Cytokine storm–based mechanisms for extrapulmonary manifestations of SARS-CoV-2 infection

Abstract

Viral illnesses like SARS-CoV-2 have pathologic effects on non-respiratory organs in the absence of direct viral infection. We injected mice with cocktails of rodent equivalents of human cytokine storms resulting from SARS-CoV-2 / COVID-19 or Rhinovirus common cold infection. At low doses, COVID-19 cocktails induced glomerular injury and albuminuria in Zhx2 hypomorph and Zhx2 +/+ mice to mimic COVID-19 related proteinuria. Common Cold cocktail induced albuminuria selectively in Zhx2 hypomorph mice to model relapse of Minimal Change Disease (MCD), that improved after depletion of TNF-α or sIL-4Rα or IL-6. The Zhx2 hypomorph state increased cell membrane to nuclear migration of podocyte ZHX proteins in vivo (both cocktails) and lowered pSTAT6 activation (COVID-19 cocktail) in vitro. At higher doses, COVID-19 cocktails induced acute heart injury, myocarditis, pericarditis, acute liver injury and acute kidney injury, and high mortality in Zhx2 +/+ mice, whereas Zhx2 hypomorph mice were relatively protected, due in part to early asynchronous activation of STAT5 and STAT6 pathways in these organs. Dual depletion of cytokine combinations of TNF-α with IL-2 or IL-13 or IL-4 in Zhx2 +/+ mice reduced multiorgan injury and eliminated mortality. Using genome sequencing and CRISPR-Cas9, an insertion upstream of ZHX2 was identified as a cause of the human ZHX2 hypomorph state.

Bioinformatics and system biology analysis revealed the crosstalk between COVID‐19 and osteoarthritis

“…SARS-Cov-2 infection activates the body's immune response and causes disorders of the immune system like cytokine storm which induces whole-body manifestations and makes it difficult to treat severe cases of COVID-19. 73 Although OA was not defined as an immune-related disease and was different from RA traditionally, recent studies demonstrated that the immune reaction was involved in OA pathogenesis, and this was also confirmed by elevated levels of immunoglobulin and complement in the synovial fluid of the joints in patients with OA. 74,75 In this study, immune infiltration levels of COVID-19 and OA were evaluated by CIBERSORT, and the results showed that Macrophages were increased while NK cells and Mast cells were decreased in both these two diseases.…”

“Idiopathic” minimal change nephrotic syndrome: a podocyte mystery nears the end

“…Co-immunoprecipitation studies using whole glomerular protein extracts showed the interaction of ZHX proteins with APA (podocyte body) and ephrin B1 (slit diaphragm) ( 8 ), suggesting that ZHX1-ZHX2 and ZHX2-ZHX3 heterodimers are tethered to the cytoplasmic domains of these proteins, respectively. Absence of APA or ephrin B1 or reduced expression of ZHX2 (BALB/cJ mice or Zhx2 flox/flox -NPHS2 promoter Cre +/+ mice) alters the proteinuria profile and suggests the presence of alternative transmembrane-binding partners ( 8 ), one of which is IL-4Rα ( 6 ), the receptor for IL-4 and IL-13 in podocytes. In proteinuric conditions, loss of heterodimerization of ZHX proteins induced migration of peripherally expressed proteins into the nucleus ( 7 , 14 ).…”

“…BALB/cJ mice develop more severe adriamycin nephrosis (FSGS model), and anti-APA antibodies induced Angptl4 upregulation only in BALB/cJ mice, which also develop significantly higher albuminuria than BALB/c mice ( 8 ). Only BALB/cJ and Zhx2 flox/flox -NPHS2 promoter Cre +/+ mice develop albuminuria when injected with a common cold cytokine cocktail (model of MCD relapse) ( 6 ). In contrast, beyond a specific threshold of podocyte-specific Zhx2 overexpression in a cell membrane distribution, NPHS2 promoter- Zhx2 transgenic rats injected with adriamycin developed the collapsing variant of FSGS, with high podocyte nuclear ZHX2 expression ( 8 ).…”

“…While exome sequencing did not find mutations in ZHX2 in patients with primary glomerular disease ( 22 , 23 ), insertions and deletions (InDels) were discovered far upstream of ZHX2 in patients with MCD and FSGS ( 6 ). Some of these InDels were shared among patients, and replicating an insertion at Chr 8: 122,533,694 in a human podocyte line induced a ZHX2 hypomorph state.…”

“…Shared InDels tend to cluster at the beginning and end of rodent expressed gene Slc22a22 , a prostaglandin transporter that is defunct in humans. Patients with collapsing glomerulopathy, including those after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, had different InDels, including some shared, and future studies will investigate if these InDels can induce ZHX2 upregulation ( 6 ). By comparison, patients with diabetic nephropathy, the most common cause of nephrotic syndrome, did not have shared InDels upstream or far upstream of ZHX2 ( 6 ).…”