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Frontiers in Microbiology 01 frontiersin.org
The role of oxidative stress in the
pathogenesis of infections with
coronaviruses
ChandrimaGain , SihyeongSong , TylerAngtuaco , SandroSatta and
TheodorosKelesidis *
Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles,
CA, United States
Coronaviruses can cause serious respiratory tract infections and may also impact
other end organs such as the central nervous system, the lung and the heart. The
coronavirus disease 2019 (COVID-19) has had a devastating impact on humanity.
Understanding the mechanisms that contribute to the pathogenesis of coronavirus
infections, will set the foundation for development of new treatments to attenuate
the impact of infections with coronaviruses on host cells and tissues. During infection
of host cells, coronaviruses trigger an imbalance between increased production of
reactive oxygen species (ROS) and reduced antioxidant host responses that leads to
increased redox stress. Subsequently, increased redox stress contributes to reduced
antiviral host responses and increased virus-induced inflammation and apoptosis
that ultimately drive cell and tissue damage and end organ disease. However,
there is limited understanding how dierent coronaviruses including SARS-CoV-2,
manipulate cellular machinery that drives redox responses. This review aims to
elucidate the redox mechanisms involved in the replication of coronaviruses and
associated inflammation, apoptotic pathways, autoimmunity, vascular dysfunction
and tissue damage that collectively contribute to multiorgan damage.
KEYWORDS
SARS-CoV-2, coronavirus, inflammation, oxidative stress, tissue damage, apoptosis
Introduction
e coronavirus disease 2019 (COVID-19) has had a devastating impact on humanity.
Coronaviruses can cause serious respiratory tract infections and may impact other end organs such
as the central nervous system. Coronaviruses are enveloped single-stranded positive-sense RNA
viruses named aer their crown-like appearance of their spike proteins on their surface (Singhal,
2020). To date, there has been seven human coronaviruses (HCoVs) identied: severe acute
respiratory syndrome coronavirus (SARS-CoV-2), SARS-CoV, Middle East respiratory syndrome
coronavirus (MERS-CoV), Human coronavirus 229E (HCoV-229E), HCoV-OC43, HCoV-NL63,
and HKU-1. Four of them including HCoV-OC43, HCoV-NL63, HCoV-229E, and HKU-1, typically
trigger only mild respiratory illnesses in humans. On the other hand, SARS-CoV-2, SARS and MERS
are known to cause more severe illness, acute respiratory distress syndrome (ARDS) or multi-organ
dysfunction, especially in aged people with comorbidities (Li etal., 2021a). Understanding the
mechanisms that contribute to the pathogenesis of coronavirus infections, will set the foundation
for development of new treatments to attenuate the impact of coronaviruses on host cells and tissues.
However, there is limited understanding how dierent coronaviruses including SARS-CoV-2,
manipulate cellular machinery to drive host cell responses.
Emerging evidence suggests that human diseases including viral infections oen disrupt the
host natural balance between increased production of reactive oxygen species (ROS) and reduced
TYPE Review
PUBLISHED 13 January 2023
DOI 10.3389/fmicb.2022.1111930
OPEN ACCESS
EDITED BY
Wenjun Song,
Guangzhou National Laboratory, China
REVIEWED BY
Paola Checconi,
San Raaele Telematic University, Italy
Sourish Ghosh,
Indian Institute of Chemical Biology, India
*CORRESPONDENCE
Theodoros Kelesidis
tkelesidis@mednet.ucla.edu
SPECIALTY SECTION
This article was submitted to
Virology,
a section of the journal
Frontiers in Microbiology
RECEIVED 30 November 2022
ACCEPTED 23 December 2022
PUBLISHED 13 January 2023
CITATION
Gain C, Song S, Angtuaco T, Satta S and
Kelesidis T (2023) The role of oxidative stress in
the pathogenesis of infections with
coronaviruses.
Front. Microbiol. 13:1111930.
doi: 10.3389/fmicb.2022.1111930
COPYRIGHT
© 2023 Gain, Song, Angtuaco, Satta and
Kelesidis. This is an open-access article
distributed under the terms of the Creative
Commons Attribution License (CC BY). The
use, distribution or reproduction in other
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comply with these terms.
Gain et al. 10.3389/fmicb.2022.1111930
Frontiers in Microbiology 02 frontiersin.org
antioxidant host responses that collectively increases redox stress
(Amini etal., 2022; Figure 1). ROS are free radical and nonradical
byproducts of metabolic processes in organelles such as plasma and
nuclear membranes, the mitochondria, peroxisomes and the
endoplasmic reticulum (ER; Reshi etal., 2014). ROS are necessary for
cellular processes like mitochondrial energy production, host defense,
cellular signaling, and the regulation of gene expression. Mitochondria
are the main location of production of ROS (mito-ROS) during energy
production. Increased ROS during viral infections have not only
detrimental impact on the cells and tissues but are also important for
antiviral immune function (Yang etal., 2007; Finkel, 2011) during viral
infections like inuenza (To et al., 2014), respiratory syncytial virus
(RSV; Fink et al., 2008) and rhinoviruses (Kaul et al., 2000; Fink
etal., 2008).
However, an excess of ROS can damage cellular components
including lipids, proteins, and DNA, alter immune functions,
inammatory responses and induce organ and tissue dysfunction
(Preiser, 2012; Reshi etal., 2014; Labarrere and Kassab, 2022). Indeed,
several studies have shown that oxidative stress contributes to the
pathogenesis of respiratory viral infections (Khomich et al., 2018),
inuenza and RSV. Increased oxidative stress in severe COVID-19
contributes to inammation, endothelial cell dysfunction, thrombosis
that can lead to multiorgan damage (Li et al., 2021a; Alam and
Czajkowsky, 2022). Oxidative stress, induced by coronavirus, also
interferes with inammatory pathways that may lead to more long-
lasting tissue damage. However, there is limited understanding how
dierent coronaviruses including SARS-CoV-2, manipulate cellular
machinery that drives redox responses.
In this review, wesummarize the scientic evidence regarding the
cellular and molecular pathways modulated by oxidative stress that
are implicated in the pathogenesis of coronavirus infections.
We specically review the role of redox pathways in major
pathophysiological underpinnings that contribute to cell and tissue
damage in coronavirus infection: (1) virus replication, (2) virus-
associated inammation, (3) virus-associated apoptosis, (4)
redox-related end organ disease. Wereview the scientic evidence
related to these redox pathways, separately for SARS-CoV-2 versus all
the other coronaviruses [SARS-CoV, MERS, respiratory coronaviruses
and other coronaviruses used to model SARS-CoV-2 infection such
as the murine hepatitis virus (MHV)]. Finally, we discuss the
relevance of these redox pathways with regards to acute severe
COVID-19 and Post-Acute Sequelae of SARS-CoV-2 infection
(PASC) and potential antioxidant treatments.
Redox mechanisms that regulate
replication of coronaviruses
Several redox mechanisms can regulate both viral entry and
cytosolic replication of coronaviruses (Figure2; Table1; Wang and
Zhang, 1999; Kulisz etal., 2002; Halestrap etal., 2004; Mizutani etal.,
2004; Emerling etal., 2005; Kefaloyianni etal., 2006; Doughan etal.,
2008; Lucas etal., 2008; Cho etal., 2009; Garrido and Griendling,
2009; Hosakote etal., 2009; Jamaluddin etal., 2009; Wosniak etal.,
2009; de Wilde et al., 2011; Kesic et al., 2011; Xia et al., 2011;
Kosmider etal., 2012; Yamada etal., 2012; Kim etal., 2012b; Lee etal.,
2013; Nguyen Dinh Cat etal., 2013; Komaravelli and Casola, 2014;
Hyser and Estes, 2015; Kindrachuk etal., 2015; Komaravelli etal.,
2015; Paszti-Gere etal., 2015; Shirihai etal., 2015; Simon etal., 2015;
Demers-Lamarche etal., 2016; Kau etal., 2016; Morris etal., 2016;
Zhang etal., 2016; Daiber etal., 2017; Trempolec etal., 2017; Khomich
etal., 2018; Tu et al., 2019; Olagnier et al., 2020; Tao etal., 2020;
Verdecchia etal., 2020; Herengt etal., 2021; Moghimi etal., 2021;
Youn etal., 2021).
