\u00e1 (PUCPR), R. Imaculada Concei\u00e7\u00e3o, 1155 Prado Velho, Curitiba 80215-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thiago Jo\u00e3o","family":"Stupak","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Pathology, School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Paran\u00e1 (PUCPR), R. 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Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1001\/jama.2020.6775","article-title":"Presenting Characteristics, Comorbidities, and Outcomes among 5700 Patients Hospitalized with COVID-19 in the New York City Area","volume":"323","author":"Richardson","year":"2020","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/s41577-020-0402-6","article-title":"T cell responses in patients with COVID-19","volume":"20","author":"Chen","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","unstructured":"Abbas, A.K., Lichtman, A.H., and Pillai, S. (2012). Imunologia Celular e Molecular, Elsevier. [8th ed.]. Available online: http:\/\/library1.nida.ac.th\/termpaper6\/sd\/2554\/19755.pdf."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2021.01.007","article-title":"Adaptive immunity to SARS-CoV-2 and COVID-19","volume":"184","author":"Sette","year":"2021","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/jmv.26232","article-title":"The cytokine storm and COVID-19","volume":"93","author":"Hu","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41577-020-0346-x","article-title":"Dysregulation of type I interferon responses in COVID-19","volume":"20","author":"Acharya","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/s41423-020-00557-9","article-title":"Unique immunological profile in patients with COVID-19","volume":"18","author":"Varchetta","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_10","first-page":"1653","article-title":"[Interferon and bone]","volume":"25","author":"Miyamoto","year":"2015","journal-title":"Clin. Calcium"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.3389\/fimmu.2021.720109","article-title":"Monocytes and Macrophages in COVID-19","volume":"12","author":"Knoll","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_12","first-page":"4","article-title":"IL-4\/IL-13 remodeling pathway of COVID-19 lung injury","volume":"10","author":"Nagashima","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lee, J.-W., Chun, W., Lee, H., Min, J.-H., Kim, S.-M., Seo, J.-Y., Ahn, K.-S., and Oh, S.-R. (2021). The Role of Macrophages in the Development of Acute and Chronic Inflammatory Lung Diseases. Cells, 10, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/33919784\/.","DOI":"10.3390\/cells10040897"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.3389\/fimmu.2020.580237","article-title":"Elevated Exhaustion Levels of NK and CD8+ T Cells as Indicators for Progression and Prognosis of COVID-19 Disease","volume":"11","author":"Li","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e02243-20","DOI":"10.1128\/mBio.02243-20","article-title":"Impaired cytotoxic CD8+ T cell response in elderly COVID-19 patients","volume":"11","author":"Westmeier","year":"2020","journal-title":"mBio"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"de Paula, C.B.V., Nagashima, S., Liberalesso, V., Collete, M., da Silva, F.P.G., Oricil, A.G.G., Barbosa, G.S., da Silva, G.V.C., Wiedmer, D.B., and Dezid\u00e9rio, F.D.S. (2021). COVID-19: Immunohistochemical Analysis of TGF-\u03b2 Signaling Pathways in Pulmonary Fibrosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010168"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e13045","DOI":"10.1111\/sji.13045","article-title":"Humoral and cellular immune responses in critically ill influenza A\/H1N1-infected patients","volume":"94","author":"Paramsothy","year":"2021","journal-title":"Scand. J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.chest.2020.09.259","article-title":"Lung Histopathology in Coronavirus Disease 2019 as Compared With Severe Acute Respiratory Sydrome and H1N1 Influenza: A Systematic Review","volume":"159","author":"Hariri","year":"2021","journal-title":"Chest"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.2214\/AJR.20.22975","article-title":"CT Features of Coronavirus Disease 2019 (COVID-19) Pneumonia in 62 Patients in Wuhan, China","volume":"214","author":"Zhou","year":"2020","journal-title":"Am. J. Roentgenol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1161\/ATVBAHA.120.314860","article-title":"Endothelial Dysfunction and Thrombosis in Patients with COVID-19\u2014Brief Report","volume":"40","author":"Nagashima","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"338","DOI":"10.3389\/fcimb.2017.00338","article-title":"Mechanisms