key: cord-0855559-j7i08a7d
authors: Rieder, M; Duerschmied, D; Bode, C; Lother, A
title: Response to Panda et al
date: 2021-05-06
journal: J Infect Dis
DOI: 10.1093/infdis/jiab238
sha: fc7287039ca08ebfcabf104cd74a2e23957e5b87
doc_id: 855559
cord_uid: j7i08a7d

nan

A c c e p t e d M a n u s c r i p t

The clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection ranges from the asymptomatic to life-threatening cases with acute respiratory distress syndrome or severe coagulopathies [1, 2] . Understanding the molecular mechanisms underlying the different susceptibility to SARS-CoV-2 infection and the predisposition for the development of severe courses of coronavirus disease 2019 (COVID-19) may help to identify patients at risk and enable targeted therapies and timelines for treatment.

We reported that the immune-regulatory molecule progranulin (GRN) is specifically upregulated in SARS-CoV-2 positive patients with an association of GRN levels and disease severity [3] . With great interest, we read the letter by Panda and collaborators that further expands this view. They studied the association of a common genetic single nucleotide polymorphism (SNP) in the 3' untranslated region (3'UTR) of the progranulin gene (C>T, rs5848) which had earlier been shown to alter GRN mRNA and protein levels [4] .

Interestingly, the authors found an association of C-allele frequency with both infection and mortality rate [5] . This finding supports the proposed link between GRN expression and the pathophysiology of COVID-19. The potential of GRN as a biomarker should be validated in an independent, prospective study.

In addition, several questions arise from this letter. First, the authors focused on a SNP that has previously been linked to GRN expression. However, it would be of interest to learn which additional associations between SNPs and COVID-19 outcomes would be uncovered by a more unbiased approach. Second, altered GRN levels in individuals carrying the Tallele have earlier been associated with an increased risk for neurodengerative disorders [6] .

Confirming these associations in the now investigated collective would support the conclusions on COVID-19 drawn from the present study. Third, the current analysis is solely A c c e p t e d M a n u s c r i p t based on determination of the genotype and does not take into account other factors that control GRN expression such as epigenetic modifiers [7] . Integrating data from genome-wide association studies with epigenetic information may reveal SNPs in non-coding regions linked to GRN expression. In addition, the role of microRNAs in the transcriptional regulation of GRN should be further investigated. Of note, miR-659-3p is downregulated by hypoxia, leading to a de-repression of GRN [8] , which might contribute to GRN upregulation in patients with respiratory failure. Interference with this mechanism using antisense oligonucleotides could represent a novel approach for the treatment of COVID-19. However, binding of miR-659-3p to GRN is stronger in the T allele transcript than the C allele transcript, suggesting a larger inhibitory potential of miR-659-3p on GRN expression in individuals carrying the T allele [8] .

In summary, the available evidence suggests that elevated GRN expression predisposes to SARS-CoV-2 infection susceptibility and mortality. Therefore, the potential of GRN as a biomarker to identify patients at risk and to predict outcome in COVID-19 should be furthr explored in a prospective study.

Extrapulmonary manifestations of COVID

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet

Serum protein profiling reveals a specific upregulation of the immunomodulatory protein progranulin in COVID-19

Granulin rs5848 (C>T) polymorphism is associated with SARS-CoV-2 infection and mortality

Association of progranulin polymorphism rs5848 with neurodegenerative diseases: a meta-analysis

Epigenetic Targeting of Granulin in Hepatoma Cells by

Synthetic CRISPR dCas9 Epi-suppressors

Progranulin Increase in Hypoxic Conditions: Implications for Frontotemporal Dementia

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