Redox mechanisms that regulate virus entry
of coronaviruses
e spike S proteins on the surface of coronaviruses are responsible
to their attachment to host receptors in airway epithelial cells such as the
angiotensin-converting enzyme 2 (ACE2) receptors that interact with
host cell proteases, such as transmembrane protease serine 2 (TMPRSS2;
Hamming etal., 2004; Irigoyen etal., 2016; Lukassen etal., 2020; Xu
et al., 2020). While many coronaviruses utilize peptidases, such as
ACE2, dipeptidyl peptidase 4, aminopeptidase N, as their cellular
receptors, SARS-CoV, SARS-CoV-2 and HCoV-NL63 utilize ACE2 as
their receptors thus disrupting the renin-angiotensin system (Verdecchia
etal., 2020).
ACE2, a peptidase that exists on the cell surfaces of most organs
(Hamming etal., 2004), is one of the most crucial key players in
induction of redox stress (Shatizadeh Malekshahi et al., 2022).
Angiotensin II (AngII), the ligand of ACE2, is a potent activator of
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
and an inducer of ROS production in the vasculature, kidney and
brain (Garrido and Griendling, 2009). Typically, ACE2 helps avert
NAPDH oxidase activity by converting Ang II into angiotensin 1–7,
thereby reducing ROS levels; Ang II stimulates NAPDH oxidase.
ACE2 overexpression has been shown to reduce ROS, and ACE2
deficiency has been shown to induce oxidative stress (Xia etal.,
2011; Pena Silva etal., 2012). The complex cross-talk between ACE2
and redox pathways is further emphasized by a possible bidirectional
redox regulation of ACE2 levels. High ACE2 activity may reduce
redox stress but vice versa high redox stress may regulate ACE2
FIGURE1
Redox imbalance in coronavirus infections. Coronavirus infection
triggers an imbalance between increased production of reactive
oxygen species (ROS) and reduced antioxidant host responses that
leads to increased redox stress in the host cell. Increased redox stress
induces inflammation, apoptosis and ultimately tissue damage and end
organ disease.
Gain et al. 10.3389/fmicb.2022.1111930
Frontiers in Microbiology 03 frontiersin.org
activity. In vitro studies showed that NOX-driven ROS may reduce
ACE2 in vascular smooth muscle cells (Lavrentyev and Malik,
2009). Consistent with this evidence, independent in vitro studies
demonstrated that Ang II-induced activation of mitochondrial
Nox4 is an important endogenous source of ROS and is related to
cell survival in kidney epithelial cells (Kim et al., 2012b). The
crosstalk between NOX and ACE2 has also been shown in vivo in
mouse models of disease and increased levels of ACE2 are generally
associated with reduced oxidative stress in mammalian cells (Xia
etal., 2011).
Angiotensin II is oen upregulated in viral infections (Doughan
etal., 2008; Wosniak etal., 2009; Lee etal., 2013; Daiber etal., 2017).
However, when cells are infected with coronavirus, there is a reduction
of ACE2 receptors on the cell surface and this results in an increase of
Ang II which binds to ACE1 and increases ROS levels through NADPH
oxidase (Nguyen Dinh Cat etal., 2013). Experimental studies have
demonstrated that in vitro exposure to S protein induces excessive
oxidative stress in endothelial cells, which is mediated specically by
activation of NADPH oxidase isoform 2 (NOX2), but not NOX1 or
NOX4 (Youn etal., 2021). However, it is unclear if there is bidirectional
link between ACE2 levels and increased redox cellular pathways in the
setting of SARS-CoV-2-induced ACE2 downregulation in airway
epithelial cells.
TMPRSS2 is expressed in both the cytoplasm as well as in the cell
membrane in epithelial cells (Lucas etal., 2008). In vitro studies with
porcine intestinal epithelial cells have shown that acute excessive
oxidative stress induces altered distribution pattern of TMPRSS2 and
relocalized transmembrane serine protease activity that may
contribute to weakening of epithelial barrier integrity (Paszti-Gere
et al., 2015). However, a small study of COVID-19 patients and
uninfected controls showed that measures of oxidative stress in sperm
epithelial cells were not associated with levels of TMPRSS2 (Moghimi
et al., 2021). Similarly, another experimental study showed that
cigarette smoking extract (CSE) that is an established trigger of
oxidative stress (Kau et al., 2016) had no eect on ACE2 and
TMPRSS2 expression in endothelial cells (Youn etal., 2021). Overall,
there is no solid evidence to support a role of increased redox stress
in regulation of TMPRSS2.
Other than redox-dependent regulation of membrane receptors for
coronaviruses, mito-ROS are also instigators of aberrant vacuole
formation (Demers-Lamarche etal., 2016) by activation of adaptor-
associated kinase 1 (AAK1), a regulator of endocytosis (Chen etal.,
2006) that has been targeted therapeutically in SARS-CoV-2 infection
with baricitinib (Stebbing etal., 2020). Mito-ROS can also induce
alterations in membrane lipid ras and lipid-based cellular signaling
changing their properties (Morris etal., 2016) and these membrane
changes may also impact viral entry of coronaviruses. us, redox
mechanisms may regulate entry of coronaviruses in mammalian cells
but these mechanisms need to befurther studied specically in airway
epithelial cells and in vivo.
FIGURE2
Schematic representation of redox pathways that contribute to viral replication, inflammation, and apoptosis during coronavirus infection.
Coronaviruses bind to the ACE2 receptor and replicate through host proteases such as TMPRSS2 and by hijacking cytosolic cellular machinery such as
the mitochondria and the endoplasmic reticulum (ER), which engages the unfolded protein response (UPR). The plasma membrane, the ER and
mitochondria harbor dierent isoforms of the NADPH oxidase (NOX) enzyme. Coronaviruses induce cellular oxidative stress with generation of reactive
oxygen species (ROS) and mitochondrial ROS (mito-ROS) and impairment of stress-inducible, antioxidant, anti-inflammatory and antiviral responses
such as the Nrf2 pathway and other key downstream mediators such as Heme oxygenase-1 (HO-1). Mito-ROS induce downstream signaling pathways
such as MAPK, JNK, MEK/MNK1 that induce both viral replication and proinflammatory pathways such as induction of cytokines (e.g., IL-1b, IL-6, and
TNF-a). Mito-ROS, ROS and ER stress response induce the proinflammatory pathway NF-κB. ROS and mito-ROS also induce apoptosis through
alterations in apoptotic pathways such as PI3K/AKT, mTOR and induction of mitochondrial apoptosis. Collectively, redox mediated pathways that drive
viral replication, inflammation and apoptosis contribute to cell and tissue damage that drive end organ disease in coronavirus infection. Endogenous
antioxidant host pathways and exogenous therapeutic antioxidants could attenuate redox mediated pathways that drive pathogenesis of coronavirus
infections.
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Redox mechanisms that regulate
cytoplasmic replication of coronavirus
Viral infections may alter the mitochondrial dynamics leading to
excessive mito-ROS generation, mitochondrial biogenesis, and altered
mitochondrial β-oxidation (Elesela and Lukacs, 2021). Mitochondria are
targeted by coronavirus (Shi etal., 2014). Coronaviruses may directly
induce production of mito-ROS in cells. Non-structured viral proteins,
such as coronavirus 3a protein directly activate NLRP3 inammasome
in macrophages, which is mediated by increased mito-ROS level (Zhou
etal., 2011; Chen etal., 2019). Finally, redox pathways also regulate
cellular machinery that propagates replication of coronaviruses through
multiple pathways.
