ABSTRACT
OBJECTIVE: Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using a multiplatform strategy. METHODS: Brain tissues from coronavirus disease 2019 (COVID-19) (n = 12) and other disease control (ODC) (n = 12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS-CoV-2, were investigated by droplet digital polymerase chain reaction (ddPCR), quantitative reverse transcriptase PCR (RT-qPCR), and immunodetection methods. RESULTS: SARS-CoV-2 RNA was detected in the CNS of 4 patients with COVID-19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID-19 showed induction of pro-inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM-CSF and IL-18) compared to CNS tissues from ODC patients (p < 0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11ß, and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID-19 compared to ODC patients (p < 0.05). SARS-CoV-2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post-infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post-infection (p < 0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS-CoV-2 infected animals (p < 0.05). INTERPRETATION: COVID-19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS-CoV-2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post-acute sequelae of COVID-19. ANN NEUROL 2023.
ABSTRACT
Background: Immunocompromised patients, including Kidney Transplant Recipients (KTRs) and lupus nephritis (LN) patients, are at increased risk for prolonged SARS-CoV-2 infection and developing COVID-19-related complications. Recently, we reported that voclosporin, a novel calcineurin inhibitor (CNI), demonstrated in vitro a more potent inhibitory effect on SARS-CoV-2 replication than other CNIs (tacrolimus and ciclosporin). Additionally the AURORA-2 study, where 216 LN patients were treated with voclosporin or placebo on top of standard of care, SARS-CoV-2 infection was detected in 12/100 placebo-treated patients (12%) compared to 7/116 voclosporin treated patients (6%) and more patients died due to COVID-19 in the placebo arm versus voclosporin arm (3% vs 0%). In this proof-of-concept study we assessed whether voclosporin demonstrated an added antiviral benefit in SARS-CoV-2 positive immunocompromised patients. Method(s): We performed a prospective, randomised, open-label, single-center, exploratory, proof of concept study in 20 KTRs with mild to moderate symptoms from a COVID-19 infection comparing time to viral clearance of SARS-CoV-2 between patients on standard immunosuppressive therapy with tacrolimus versus voclosporin (the VOCOVID study). Result(s): In the VOCOVID study no difference in time to viral clearance or time to clinical recovery was found between both treatment arms. Pharmacokinetic analysis demonstrated that adequate trough levels of voclosporin were reached from day 4-8 after randomization. Looking at specific timepoint in a post-hoc analysis, indeed a significantly better viral clearance of SARS-CoV-2 was observed in voclosporin treated patients at day 4-8. No safety concerns were raised. Conclusion(s): The present study provides evidence that voclosporin has a favorable benefit-risk profile for immunocompromised kidney disease patients who contract a SARS-CoV-2 infection while requiring the continuation of their immunosuppressants.