of severe mortality-associated bacterial co-infections following influenza virus infection","volume":"7","author":"Jia","year":"2017","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e00299-20","DOI":"10.1128\/CMR.00299-20","article-title":"Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis","volume":"34","author":"Ramasamy","year":"2021","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1159\/000514822","article-title":"COVID-19 Interstitial Pneumonia: Histological and Immunohistochemical Features on Cryobiopsies","volume":"100","author":"Doglioni","year":"2021","journal-title":"Respiration"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.cytogfr.2007.06.001","article-title":"Interferon, Mx, and viral countermeasures","volume":"18","author":"Haller","year":"2007","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41586-021-04142-6","article-title":"Untimely TGF\u03b2 responses in COVID-19 limit antiviral functions of NK cells","volume":"600","author":"Witkowski","year":"2021","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108991","DOI":"10.1016\/j.clim.2022.108991","article-title":"Temporal changes in T cell subsets and expansion of cytotoxic CD4+ T cells in the lungs in severe COVID-19","volume":"237","author":"Kaneko","year":"2022","journal-title":"Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.3389\/fimmu.2020.01441","article-title":"Immune Response, Inflammation, and the Clinical Spectrum of COVID-19","volume":"11","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"198171","DOI":"10.1016\/j.virusres.2020.198171","article-title":"IFN-\u03b3 is an independent risk factor associated with mortality in patients with moderate and severe COVID-19 infection","volume":"289","author":"Gadotti","year":"2020","journal-title":"Virus Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"678","DOI":"10.3389\/fimmu.2018.00678","article-title":"The CD8 T cell response to respiratory virus infections","volume":"9","author":"Schmidt","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Xu, W., and Larbi, A. (2017). Markers of T Cell Senescence in Humans. Int. J. Mol. Sci., 18, Available online: https:\/\/www.mdpi.com\/1422-0067\/18\/8\/1742\/htm.","DOI":"10.3390\/ijms18081742"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.cell.2009.06.036","article-title":"Redefining chronic viral infection","volume":"138","author":"Virgin","year":"2009","journal-title":"Cell"},{"key":"ref_32","first-page":"1672","article-title":"Critically Ill Coronavirus Disease 2019 Patients Exhibit Hyperactive Cytokine Responses Associated with Effector Exhausted Senescent T Cells in Acute Infection","volume":"224","author":"Arcanjo","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"507","DOI":"10.2169\/internalmedicine.51.6197","article-title":"Immunohistochemical findings of an autopsied lung specimen from a patient with pandemic influenza (A\/H1N1pdm) virus infection","volume":"51","author":"Fujita","year":"2012","journal-title":"Intern Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/icb.2015.1","article-title":"Heterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals","volume":"93","author":"House","year":"2015","journal-title":"Immunol. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/nri3839","article-title":"Perforin and granzymes: Function, dysfunction and human pathology","volume":"15","author":"Voskoboinik","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zanchettin, A.C., Barbosa, L.V., Dutra, A.A., Pr\u00e1, D.M.M., Pereira, M.R.C., Stocco, R.B., Martins, A.P.C., Vaz de Paula, C.B., Nagashima, S., and de Noronha, L. (2022). Role of Genetic Polymorphism Present in Macrophage Activation Syndrome Pathway in Post Mortem Biopsies of Patients with COVID-19. Viruses, 14.","DOI":"10.3390\/v14081699"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.leukres.2017.12.011","article-title":"Perforin gene variation influences survival in childhood acute lymphoblastic leukemia","volume":"65","author":"Jaworowska","year":"2018","journal-title":"Leuk. Res."},{"key":"ref_39","unstructured":"dbSNP (2021, October 16). NCBI Reference SNP Report, Available online: https:\/\/www.ncbi.nlm.nih.gov\/snp\/?term=rs885822."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13734\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:12:42Z","timestamp":1760145162000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13734"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,8]]},"references-count":39,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232213734"],"URL":"https:\/\/doi.org\/10.3390\/ijms232213734","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,11,8]]}}}