First, Mito-ROS regulate the endoplasmic reticulum stress and
the unfolded protein response (UPR) that contribute to replication of
coronaviruses (de Wilde et al., 2011; Hyser and Estes, 2015;
Kindrachuk et al., 2015; Zhang et al., 2016) and associated Ca
2+
signaling systems. Second, mito-ROS induce the mitochondrial
permeability transition pore (mPTP) that is a proviral factor for
replication of coronaviruses. Indeed, by blocking the mPTP,
cyclosporin A impacts coronavirus replication (Halestrap et al.,
2004). Mitochondria-targeted antioxidants inhibit mPTP, mito-ROS
(Halestrap etal., 2004), and ROS (Dikalova etal., 2010; Dikalov etal.,
2014). ird, mito-ROS regulate mitophagy that regulates replication
of coronaviruses. Protein misfolding mitochondrial depolarization
and ROS activate mitophagy (Shirihai etal., 2015). Viral proteins like
SARS-CoV ORF-9 (Shi et al., 2014) interact with mitophagic
machinery such as LC3 and Beclin1 (Zhang etal., 2018). erapeutic
targeting of aberrant autophagy through Beclin1 reduces MERS
infection (Gassen etal., 2019). Fih, mito-ROS trigger MEK (Zhang
etal., 2016), MNK1 (Wang and Zhang, 1999) and MAPK signaling
pathways (Kulisz etal., 2002; Emerling etal., 2005; Trempolec etal.,
2017) that propagate viral protein synthesis and SARS-Co-V
replication (Mizutani etal., 2004; Kefaloyianni etal., 2006; Jamaluddin
etal., 2009). Sixth, ROS regulate cytoplasmic interferon host antiviral
responses during coronavirus infection. ROS promotes MHV
replication by downregulating interferon host responses during MHV
infection (Tao etal., 2020). Lastly, preclinical studies suggest that
mito-ROS may contribute to viral reservoirs and replication of SARS-
CoV-2in macrophages, but this has not been clearly demonstrated in
vivo (Codo etal., 2020). us, mito-ROS induce multiple proviral
cytoplasmic pathways.
TABLE1 Redox mechanisms that regulate replication of coronaviruses.
Mediators Eect on redox balance References
Redox mechanisms that may regulate viral entry of coronaviruses
Bidirectional cross talk
between virus and the
ACE2-AngII (ligand of
ACE2)-NOX axis
• ↑Ang II →↑ activation of Nox4 Doughan etal. (2008), Garrido and Griendling (2009),
Wosniak etal. (2009), Xia etal. (2011), Kim etal.
(2012b), Lee etal. (2013), Nguyen Dinh Cat etal. (2013),
Daiber etal. (2017), Verdecchia etal. (2020)
• ↑ACE2 → ↓ NOX
• Virus ↓ ACE2 →↑ NOX
• Bidirectional crosstalk between virus, mitochondria and NOX
TMPRSS2 (host protease
essential for replication of
coronavirus)
• No solid evidence to support role of redox stress in TMPRSS2 regulation but excess
redox stress may alter distribution pattern of TMPRSS in epithelial cells
Lucas etal. (2008), Paszti-Gere etal. (2015), Kau etal.
(2016), Moghimi etal. (2021), Youn etal. (2021)
Mito-ROS • ↑ vacuole formation through AAK activation Demers-Lamarche etal. (2016), Morris etal. (2016)
• Alters membrane lipid-based cellular signaling
Redox mechanisms regulating cytoplasmic replication of coronaviruses
Mito-ROS • Regulate ER stress and unfolded protein response Wang and Zhang (1999), Kulisz etal. (2002), Halestrap
etal. (2004), Mizutani etal. (2004), Emerling etal.
(2005), Kefaloyianni etal. (2006), Jamaluddin etal.
(2009), de Wilde etal. (2011), Hyser and Estes (2015),
Kindrachuk etal. (2015), Shirihai etal. (2015), Zhang
etal. (2016), Trempolec etal. (2017), Tao etal. (2020)
• Regulate Ca2+ signaling systems
• ↑ MPTP
• Regulate mitophagy (protein misfolding, depolarization of mitochondria)
• ↑ MEK, MNK1, MAPK →↑ viral protein synthesis
• Regulate interferon host responses
• ↑ Nrf2 pathway
Keap1-Nrf2-ARE pathway • ROS ↑ antioxidant gene expression, →↑ HO-1, NQo-1, SOD, glutathione derived
molecules catalase, peroxiredoxins, glutathione peroxidases Respiratory viruses ↓
Nrf2
Cho etal. (2009), Hosakote etal. (2009), Kesic etal.
(2011), Yamada etal. (2012), Kosmider etal. (2012),
Komaravelli and Casola (2014), Komaravelli etal. (2015),
Simon etal. (2015), Khomich etal. (2018), Tu etal.
(2019), Olagnier etal. (2020), Herengt etal. (2021)
• ↑ stress-inducible, anti-inammatory, antiviral responses
• ↑ antiviral HO-1
• ↑ antiviral immunity
• Mediates pathogenesis and tissue damage of many viral infections, including HIV,
RSV, Inuenza, SARS-CoV-2
• ↓ apoptosis that regulates viral replication (cell death and release of virions)
Abbreviations: AAK, adaptor-associated kinase; ACE2, Angiotensin-converting enzyme 2; AngII, Angiotensin II; ARE, antioxidant response element; Ca2+, Calcium (II) ion; ER, endoplasmic
reticulum; HIV, human immunodeciency virus; HO-1, Heme oxygenase 1; Keap1, Kelch-like ECH-associated protein 1; MAPK, mitogen-activated protein kinase; MEK, Mitogen-activated protein
kinase; Mito-ROS, Mitochondrial reactive oxygen species; Mnk1, mitogen-activated protein kinase (MAPK) interacting protein kinase 1; mPTP, mitochondrial permeability transition pore; NOX,
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; Nrf2, nuclear factor erythroid 2–related factor 2; NQo-1, NAD(P)H quinone oxidoreductase; RSV, Respiratory Syncytial Virus;
SOD, Superoxide dismutase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, Transmembrane serine protease 2; UPR, unfolded protein response.
Gain et al. 10.3389/fmicb.2022.1111930
Frontiers in Microbiology 05 frontiersin.org
Antioxidant mechanisms that regulate
cytoplasmic replication of coronavirus
e primary transcription factor regulating the antioxidant
response is the nuclear factor E2-related factor 2 (Nrf2), which regulates
the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2-antioxidant
response elements (ARE) pathway (Khomich et al., 2018). Under
normal circumstances, the Keap1-Nrf2-ARE pathway is activated by
the oxidative stress resulting from ROS production. Nrf2, which is
usually bound to Keap1 by ubiquitination or degraded by Keap1in the
absence of oxidative stress, is translocated to the nucleus when oxidative
stress modies the conformational structure of Keap1 and prevents it
from binding Nrf2 (Komaravelli and Casola, 2014; Han etal., 2021).
Mito-ROS activate Nrf2 through protein kinases, and induce
production of antioxidant proteins and genes involved in mitochondrial
quality control (Kasai etal., 2020). e activation of Nrf2 results in the
upregulation of antioxidant gene expression as Nrf2 binds to
antioxidant response element (ARE) sites, leading to the expression of
key players of the antioxidant response, including heme oxygenase-1
(HO-1), NADPH quinone oxidoreductase 1 (NQO-1), superoxide
dismutases (SOD), and glutathione derived molecules catalase,
peroxiredoxins, and glutathione peroxidases which collectively
attenuate oxidative stress (Khomich etal., 2018; Tu etal., 2019).
Several studies have found that respiratory viruses downregulate the
expression of antioxidant genes by inhibiting Nrf2, preventing it from
mobilizing to the nucleus and binding to ARE sites (Komaravelli and
Casola, 2014). e Nrf2 pathway that mediates pathogenesis and tissue
damage of several viral infections including HIV, RSV (Cho etal., 2009;
Hosakote etal., 2009; Komaravelli etal., 2015), inuenza (Kesic etal.,
2011; Kosmider etal., 2012; Yamada etal., 2012; Simon etal., 2015), and
SARS-CoV-2 (Olagnier etal., 2020). Induction of the Nrf2 pathway and
key downstream mediators such as Heme oxygenase-1 (HO-1) triggers
stress-inducible, anti-inammatory, and antiviral responses present in
most human cells (Espinoza etal., 2017). NRF2 has antiviral properties
but, it remains unclear which genes mediate these eects and how they
exert antiviral eect (Herengt etal., 2021).
