Systems Immunology Analysis Reveals the Contribution of Pulmonary and Extrapulmonary Tissues to the Immunopathogenesis of Severe COVID-19 Patients

Abstract

As one of the current global health conundrums, COVID-19 pandemic caused a dramatic increase of cases exceeding 79 million and 1.7 million deaths worldwide. Severe presentation of COVID-19 is characterized by cytokine storm and chronic inflammation resulting in multi-organ dysfunction. Currently, it is unclear whether extrapulmonary tissues contribute to the cytokine storm mediated-disease exacerbation. In this study, we applied systems immunology analysis to investigate the immunomodulatory effects of SARS-CoV-2 infection in lung, liver, kidney, and heart tissues and the potential contribution of these tissues to cytokines production. Notably, genes associated with neutrophil-mediated immune response (e.g. CXCL1) were particularly upregulated in lung, whereas genes associated with eosinophil-mediated immune response (e.g. CCL11) were particularly upregulated in heart tissue. In contrast, immune responses mediated by monocytes, dendritic cells, T-cells and B-cells were almost similarly dysregulated in all tissue types. Focused analysis of 14 cytokines classically upregulated in COVID-19 patients revealed that only some of these cytokines are dysregulated in lung tissue, whereas the other cytokines are upregulated in extrapulmonary tissues (e.g. IL6 and IL2RA). Investigations of potential mechanisms by which SARS-CoV-2 modulates the immune response and cytokine production revealed a marked dysregulation of NF-κB signaling particularly CBM complex and the NF-κB inhibitor BCL3. Moreover, overexpression of mucin family genes (e.g. MUC3A, MUC4, MUC5B, MUC16, and MUC17) and HSP90AB1 suggest that the exacerbated inflammation activated pulmonary and extrapulmonary tissues remodeling. In addition, we identified multiple sets of immune response associated genes upregulated in a tissue-specific manner (DCLRE1C, CHI3L1, and PARP14 in lung; APOA4, NFASC, WIPF3, and CD34 in liver; LILRA5, ISG20, S100A12, and HLX in kidney; and ASS1 and PTPN1 in heart). Altogether, these findings suggest that the cytokines storm triggered by SARS-CoV-2 infection is potentially the result of dysregulated cytokine production by inflamed pulmonary and extrapulmonary (e.g. liver, kidney, and heart) tissues.

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Other critical hub-high traffic genes in the blue module included EP300 ( 146 , 147 ), CDK1 ( 4 , 148 ), VEGFA ( 149 – 151 ), CTNNB1 ( 151 , 152 ), IL10 ( 9 , 153 – 155 ), SOCS1 , SOCS3 ( 156 ), SIRT1 ( 157 , 158 ), TFRC ( 159 – 161 ), HSP90AB1 ( 162 ), CYCS ( 163 ), EZR ( 164 ), TNFAIP3 , ICAM1 ( 10 ), and PIK3R1 ( 139 ) as well as TFs such as ATF4 ( 165 ), ATF3 ( 166 , 167 ), and BCL6 ( 152 ) which have important roles in pathogenesis of SARS-CoV-2, and some of which are potential therapeutic targets. For instance, SOCS1 / 3 antagonists may be prophylactic or therapeutic against the COVID-19 pandemic ( 156 ).…”

“…Other hub-high traffic genes in this module, such as BTAF1 ( 216 ), EZH2 ( 346 ), NPM1 ( 347 ), TPT1 ( 151 , 269 , 348 ), LDHA ( 217 , 268 ), PTPRC ( 189 ), SOS1 ( 349 , 350 ), DDX5 ( 351 , 352 ), BCL10 ( 162 , 353 ), EEF1B2 ( 354 ), CALM1 ( 344 ), EIF4A2 , EIF4B ( 336 , 355 , 356 ), EEF1A1 ( 269 , 354 ), HNRNPA1 ( 228 , 347 ), and IFNG ( 8 , 357 , 358 ), have important roles in development/inhibition of COVID-19. Overexpression of SARS-CoV-2 ORF6 caused HNRNPA1 nuclear accumulation, subverting the host mRNA export system and reducing nucleus size ( 359 ).…”

“…Additionally, some of the purple module hub-high traffic genes, such as MAPK1 ( 189 , 374 ), CUL2 ( 210 ), CMTM6 ( 162 ), TXNRD1 ( 375 ), RAB1A ( 376 ), DICER1 ( 377 ), RAB5A ( 209 ), HSP90B1 ( 343 ), MAGT1 ( 378 ), ADAM10 ( 379 , 380 ), SNX2 ( 89 ), OLA1 ( 381 ), SPTLC1 ( 382 ), SH3GLB1 ( 383 ), TIMM10B ( 384 ), and CREB1 ( 385 ) hub-high traffic TF, which are central for information exchange in this module, are potential targets for development of COVID-19 therapeutic strategies. Among these, the mitogen-activated protein kinase 1 ( MAPK1 ) hub-high traffic gene is a potential core target for many anti-COVID-19 therapeutic strategies ( 189 , 374 , 386 – 390 ).…”

Role of Senescence and Aging in SARS-CoV-2 Infection and COVID-19 Disease

“…Imbalanced cytokine responses for example, rather than magnitude of cytokine storm may contribute to cardiac dysfunction in juvenile multisystem inflammatory syndrome (MIS) [ 201 ]. A tissue wide systems immunology-based study reveals that the cytokine storm triggered by SARS-CoV-2 infection may result from dysregulated cytokine production by inflamed pulmonary, heart, liver, and kidney tissues [ 202 ]. Further studies are warranted to further explore the association between COVID-19, immune dysregulation, and cytokine storm.…”

Application of omics technology to combat the COVID‐19 pandemic

“…SARS‐CoV‐2 infection‐induced systematic tissue damage was marked by inflammation and coagulopathy in blood and tissues. 142 , 143 In the lungs of fatal COVID‐19 patients, dysregulated genes were mostly associated with dysregulated activation of granulocyte and complement, lymphocyte differentiation and certain T cell activation, as well as correlated pulmonary fibrosis. 12 , 144 , 145 Overactive immune responses‐related genes resulted in chemokines (such as CXCL1 and CXCL8) induced neutrophil pulmonary infiltration.…”