000117425 001__ 117425 000117425 005__ 20240319080956.0 000117425 0247_ $$2doi$$a10.7150/thno.63463 000117425 0248_ $$2sideral$$a128254 000117425 037__ $$aART-2022-128254 000117425 041__ $$aeng 000117425 100__ $$aUranga-Murillo, Iratxe 000117425 245__ $$aIntegrated analysis of circulating immune cellular and soluble mediators reveals specific COVID19 signatures at hospital admission with utility for prediction of clinical outcomes 000117425 260__ $$c2022 000117425 5060_ $$aAccess copy available to the general public$$fUnrestricted 000117425 5203_ $$aCoronavirus disease 2019 (COVID19), caused by SARS-CoV-2, is a complex disease, with a variety of clinical manifestations ranging from asymptomatic infection or mild cold-like symptoms to more severe cases requiring hospitalization and critical care. The most severe presentations seem to be related with a delayed, deregulated immune response leading to exacerbated inflammation and organ damage with close similarities to sepsis. Methods: In order to improve the understanding on the relation between host immune response and disease course, we have studied the differences in the cellular (monocytes, CD8+ T and NK cells) and soluble (cytokines, chemokines and immunoregulatory ligands) immune response in blood between Healthy Donors (HD), COVID19 and a group of patients with non-COVID19 respiratory tract infections (NON-COV-RTI). In addition, the immune response profile has been analyzed in COVID19 patients according to disease severity. Results: In comparison to HDs and patients with NON-COV-RTI, COVID19 patients show a heterogeneous immune response with the presence of both activated and exhausted CD8+ T and NK cells characterised by the expression of the immune checkpoint LAG3 and the presence of the adaptive NK cell subset. An increased frequency of adaptive NK cells and a reduction of NK cells expressing the activating receptors NKp30 and NKp46 correlated with disease severity. Although both activated and exhausted NK cells expressing LAG3 were increased in moderate/severe cases, unsupervised cell clustering analyses revealed a more complex scenario with single NK cells expressing more than one immune checkpoint (PD1, TIM3 and/or LAG3). A general increased level of inflammatory cytokines and chemokines was found in COVID19 patients, some of which like IL18, IL1RA, IL36B and IL31, IL2, IFN alpha and TNF alpha, CXCL10, CCL2 and CCL8 were able to differentiate between COVID19 and NON-COV-RTI and correlated with bad prognosis (IL2, TNF alpha, IL1RA, CCL2, CXCL10 and CXCL9). Notably, we found that soluble NKG2D ligands from the MIC and ULBPs families were increased in COVID19 compared to NON-COV-RTI and correlated with disease severity. Conclusions: Our results provide a detailed comprehensive analysis of the presence of activated and exhausted CD8+T, NK and monocyte cell subsets as well as extracellular inflammatory factors beyond cytokines/chemokines, specifically associated to COVID19. Importantly, multivariate analysis including clinical, demographical and immunological experimental variables have allowed us to reveal specific immune signatures to i) differentiate COVID19 from other infections and ii) predict disease severity and the risk of death. 000117425 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PID2020-113963RB-I00$$9info:eu-repo/grantAgreement/ES/DGA-FEDER/B29-17R$$9info:eu-repo/grantAgreement/ES/MCIU-AEI/SAF2017-83120-C2-1-R 000117425 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/ 000117425 590__ $$a12.4$$b2022 000117425 592__ $$a2.381$$b2022 000117425 591__ $$aMEDICINE, RESEARCH & EXPERIMENTAL$$b8 / 136 = 0.059$$c2022$$dQ1$$eT1 000117425 593__ $$aPharmacology, Toxicology and Pharmaceutics (miscellaneous)$$c2022$$dQ1 000117425 593__ $$aMedicine (miscellaneous)$$c2022$$dQ1 000117425 594__ $$a20.9$$b2022 000117425 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000117425 700__ $$aMorte, Elena$$uUniversidad de Zaragoza 000117425 700__ $$aHidalgo, Sandra 000117425 700__ $$aPesini, Cecilia 000117425 700__ $$aGarcia-Mulero, Sandra 000117425 700__ $$0(orcid)0000-0002-8796-2717$$aSierra, Jose L. 000117425 700__ $$0(orcid)0000-0002-1861-5981$$aSantiago, Llipsy 000117425 700__ $$aArias, Maykel 000117425 700__ $$0(orcid)0000-0002-8486-8514$$aDe Miguel, Diego$$uUniversidad de Zaragoza 000117425 700__ $$0(orcid)0000-0003-4891-105X$$aEncabo-Berzosa, Maria Del Mar 000117425 700__ $$aGracia-Tello, Borja$$uUniversidad de Zaragoza 000117425 700__ $$aSanz-Pamplona, Rebeca 000117425 700__ $$0(orcid)0000-0003-3043-147X$$aMartinez-Lostao, Luis$$uUniversidad de Zaragoza 000117425 700__ $$0(orcid)0000-0001-6928-5516$$aGalvez, Eva M. 000117425 700__ $$0(orcid)0000-0002-9600-8116$$aPaño-Pardo, Jose R.$$uUniversidad de Zaragoza 000117425 700__ $$aRamirez-Labrada, Ariel 000117425 700__ $$0(orcid)0000-0003-0154-0730$$aPardo, Julian$$uUniversidad de Zaragoza 000117425 7102_ $$11007$$2610$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cArea Medicina 000117425 7102_ $$11011$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Inmunología 000117425 7102_ $$11002$$2050$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Biología Celular 000117425 773__ $$g12, 1 (2022), 290-306$$pTHERANOSTICS$$tTheranostics$$x1838-7640 000117425 8564_ $$s2623929$$uhttps://zaguan.unizar.es/record/117425/files/texto_completo.pdf$$yVersión publicada 000117425 8564_ $$s2460941$$uhttps://zaguan.unizar.es/record/117425/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000117425 909CO $$ooai:zaguan.unizar.es:117425$$particulos$$pdriver 000117425 951__ $$a2024-03-18-13:36:43 000117425 980__ $$aARTICLE