Emerging evidence has increased our understanding of the role of
Nrf2 activation in SARS-CoV-2 infection. In vitro experiments with
Vero hTMPRSS2 cells, Calu-3 and primary human airway epithelial cell
lines and using gene silencing of Keap1 and Nrf2 agonists 4-octyl-
itaconate (4-OI) and dimethyl fumarate (DMF), it was shown that the
Nrf2 pathway has a critical role in inhibiting SARS-CoV-2 replication,
in addition to limiting the host inammatory response. SARS-CoV-2
reduced in vitro basal levels of HO-1 and NQO-1in lung cells. Notably,
considering Nrf2’s known role in inhibiting anti-viral IFN responses, it
was shown that the antiviral eect of Nrf2 is independent of interferon
responses (Olagnier etal., 2020). Mechanistic preclinical studies showed
that Nrf2 activation reduced SARS-CoV-2 replication by inducing the
metabolite biliverdin, whereas SARS-CoV-2 altered the NRF2 axis
through the cross-talk between the nonstructural viral protein NSP14
and the NAD-dependent deacetylase Sirtuin 1 (SIRT1; Olagnier etal.,
2020; Zhang etal., 2022).
Experimental studies have also shown that downregulation of
antioxidant genes by SARS-CoV-2 and SARS-CoV-1 is combined with
an upregulation of oxidative stress genes like myeloperoxidase (MPO),
calprotectin (S100A8 and S100A9), sulredoxin-1 (SRXN1), glutamate
cysteine ligase modier subunit (GCLM), sestrin2 (SESN2), and
thioredoxin-1 (TXN; Saheb Sharif-Askari etal., 2021). e results of
these studies have revealed key aspects of SARS-CoV-2 infection: such
as downregulation of host’s antioxidant pathway as an important role in
viral replication, and possible utility of activators of antioxidant
pathways as specic therapeutic targets.
Redox mechanisms that regulate replication
of coronavirus through apoptotic pathways
Many viruses alter apoptosis or programmed cell death of the
infected cell as a mechanism of increased production of virus progeny,
cell killing and virus spread (Roulston etal., 1999). Apoptosis is the
programmed cell death that involves the activation of proteases called
caspases and a cascade of events that link apoptosis-initiating stimuli
to nal death of the cell. ROS (Pierce etal., 1991; Kasahara etal.,
1997) and mitochondria play pivotal roles in induction of apoptosis
under both physiologic and pathologic conditions. Increased
mito-ROS induce apoptosis and cell death (Orrenius etal., 2007).
Excessive ROS can activate pro-apoptotic Bcl-2 family proteins by
increasing mitochondrial permeability to drive the mitochondrial
membrane potential, release cytochrome c, mtDNA (Santos etal.,
2003), and pro-apoptotic caspase-3 and-9. is leads to the activation
of intrinsic or mitochondrial driven cell death by apoptosis (Green
and Llambi, 2015). Coronaviruses impact apoptosis through several
pathways. Notably, mitochondrial apoptosis is directly and uniquely
induced by SARS-CoV (Pfeerle et al., 2011) triggering viral
replication (Supinski etal., 2009; Maiti etal., 2017). SARS-CoV-2
infection also downregulates the Nrf2 pathway (Olagnier etal., 2020;
Zhang etal., 2022) which has antiapoptotic cellular eect (Niture and
Jaiswal, 2012; Khan etal., 2018). us, coronaviruses induce apoptosis
through multiple pathways, either directly (Pfeerle etal., 2011), or
indirectly by inducing production of mito-ROS and downregulating
antiapoptotic pathways such as Nrf2 and the virus-induced alteration
of mitochondrial apoptosis contributes to increased replication of
coronaviruses (Supinski et al., 2009; Pfeerle et al., 2011; Maiti
etal., 2017).
Redox mechanisms that regulate replication
of coronavirus through the complement
system
e complement system is a major host defense mechanism against
viral replication. Several viruses hijack the complement system for
cellular entry and spread (Agrawal et al., 2017). e role of the
complement system in the pathogenesis of coronavirus infections is
complex and contradictory (Santiesteban-Lores etal., 2021). During
SARS-CoV-2 infection, the complement system is a host defense
mechanism against viral replication in asymptomatic or mild cases
(Santiesteban-Lores etal., 2021). However, complement activation has
also potent proinammatory eect and can increase local and systemic
damage in severe COVID-19 (Santiesteban-Lores et al., 2021). As
outlined above, coronavirus induce production of mito-ROS during
infection. Mito-ROS induce the “complement–metabolism–
inammasome axis”(Arbore and Kemper, 2016). MERS-CoV can also
directly induce the complement system (Chen etal., 2010). Collectively,
limited evidence suggests that complement activation through redox
pathways may have a more important role in cell and tissue damage in
severe coronavirus infections rather than a major regulatory role in
replication of coronaviruses.
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Redox mechanisms that regulate replication
of coronavirus through mitophagy
Mitophagy, the cellular process that clears excess or damaged
mitochondria, has a key role in function of mitochondria and
mammalian cells and regulates severeal physiological and
pathological processes, including apoptosis, immunity and
inflammation. Emerging evidence suggests that several viruses
hijack mitophagy to enable viral replication and escape host
immune responses (Li etal., 2022). SARS-CoV can encode open
reading frame-9b (ORF-9b), which is localized in mitochondria and
induces mitochondrial elongation which further triggers mitophagy
and coronavirus replication (Shi etal., 2014). Preclinical studies
have shown that SARS-CoV-2 directly causes mitochondrial
dysfunction and mitophagy impairment (Shang et al., 2021).
Notably, defects in autophagy and mitophagy processes may regulate
host response to coronavirus infection (Pacheco et al., 2021).
Coronaviruses also induce production of mito-ROS that have an
established complex crosstalk with mitophagy (Schofield and
Schafer, 2021). Overall, further evidence is needed to clearly link the
role of aberrant redox pathways and mitophagy in the regulation of
replication of coronaviruses.
Redox pathways that regulate
inflammation during infection with
coronaviruses
Several redox mechanisms regulate inflammation during
infection with coronaviruses (Figure2; Table2; Shono etal., 1996;
Wesselborg et al., 1997; Chua et al., 1998; Canty et al., 1999;
Tenjinbaru etal., 1999; Wang and Zhang, 1999; Cooke and Davidge,
2002; Pearlstein etal., 2002; Takada etal., 2003; Mizutani etal.,
2004; Desouki et al., 2005; Mukherjee etal., 2005; Kefaloyianni
etal., 2006; Xie and Shaikh, 2006; Schrader etal., 2007; Doughan
etal., 2008; Nanduri etal., 2008; Cho etal., 2009; Hosakote etal.,
2009; Jamaluddin etal., 2009; Martinon etal., 2009; Wosniak etal.,
2009; Dikalova etal., 2010; Bulua et al., 2011; Kesic etal., 2011;
Kosmider etal., 2012; Yamada etal., 2012; Lee etal., 2013; Nakajima
and Kitamura, 2013; Nguyen Dinh Cat etal., 2013; Komaravelli and
Casola, 2014; Zinovkin etal., 2014; Komaravelli etal., 2015; Simon
etal., 2015; Sun etal., 2016; Zhang etal., 2016; Daiber etal., 2017;
Espinoza etal., 2017; Khomich etal., 2018; Tu et al., 2019; Valle
etal., 2019; Connors and Levy, 2020; Mahmud-Al-Rafat etal., 2020;
Olagnier etal., 2020; Herengt etal., 2021; Saheb Sharif-Askari etal.,
2021; Toro etal., 2022).
