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\begin{document}

\title{Effect of DNA methylation on impaired Interferon type I signaling as a
strategy to escape of SARS-CoV-2 from innate immune response: a
hypothesis}



\author[1]{Somayeh Shokri}%
\author[1]{Shahab Mahmoudvand}%
\affil[1]{Hamadan University of Medical Sciences}%


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  \date{June 17, 2024}


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\textbf{Effect of DNA methylation on impaired Interferon type I
signaling as a strategy to escape of SARS-CoV-2 from innate immune
response: a hypothesis}

Somayeh Shokri \textsuperscript{\textbf{1,2}} , Shahab
Mahmoudvand\textsuperscript{\textbf{1,2,} *}

\textsuperscript{\textbf{1}} Research Center for Molecular Medicine,
Hamadan University of Medical Sciences, Hamadan, Iran

\textsuperscript{\textbf{2}} Department of Virology, School of Medicine,
Hamadan University of Medical Science, Hamadan, Iran.

\textsuperscript{\textbf{*}} \textbf{Corresponding Author:} Shahab
Mahmoudvand, Department of Virology, School of Medicine, Hamadan
University of Medical Science, Hamadan, Iran. Phone Number:
+989188523259,

Email: \emph{mahmoudvandsh100@yahoo.com}

\textbf{Dear Editor,}

Epigenetic changes play an important role in the immunological response
against viruses. In recent years, DNA methylation as an epigenetic
mechanism has attracted more attention as a disease biomarker. DNA
methylation regulates gene expression in two ways: by recruiting
proteins involved in gene repression and by inhibiting the binding of
transcription factors to DNA (1). It is interesting to know that many
studies have shown that epigenetics regulates interferon (IFN)
production as well (2). On the other hand, it has been determined that
viral infections can employ an epigenetic mechanism to escape from the
innate immune system (3). Type I IFNs (IFN-I) play a key role for host
defence against viruses (4). Recent articles described how the
SARS-CoV-2 genome encodes accessory proteins, ORF3a, ORF3b, ORF6, ORF7a,
ORF7b, ORF8, ORF9b, ORF9c and ORF10, which may contribute to immune
evasion (5-7). In this regard, it has been determined that accessory
proteins ORF3b, ORF6, ORF7a and ORF8 have been shown to be important
IFN-I antagonists which in turn lead to disruption of the host's immune
response (8). Li et al. also reported that the overexpression of ORF10
significantly inhibited the expression of IFN-I genes and
interferon-stimulated genes by SARS-CoV-2-infected HeLa cells in vitro
(7). On the other hand, Gao et al. showed that single-CpG-nucleotide
methylation is an essential mechanism that controls IFN-I induction and
antiviral immunity in both humans and mice. They showed that
single-nucleotide methylation can disrupt the recruitment of interferon
regulatory transcription factor 3 (IRF3) to the IFN-beta promoter (9).
Our hypothesis is that the activity of accessory proteins encoded by
SARS-CoV-2 may cause promoter methylation of IFN-I, which in turn
results in suppressing the IFN-I response against SARS-CoV-2.

In summary, our study provides a new insight into whether accessory
proteins encoded by SARS-CoV-2 can affect IFN-I signaling via DNA
methylation. However, further study is necessary to clarify the role of
DNA methylation in the regulation of IFN-I signaling in SARS-CoV-2
infection.

\textbf{References}

1. Wang X, Xia H, Liu S, Cao L, You F. Epigenetic regulation in
antiviral innate immunity. European Journal of Immunology.
2021;51(7):1641-51.

2. Selinger E, Reini\selectlanguage{polish}š \selectlanguage{english}M. Epigenetic View on Interferon \selectlanguage{greek}γ \selectlanguage{english}Signalling in
Tumour Cells. Folia Biologica. 2018;64(4):125.

3. Saksena N, Bonam SR, Miranda-Saksena M. Epigenetic lens to visualize
the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
infection in COVID-19 pandemic. Frontiers in Genetics. 2021;12:291.

4. McNab F, Mayer-Barber K, Sher A, Wack A, O'garra A. Type I
interferons in infectious disease. Nature Reviews Immunology.
2015;15(2):87-103.

5. Wong L-YR, Perlman S. Immune dysregulation and immunopathology
induced by SARS-CoV-2 and related coronaviruses---are we our own worst
enemy? Nature Reviews Immunology. 2022;22(1):47-56.

6. Andres AD, Feng Y, Campos AR, Yin J, Yang C-C, James B, et al.
SARS-CoV-2 ORF9c is a membrane-associated protein that suppresses
antiviral responses in cells. bioRxiv. 2020.

7. Li X, Hou P, Ma W, Wang X, Wang H, Yu Z, et al. SARS-CoV-2 ORF10
suppresses the antiviral innate immune response by degrading MAVS
through mitophagy. Cellular \& molecular immunology. 2022;19(1):67-78.

8. Redondo N, Zald\selectlanguage{ngerman}ívar-López S, Garrido JJ, Montoya M. SARS-CoV-2
accessory proteins in viral pathogenesis: knowns and unknowns. Frontiers
in Immunology. 2021:2698.

9. Gao Z-j, Li W-p, Mao X-t, Huang T, Wang H-l, Li Y-n, et al.
Single-nucleotide methylation specifically represses type I interferon
in antiviral innate immunity. Journal of Experimental Medicine.
2021;218(3).

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