Heightened Circulating Interferon-Inducible Chemokines, and Activated Pro-Cytolytic Th1-Cell Phenotype Features Covid-19 Aggravation in the Second Week of Illness

Abstract

Covid-19 features a delayed onset of critical illness occurring approximately one week from the beginning of symptoms, which corresponds to the bridging of innate and adaptive immunity. We reasoned that the immune events occurring at the turning point of disease might mark the direction toward pathogenic versus protective inflammatory responses. Subjects with either severe (s; PaO2/FiO2 ratio <200) or mild (m; PaO2/ FiO2 ratio>300) Covid-19 were enrolled. A range of chemokines and cytokines as well as reactive oxygen species (ROS) were measured in plasma. Dendritic and NK cell frequency, monocyte and B-/T-cell phenotype and SARS-CoV-2-specific T-cell responses were assessed in PBMC. Twenty mCovid-19 and 20 sCovid-19 individuals were studied. sCovid-19 patients displayed higher non-classical monocytes, plasma chemokines (CXCL8, CXCL9, CXCL10), cytokines (IL-6, IL-10), and ROS versus mCovid-19. sCovid-19 also showed significantly increased activated CD38+HLA-DR+ Tlymphocyte, and granzyme-B+/perforin+ pro-cytolytic T-cells. All Covid-19 patients showed SARS-CoV-2 specific-T-cell response with a predominance of Th1 bi-or trifunctional IFN-g/IL-2/TNF-a-expressing CD4+, while no difference according to disease severity was observed. Severe Covid-19 features heightened circulating IFNinducible chemokines and activated pro-cytolytic Th1 cell phenotype in the second week of illness, yet SARS-CoV-2-specific responses are similar to that of mild illness. Altogether, our observations suggest Th1 polarization coupled to higher cytolytic profile in sCovid-19 as correlate of disease pathogenesis and as potential targets to be investigated in the roadmap to therapy and vaccine development.

The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved

“… CHEMOKINE STUDIES REFERENCE CXC FAMILY CXCL1 Chua et al; Ghebremedhin et al [ 7 , 15 ] CXCL3 Chua et al [ 7 ] CXCL5 Blanco-Melo et al; Vanderheiden et al [ 10 , 18 ] CXCL6 Blanco-Melo et al; Vanderheiden et al [ 10 , 18 ] CXCL8 Chua et al ; Vanderheiden et al ; Liu et al ; Li et al ; Tincati et al; Diorio et al ; Del Valle et al, Moratto et al [7, [18] , [19] , [20] , [22] , [23] , [24] , 28 ] CXCL9 Chi et al, Lucas et. al Moratto et al Chen et al;, Kwon et al [ 8 , 9 , 28 , 36 , 45 ] CXCL10 Xiong et al; Chua et al; Chi et al, Li et al, Huang et al; Tincati et al, Moratto et al; Yang et al ; Zhang et al ; Zhang et al ; Hue et al ; Chen et al; Blot et al, Kwon et al, Yao et al, Blot et al [ 4 , 7 , 8 , [20] , [21] , [22] , 28 , [32] ...…”

“…al [ 9 ] CC FAMILY CCL1 Lucas et. al [ 9 ] CCL2 Xiong et al ; Zhou et al; Liao et al; Chua et al ; Chi et al, Lucas et al, Blanco-Melo et al ; Li et al; Huang et al ; Tincati et al, Moratto et al ; Zhang et al ; Chen et al; Abers et al;Kwon et al, Sierra et al, Yao et al [ [4] , [5] , [6] , [7] , [8] , [9] , [10] , [20] , [21] , [22] , 28 , 34 , 36 , [44] , [45] , [46] , 54 ] CCL3 Xiong et al; Zhou et al ; Liao et al ; Chua et al, Chi et al,Chen et al ; Sierra et al; Gruber et al ; Yao et al [ [4] , [5] , [6] , [7] , [8] , 36 , 46 , 50 , 54 ] CCL4 Xiong et al ; Zhou et al ; Liao et al ; Lucas et. al.…”

“…In particular, high CXCL8 levels persisted until hospital day-5, being associated with disease progression [ 21 ]. The Authors, suggested that, the neutrophilia, frequently occurring in severe COVID-19, might be ascribed to the abnormal elevation of CXCL8 and granulocyte-macrophage colony-stimulating factor [ 21 , 22 ]. In a subsequent study, a direct comparison between patients with severe versus moderate disease found that higher levels of inflammatory chemokines including MCP-1/CCL2, IP-10/CXCL10, IL-8/CXCL8, are found in patients with critical illness, correlating with both neutrophilia and increased circulating pro-inflammatory CD14+ CD16++ monocytes [ 23 ].…”

“…Moreover, the circulating levels of CCL2 were nearly doubled (264 vs. 134 pg/mL) in the severe group compared to non-severe group [ 21 ]. Also Huang et al, confirmed that intensive care unit (ICU) patients showed significantly higher plasma levels of GSCF, CXCL10, CCL2, CCL3, and TNF-α than those not requiring ICU, further indicating that the occurrence of the “cytokine storms” largely contributes in aggravating the disease, being also associated with the progression of pneumonia/respiratory failure [ 22 ]. As previously reported, CCL2 (together with CXCL10) was appear to be associated to disease severity in COVID-19 patients [ 36 ].…”

“…The idea that CXCL10 and CCL2 should be regarded as “dominant” in the chemokine immune signature stems from the number of studies consistently reporting their crucial role in the onset of the cytokine storm of COVID-19 and from their relevance in determining specific features of this condition. Indeed, among the several chemokines which have been evaluated and found to be involved in COVID-19, CXCL10 and CCL2 were found to be the most up-regulated ones as compared to controls, showing different degrees of correlation with the viral load as well as with several peculiar symptoms (asthenia, dyspnea, anosmia) [ 5 , [7] , [8] , [9] , [10] , [11] , [21] , [22] , [23] , 29 , 36 , 37 , [44] , [45] , [46] , 49 , 54 , [65] , [66] , [67] ]. Most importantly, CXCL10 and CCL2 were identified to be rather good markers of disease severity since their circulating levels progressively increase in patients with moderate, mild and severe clinical manifestations.…”