NF-κB pathway
Nuclear factor-κB (NF-κB) is a redox-sensitive transcription factor
that is regulated by ROS through the classical IkB kinase (IKK)-
dependent canonical pathway (Liu etal., 2017) and coordinates innate
and adaptive immunity, inammation, and apoptosis (Piette etal.,
1997). e redox regulation of the NF-κB pathway has been reviewed
elsewhere and varies between dierent mammalian cells and in the
setting of cancer (Gloire etal., 2006). Although it is established that
cytokines and lipopolysaccharides induce proinammatory activation
of NF-κB (Schreck and Baeuerle, 1991), ROS may also reduce NF-κB
activity (Nakajima and Kitamura, 2013). Oxidative stress in the early
phase may induce activation of NF-κB in epithelial cells (Wesselborg
etal., 1997; Tenjinbaru etal., 1999; evenod etal., 2000) and endothelial
cells (Shono etal., 1996; Chua etal., 1998; Canty etal., 1999; Cooke and
Davidge, 2002) which are targets of coronaviruses. Redox stress in
epithelial cells in the late phase may also inhibit basal and inducible
activation of NF-κB (Xie and Shaikh, 2006; Yang etal., 2007; Nakajima
and Kitamura, 2013). e regulation of NF-κB by ROS is dependent not
only on the phase of responses and the pattern of stimulation, but also
depends on specic cell types (Nakajima and Kitamura, 2013). However,
most of the evidence regarding redox regulation of the NF-κB pathway
is not based on airway epithelial cells, the main target of SARS-CoV-2,
and heterogeneous redox stimuli have been utilized in several
experimental studies, oen in supraphysiological concentrations. us,
it is not well dened how ROS regulate activity of NF-κB in a
bidirectional fashion in airway epithelial cells (Nakajima and
Kitamura, 2013).
Overall, cumulative evidence suggests that there is context-
dependent regulation of NF-κB by ROS (Nakajima and Kitamura,
2013). Preclinical studies have shown that ROS trigger NF-κB
activation in airway epithelial cells (Jany etal., 1995; Ito etal., 2004).
In contrast, inhibition of cytokine-triggered NF-κB activation under
pre-exposure to ROS has been described in distal airway alveolar
epithelial cells (Korn et al., 2001; Reynaert et al., 2006). The
oxidative stress– unfolded protein response (UPR) pathway and
redox ER responses play a key role in the bidirectional control of
NF-κB (Nakajima and Kitamura, 2013). Thus, the opposite,
bidirectional effects of redox stimuli on NF-κB seem to depend on
the phase of response, the context, the type of cells and the specific
redox stimuli. Overall, this bidirectional crosstalk is not well
characterized specifically in coronavirus infections.
Viruses may hijack cellular signaling pathways and transcription
factors and control them to their own advantage. In particular, the
NF-κB pathway appears to bean attractive target for common human
viral pathogens (Santoro etal., 2003). Distinct viral proteins encoded
by viruses such as HCV, rotavirus, EBV, HBV, HTLV-1, and HIV-1
activate NF-κB by interacting with cellular signaling pathways
including calcium-or redox-regulated signals or through ER stress
mechanisms. Accumulation of viral dsRNA activates PKR, which in
turn stimulates IKK. However, most of the evidence regarding virus-
induced regulation of the NF-κB pathway is based on chronic viral
infections or infections with DNA viruses (Santoro etal., 2003). ere
is limited evidence regarding the direct impact of coronaviruses on
this pathway.
Evidence has suggested that proteins of SARS-CoV-2 can
directly or indirectly impact NF-kB activation. In vitro studies
showed that the spike protein of SARS-CoV induces a strong
cytokine response through the NF-kB pathway (Dosch etal., 2009).
It was also shown that SARS-CoV nucleocapsid protein activated
NF-kB in Vero E6 cells in a dose dependent manner (Liao etal.,
2005). ORF7a protein of SARS-CoV-2 mediates activation of
NF-kB and induced proinflammatory expression of cytokines (Su
et al., 2021). Similarly, Nsp5in SARS-CoV-2 activated NF-kB
pathway through upregulation of SUMOylation of mitochondrial
antiviral-signaling proteins (Li etal., 2021b). Notably, studies show
that the NF-κB signal pathway is a central pathway involved in
induction of pro-inflammatory cytokines and chemokines in
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respiratory virus infection, including SARS-CoV-2-triggered
COVID-19 (Kircheis etal., 2020; Hariharan etal., 2021; Kandasamy,
2021). Thus, the pharmacological inactivation of the NF-κB
signaling pathway can represent a potential therapeutic target to
treat severe COVID-19 (Kircheis etal., 2020; Hariharan etal., 2021;
Kandasamy, 2021).
TABLE2 Redox mechanisms that regulate cell and tissue damage during infection with coronaviruses.
Mediators Eect on redox balance References
Redox NF-kB • Context-dependent since ROS can in theory ↑ or ↓ NF-kB (e.g., phase of responses, pattern of
stimulation, cell types of kB, etc).
Nakajima and Kitamura (2013)
• Overall evidence supports that ROS ↑ NF-kB during acute infection
• Drive cytokine storm, triggering lung damage during viral infection
ROS • ↑ NF-kB Pearlstein etal. (2002), Mukherjee etal. (2005),
Zinovkin etal. (2014)
• ↑ TNF-induced IL-6 expression.
• ↑ TNF-dependent ↑ expression of the adhesion molecules and ↑ endothelial permeability.
• ↑ apoptosis and cell/tissue damage
• ↑ end organ disease (brain, lung, cardiometabolic damage) in Long COVID
Mito-ROS • ↑ NF-kB Shono etal. (1996), Wesselborg etal. (1997), Chua
etal. (1998), Canty etal. (1999), Tenjinbaru etal.
(1999), Wang and Zhang (1999), Cooke and
Davidge (2002), Mizutani etal. (2004), Desouki
etal. (2005), Kefaloyianni etal. (2006), Xie and
Shaikh (2006), Doughan etal. (2008), Jamaluddin
etal. (2009), Martinon etal. (2009), Wosniak etal.
(2009), Bulua etal. (2011), Lee etal. (2013), Sun
etal. (2016), Zhang etal. (2016), Daiber etal.
(2017), Saheb Sharif-Askari etal. (2021)
• ↑ complement-metabolism-inammasome axis
• ↑ Indirectly inammatory caspases 1, 12, cytokines IL-1B, IL-18 through NLRP3 inammasome
• ↑ activation of MAPK, MEK, MNK1 pathways →↑ production of IL-6 and TNF-a
• ↑ induce release of IL-1B, IL-6 and lung injury under viral infection
• ↑ Mito-ROS regulates NOX and impacts survival rates of mice with post-viral pneumonia
• Regulate Ca2+ signaling systems that may impact inammatory host responses
• ↑ Nrf2 pathway
• Regulate ER stress and unfolded protein response that may impact inammatory host responses
• Regulate interferon host responses
• ↑ apoptosis and cell/tissue damage
• Regulate mitophagy/autophagy and cell/tissue damage
Keap1-Nrf2-
ARE pathway
• ↑ anti-viral responses Cho etal. (2009), Hosakote etal. (2009), Kesic etal.
(2011), Yamada etal. (2012), Kosmider etal. (2012),
Komaravelli and Casola (2014), Komaravelli etal.
(2015), Simon etal. (2015), Espinoza etal. (2017),
Khomich etal. (2018), Tu etal. (2019), Olagnier
etal. (2020), Herengt etal. (2021), Toro etal. (2022)
• ↑ anti-inammatory responses
• Remove toxic heme
• Protect against oxidative injury
• ↑ anti-apoptotic responses
• Regulates angiogenesis
• Regulates autoimmunity
• Regulates vascular injury
• Mediates pathogenesis and tissue damage of many viral infections, including HIV, RSV, Inuenza,
SARS-CoV-2
• ↓ apoptosis that regulates cell death and tissue damage
Ang II • ↑ ROS levels through NADPH oxidase, →↑ cytokines (e.g., IL-6, IL-8, TNF-a) through NF-kB
upregulation →↑ pro-inammatory response
Nguyen Dinh Cat etal. (2013), Mahmud-Al-Rafat
etal. (2020)
Type IIFNs • Coronaviruses and ROS downregulate interferon host responses that impact a cascade of signaling
events that may drive tissue damage
Dikalova etal. (2010)
Cytokines
(bidirectional
link with redox
stress)
• Cytokines (e.g., IL-1, IL-6, TNFa) activate macrophages, neutrophils, endothelial cells through
NOX, disrupting redox balance of the cell
Takada etal. (2003), Schrader etal. (2007), Nanduri
etal. (2008), Valle etal. (2019), Connors and Levy
(2020)
• IL-6 directly induces mito-ROS production and NOX in endothelial cells
Abbreviations: ACE2, Angiotensin-converting enzyme 2; AngII, Angiotensin II; ARE, antioxidant response element; COVID, COrona Virus Disease; Ca2+, Calcium (II) ion; ER, endoplasmic
reticulum; HIV, human immunodeciency virus; HO-1, Heme oxygenase 1; IFNs, Interferons; IL, interleukin; Keap1, Kelch-like ECH-associated protein 1; MAPK, mitogen-activated protein
kinase; MEK, Mitogen-activated protein kinase; Mito-ROS, Mitochondrial reactive oxygen species; Mnk1, mitogen-activated protein kinase (MAPK) interacting protein kinase 1; NF-κB, Nuclear
factor kappa B; NOX, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; Nrf2, nuclear factor erythroid 2–related factor 2; NQo-1, NAD(P)H quinone oxidoreductase; ROS, reactive
oxygen species; RSV, Respiratory Syncytial Virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF, Tumor necrosis factor; UPR, unfolded protein response.
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Mito-ROS pathways
As outlined above, coronavirus induce production of mito-ROS
during infection. Mito-ROS have been shown to inhibit interferons
and induce aberrant alterations of lipids, membranes, proteins and
ultimately tissue damage. Mito-ROS induce inflammasome
activation (Dashdorj et al., 2013; Han et al., 2018) and the
“complement–metabolism–inflammasome axis”(Arbore and
Kemper, 2016), Mito-ROS indirectly regulate inflammatory
caspases 1 and 12, as well as the cytokines IL-1β and IL-18in
macrophages through the NLRP3 inflammasome (Martinon etal.,
2009). Mito-ROS induce NFκB (Imai etal., 2008) which drives a
cytokine storm, triggering lung damage during viral infection.
Mito-ROS also induce activate MAPK pathways and promote
production of IL-6 and TNF-α (Wang and Zhang, 1999; Mizutani
etal., 2004; Kefaloyianni etal., 2006; Jamaluddin etal., 2009; Bulua
etal., 2011; Zhang etal., 2016). Mito-ROS directly induce release of
IL-1β (Dashdorj etal., 2013; Han etal., 2018), IL-6 (Lowes etal.,
2008, 2013; Bulua etal., 2011; Li etal., 2019). Consistent with this
evidence it has been shown that Mito-ROS induce inflammatory
response and lung injury in mouse models of viral infections (Hu
et al., 2019a; Hu et al., 2019b). Thus, mito-ROS may regulate
redox cytoplasmic proinflammatory responses in respiratory
viral infections.
Nf2 pathways
Heme oxygenase 1 (HO-1), a downstream protein of the Nrf2
pathway, contributes to anti-inammatory and antiviral responses,
removes toxic heme, protects against oxidative injury and also regulates
apoptosis, inammation and angiogenesis (Espinoza etal., 2017). While
the exact mechanism by which SARS-CoV-2 aects HO-1 and,
conversely, how HO-1 exerts its antiviral eects against SARS-CoV-2 is
still being studied, there is an established association between HO-1 and
a reduction of tissue damage through its anti-inammatory and
antioxidative functions throughout the body (Toro etal., 2022). is
makes HO-1 an important target for developing novel COVID-19
therapeutics.
Angiotensin II and NOX
During SAS-CoV-2 infection, the reduction of ACE2 on the cell
surface leads to increase of Ang II and NOX (Nguyen Dinh Cat etal.,
2013). Bidirectional crosstalk between mitochondria and NOX,
markedly aects redox responses to angiotensin II, the ligand of ACE2
that is upregulated in viral infections (Doughan etal., 2008; Wosniak
etal., 2009; Lee etal., 2013; Daiber etal., 2017). Indeed, therapeutic
targeting of NOX, triggered by mito-ROS (Desouki et al., 2005),
increased the survival of mice with post-inuenza pneumonia (Sun
etal., 2016). us, as a result of increased NOX, NF-κβ activation there
is activation of the pro-inammatory response and release of cytokines
like IL-6, IL-8, and TNFα (Mahmud-Al-Rafat et al., 2020).
Pro-inammatory cytokines like IL-1, IL-6, and TNFα activate
macrophages, neutrophils, and endothelial cells through NADPH
oxidase, resulting in a greater production of superoxide and H2O2
(Takada etal., 2003; Nanduri etal., 2008; Connors and Levy, 2020).
The complement system
As outlined above, coronavirus induce production of mito-ROS
which trigger the “complement–metabolism–inflammasome
axis”(Arbore and Kemper, 2016). MERS-CoV can also directly
induce the complement system (Chen etal., 2010). The complement
activation has also potent proinflammatory effect and can increase
local and systemic damage in severe COVID-19 (Santiesteban-Lores
etal., 2021). Preclinical in vitro studies have shown controversial
data regarding the role of the complement system in binding
coronaviruses (Santiesteban-Lores et al., 2021). Experimental
studies with animals have shown that complement activation
induces a systemic pro-inflammatory response during experimental
infection with SARS-CoV and MERS that drives disease progression
(Gralinski etal., 2018; Jiang etal., 2018). Small human cohorts also
show that complement activation is associated with disease
progression of SARS (Wang etal., 2005). Collectively, limited and
often controversial evidence suggests that complement activation
through redox pathways may have an important role in cell and
tissue damage in severe coronavirus infections.
Other proinflammatory mechanisms in
coronavirus infections
Other than activation of proinammatory NF-kB, mito-ROS and
NOX pathways and downregulation of anti-inammatory ACE2 and
Nrf2 pathways, dierent coronaviruses may also directly induce other
proinammatory eects. MERS-CoV can induce the complement
system and increase inammatory response, pyroptosis and eventually
lung tissue damage (Chen et al., 2010). MERS-CoV infected
macrophages increase pro-inammatory cytokines and chemokines
(Pruijssers and Denison, 2019). SARS-CoV and MERS-CoV may also
attenuate levels of endogenous Type IIFNs that are immunomodulatory
(Dikalova etal., 2010). Finally, mouse hepatitis virus (MHV) directly
upregulated interleukin signaling such as IL-27 during
acute encephalomyelitis.
Redox pathways that regulate
apoptosis during infection with
coronaviruses
As described above, coronaviruses induce apoptosis through
multiple pathways, either directly (Pfefferle et al., 2011), or
indirectly by inducing production of mito-ROS and downregulating
antiapoptotic pathways such as Nrf2. Excessive ROS generation can
lead to loss of mitochondrial function and apoptosis of lung
epithelial cells (Sun etal., 2013). Increased mito-ROS also directly
contribute to acute injury in lung tissue in mouse models of viral
infections (Hu et al., 2019a,b). Indeed, increased apoptosis of
epithelial cells is associated with lung injury in COVID-19
(Hussman, 2020). Studies have also shown that CD4 and CD8 T
cells in patients with COVID-19 are more likely to get affected by
apoptosis (Nieto-Torres et al., 2015). Thus, increased apoptosis
during coronavirus infection contributes to increased tissue damage
and pathogenesis of coronavirus infections.
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Redox pathways that regulate
mitophagy during infection with
coronaviruses
As outlined above, coronaviruses induce production of mito-ROS
that have an established complex crosstalk with mitophagy (Schoeld
and Schafer, 2021). Mitochondrial ROS and damage-associated
molecular patterns (DAMPs) activate inammasomes to induce
inammatory responses and tissue injury. Emerging evidence suggests
that mitophagy protects against the hyperinammation induced by ROS
and DAMPs and regulates inammatory responses in several diseases
(Zhao et al., 2015). us, by inducing production of mito-ROS,
mitochondrial dysfunction and mitophagy impairment, SARS-CoV-2
may contribute to inammation and tissue damage (Shang etal., 2021).
Redox pathways that regulate other
instigators of tissue damage during
infection with coronaviruses
Other than regulation of viral replication, inammation and
apoptosis, redox pathways may also contribute to regulation of other
pathways that contribute to tissue damage such as autoimmunity and
vascular dysfunction. Oxidative stress plays a central in autoimmune
diseases (Ramani etal., 2020). Specically, the antioxidant pathway
Nrf2 has also a key role in regulation of autoimmunity (Freeborn and
Rockwell, 2021). Given the possible role of autoimmunity in
pathogenesis of COVID-19 and Long COVID, further understanding
of the contribution of dysregulation redox pathways in development
of autoimmunity during coronavirus infections is needed (Liu etal.,
2021; Saad etal., 2021).
ROS induce levels of the adhesion molecules and increase
permeability in endothelial cells (Mukherjee etal., 2005; Zinovkin etal.,
2014). ROS also contribute to TNF-induced IL-6 expression and NF-κB
activation (Pearlstein et al., 2002). Notably, IL-6 directly induces
mito-ROS production and NOX in endothelial cells (Schrader etal.,
2007; Valle etal., 2019) and impact NO bioavailability and endothelial
function (Saura etal., 2006). SARS-CoV-2 S-protein binds to ACE2 and
subsequently triggers reduction in ACE2 levels that cleaves ATII. High
ATII level further leads to oxidative stress and endothelial dysfunction
(Chernyak et al., 2020) and induces ROS production via NOX in
endothelial cells. us, increased redox stress induced by SARS-CoV-2
may impact not only vascular permeability and vasodilation but also
vascular inammation.
Oxidative stress and end organ
damage during infection with
coronaviruses
All coronaviruses have the potential to induce tissue damage and
end organ disease through viral replication, increased inammation
and apoptosis, induction of ROS and reduction of cytoprotective
pathways such as the Nrf2 and HO-1 pathways. Increased redox
stress is known instigator of lung dysfunction (Kellner etal., 2017),
cardiovascular disease (Dubois-Deruy etal., 2020), central nervous
system dysfunction such as neurodegeneration and neuropsychiatric
disease (Reiter, 1998; Patel, 2016; Salim, 2017) and the metabolic
syndrome (Ando and Fujita, 2009; Roberts and Sindhu, 2009;
Carrier, 2017) which are all manifestations of both acute severe
COVID-19 and post-acute sequelae of SARS-CoV-2 infection (oen
called Long COVID syndrome; Figure3; Nalbandian etal., 2021).
Coronaviruses dier in their potential to induce end organ damage
(Table3; Bonavia etal., 1997; De Albuquerque etal., 2006; de Wilde
et al., 2013; Josset etal., 2013; Zhao etal., 2015; Li et al., 2016;
Agostini etal., 2018; Coperchini etal., 2020; Huang etal., 2020;
Petersen etal., 2020; Wang et al., 2020; Yi et al., 2020; Caldera-
Crespo etal., 2021; Paidas etal., 2021; Tian etal., 2021; Jansen etal.,
2022). Among the various human coronaviruses, end organ damage
is observed in MERS, SARS-CoV-1, and SARS-CoV-2. ese
coronaviruses demonstrate a more severe pathology than HCoV-
229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1in terms of
their fatality and systemic eects on multiple organ systems. Multiple
animal models have been used to uncover the ways coronaviruses
lead to the end organ damage that presents in patient autopsies. e
MHV mice model is the most studied model among the
coronaviruses, and it has served as a useful proxy in understanding
SARS-CoV-2 (Paidas etal., 2022); MHV is known to enteric and
respiratory disease, hepatitis, encephalitis, and chronic demyelination
and is useful in studying infection of the liver and brain (Weiss and
Navas-Martin, 2005). Despite MHV-1 utilizing a dierent receptor
than either MERS or the SARS coronaviruses (carcinoembryonic
antigen-related cell adhesion molecule 1 instead of
dipeptidylpeptidase 4 and angiotensin-converting enzyme 2), end
organ damage in the MHV-1 model has been acclaimed as an
appropriate model for MERS, SARS-CoV-1, and SARS-CoV-2 (De
Albuquerque etal., 2006; Agostini etal., 2018; Caldera-Crespo etal.,
2021; Paidas et al., 2021; Tian et al., 2021). Herein, we briey
summarize redox pathways that regulate damage of the lung and the
brain, the two main target organs for end organ disease in acute
COVID-19 and Long COVID.
Lung damage
e excessive generation of oxygen radicals under pathological
conditions such as acute lung injury (ALI) and its most severe form
acute respiratory distress syndrome (ARDS) leads to increased
endothelial permeability. Increased redox stress leads to increased
permeability of lung blood vessels, increased inltration of immune cells
and increased accumulation of uids in the alveolar system (Kellner
etal., 2017). Mitochondria, NADPH oxidase (NOX), xanthine oxidase
(Shasby etal., 1985; Barnard and Matalon, 1992), and eNOS are the
major contributors of ROS in cells of vasculature during active
metabolism that also contribute to the pathogenesis of ALI (Gross etal.,
2015). Imbalance of antioxidant enzymes such as superoxide dismutase
(SOD; Ndengele etal., 2005; Cai etal., 2014), catalase (Flick etal., 1988;
Kozower etal., 2003) and glutathione peroxidase (GPx; Aggarwal etal.,
2012; Kim etal., 2012a) and Nrf2 (Zhu etal., 2013; Peng etal., 2016) also
contribute to pathogenesis of ALI and ARDS. Similarly, to MERS and
SARS, severe SARS-CoV-2 infection presents with high levels of
pro-inammatory cytokines like IL-6, and can lead to ARDS, which is
associated with acute renal injury, acute respiratory injury, and septic
shock (Chen et al., 2020). COVID-19-related ARDS has a high
prevalence and is dierent to ARDS due to other etiologies (Park
etal., 2009).
SARS-CoV-2 directly impacts several of established instigators
that contribute to pathogenesis of ALI/ARDS including
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mitochondrial function (Srinivasan etal., 2021), NOX (Damiano
etal., 2020; Violi etal., 2020; de Oliveira and Nunes, 2021), xanthine
oxidase (Pratomo etal., 2021; Al-Kuraishy et al., 2022), eNOS
(Guimaraes etal., 2021), glutathione peroxidase (Labarrere and
Kassab, 2022) and Nrf2 (Olagnier etal., 2020; Zhang etal., 2022).
To date, there is no treatment for ARDS in COVID-19 disease
(Jafari-Oori etal., 2021).
Brain damage
e brain is highly susceptible to oxidative stress due to
enrichment for lipids, mitochondria, calcium, glutamate and
increased redox stimuli (Cobley etal., 2018). Brain damage induced
by oxidative stress may negatively impact normal functions of central
nervous system and may contribute to the pathogenesis of
neurodegenerative disorders such as Alzheimer and Parkinson
disease and in the pathogenesis of neuropsychiatric disorders,
including anxiety and depression (Salim, 2017). For these, increased
oxidative stress through mitochondrial dysfunction, increased
inammation and energy imbalance has also been hypothesized to
contribute to pathogenesis of neurocognitive dysfunction in Long
COVID (Paul etal., 2021; Jarrott etal., 2022).
Antioxidant therapies in coronavirus
infections
Multiple trials underway have tested antioxidants as therapeutic
agents in COVID-19.
1
Several therapies targeting redox imbalance
already have been used for the treatment of COVID-19 including
inhaled NO (Lotz et al., 2021), ubiquinol (Fukuda et al., 2016),
combination of NADH and CoQ10 (Castro-Marrero et al., 2015),
N-acetyl cysteine, mitochondria-targeted antioxidant MitoQ (Codo
etal., 2020; Petcherski etal., 2022) and Nrf2 agonists (Zinovkin and
Grebenchikov, 2020). Other potential antioxidant treatments that have
been considered include, ubiquinol, nicotinamide, glutathione (and
glutathione donors), cysteamine, sulforaphane, melatonin vitamin C,
vitamin D, vitamin E, melatonin plus pentoxifylline and selenium.
However, most of the proposed antioxidant treatments have either not
been directly tested in humans in the setting of randomized control
clinical trials or due to several methodological issues of heterogeneous
studies, the data were inconclusive (Table4). Many ongoing clinical
trials regarding the use of antioxidants in treatment of COVID-19 have
not been published. Notably, oral antioxidants have not produced
dramatic improvements in conditions associated with redox imbalance
(Barcelos etal., 2020). No single antioxidant can scavenge all the various
ROS and reactive nitrogen species (RNS). Further validation with
animal models and clinical trials are necessary to reveal therapeutic
potential of combination therapies of antivirals, antioxidant and anti-
inammatory treatments.
Conclusion
ere is limited understanding how dierent coronaviruses
including SARS-CoV-2, manipulate cellular redox machinery to drive
viral replication and associated host cell responses including
inammation, apoptosis and associated end organ disease. e
crosstalk between NOX and ACE2 as well mito-ROS may impact viral
entry of coronaviruses while mito-ROS may also induce multiple
proviral cytoplasmic pathways. Experimental studies have also shown
that coronaviruses induce downregulation of antioxidant genes such as
Nrf2in combination with an upregulation of oxidative stress genes like
myeloperoxidase that may contribute to both increased viral replication
and inammation. Coronaviruses may induce several redox sensitive
proinammatory pathways such NF-kB, mito-ROS and NOX pathways
and downregulate anti-inammatory ACE2 and Nrf2 pathways.
Coronaviruses may further trigger cell damage through activation of
redox sensitive pyroptosis and apoptosis. Finally, other than regulation
of viral replication, inammation and apoptosis, redox pathways may
also contribute to regulation of other pathways that contribute to tissue
damage such as autoimmunity and vascular dysfunction. us,
coronaviruses have the potential to induce tissue damage and end
organ disease through viral replication, increased inammation and
apoptosis, induction of ROS and reduction of cytoprotective pathways
such as the Nrf2 and HO-1 pathways. Coronaviruses dier in their
potential to induce end organ damage. Among the various human
coronaviruses, end organ damage is observed in MERS, SARS-CoV-1,
and SARS-CoV-2. Increased redox stress is known instigator of lung
1 https://clinicaltrials.gov/
FIGURE3
Viral infection and end organ damage. Increased redox stress drives
viral replication, inflammation, apoptosis, vascular dysfunction and
autoimmunity, in both acute infection with coronaviruses and in the
setting of Post-Acute Sequelae of SARS-CoV-2 (PASC or Long COVID).
Collectively, redox mediated pathways that drive viral replication,
inflammation, apoptosis, autoimmunity, and vascular dysfunction
contribute to cell and tissue damage that drives end organ disease in
coronavirus infection. Cells enriched in mitochondria such as neurons,
endothelial and epithelial cells may beparticularly susceptible to
increased redox stress driven by coronaviruses. Ultimately, increased
redox stress during acute infection with coronaviruses and in the
setting of PASC can directly or indirectly drive end organ disease such
as brain, lung, liver, kidney and cardiovascular damage and induce
intestinal dysfunction.
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TABLE3 Comparison of coronaviruses with regards to impact on end organ disease.
Dierences SARS-CoV-2 with other coronaviruses Similarities between SARS-CoV-2 with other coronaviruses
• ↑ Transmissibility and ↑ anity to the ACE2 receptor compared to other
coronaviruses (Coperchini etal., 2020).
• ↑ cytokine storm, severe pneumonia, septic shock and multiorgan damage similarly
to SARS and MERS
• ↑ Viral replication compared to SARS (Huang etal., 2020). • Infects the airways
• ↑ Cytokine storm similarly to SARS • Impacts the brain similarly to MHV (De Albuquerque etal., 2006; Agostini etal.,
2018; Caldera-Crespo etal., 2021; Paidas etal., 2021; Tian etal., 2021), HCoV-OC43
and HCoV-229E (Bonavia etal., 1997).
• ↑ Cytokine TH1 pro-inammatory cytokines compared to SARS (Huang etal.,
2020).
• Infects the liver (Wang etal., 2020) similarly to MHV (De Albuquerque etal., 2006;
Agostini etal., 2018; Caldera-Crespo etal., 2021; Paidas etal., 2021; Tian etal., 2021)
and MERS (Zhao etal., 2015).
• ↓ Interferon response compared to SARS and MERS (Li etal., 2016) • Impacts the heart similarly to MHV (De Albuquerque etal., 2006; Agostini etal.,
2018; Caldera-Crespo etal., 2021; Paidas etal., 2021; Tian etal., 2021).
• Unlike MERS requires a TH17 type response (Yi etal., 2020) • Impacts the kidney (Jansen etal., 2022) similarly to MHV (De Albuquerque etal.,
2006; Agostini etal., 2018; Caldera-Crespo etal., 2021; Paidas etal., 2021; Tian etal.,
2021).
• ↓ Severe symptoms compared to SARS/MERS (Petersen etal., 2020). • ↑ vascular injury and thrombosis (Siddiqi etal., 2021) similarly to MHV (De
Albuquerque etal., 2006; Agostini etal., 2018; Caldera-Crespo etal., 2021; Paidas
etal., 2021; Tian etal., 2021).
• MERS is more cytopathic and causes greater immune system dysregulation compared
to SARS-CoV-2 (de Wilde etal., 2013; Josset etal., 2013)
Abbreviations: ACE2, Angiotensin-converting enzyme 2; HCoV-229E, Human coronavirus 229E; HCoV-OC43; Human coronavirus OC43; HCoV-NL63; HKU-1, HCoV-HKU1 = human
coronavirus HKU1; MERS-CoV, Middle E ast respiratory syndrome coronavirusl MHV, mouse hepatitis virus; SARS-CoV, S evere acute respiratory syndrome coronavirus; SARS-CoV-2, Severe
acute respiratory syndrome coronavirus 2; TH1, Type 1 T helper
TABLE4 Antioxidant treatments that have been tested in humans for treatment of coronavirus infections.
Mediators Eect References
Inhaled NO ↑ oxygenation in severe COVID-19, no eect on
mortality
Lotz etal. (2021), Prakash etal. (2021)
Ubiquinol (CoQ10) Does not ↓ the number or severity of PASC-related
symptoms when compared to placebo
Hargreaves and Mantle (2021), Hansen etal. (2022)
N-acetyl cysteine Oral high dose of N-acetyl cysteine may ↓ morbidity in
severe COVID-19in observational studies; many
ongoing clinical trials with unpublished data
Wong etal. (2021), Izquierdo etal. (2022)
Glutathione ↓ reduces dyspnea in COVID-19in a case series Horowitz etal. (2020)
Melatonin May improve clinical outcomes in patients with
COVID-19 based on RCTs
Lan etal. (2022)
Vitamin C Controversial data may have some benet in morbidity
in COVID-19 based on clinical trials
Olczak-Pruc etal. (2022)
Vitamins Controversial data overall weak/negative;
supplementation with vitamins A, B, C, D, and E could
improve the inammatory response and decrease the
severity of disease in ICU-admitted patients with
COVID-19
Beigmohammadi etal. (2021)
Zinc Overall limited data/no major eect on morbidity in
COVID-19, many ongoing clinical trials with
unpublished data
Perera etal. (2020), Balboni etal. (2022)
Selenium Overall limited data/no major eect on morbidity in
COVID-19, many ongoing clinical trials with
unpublished data
Alshammari etal. (2022), Balboni etal. (2022)
Pentoxifylline May reduce lung inammation, ongoing clinical trials
with unpublished data
Feret etal. (2021)
Abbreviations: RCT, R andomized control clinical trial; PASC, Post Acute Sequalae of SARS-CoV-2 infection.
Gain et al. 10.3389/fmicb.2022.1111930
Frontiers in Microbiology 12 frontiersin.org
dysfunction (Kellner etal., 2017), cardiovascular disease (Dubois-
Deruy et al., 2020), central nervous system dysfunction such as
neurodegeneration and neuropsychiatric disease (Reiter, 1998; Patel,
2016; Salim, 2017) and the metabolic syndrome (Ando and Fujita,
2009; Roberts and Sindhu, 2009; Carrier, 2017) which are all
manifestations of both acute severe COVID-19 and Long COVID
syndrome (Nalbandian et al., 2021). Given the complexity of the
pathogenesis of coronavirus infections and that oral antioxidants have
not produced dramatic improvements in conditions associated with
redox imbalance, further validation with animal models and clinical
trials are necessary to reveal therapeutic potential of combination
therapies of antivirals, antioxidant and anti-inammatory treatments.
Understanding the mechanisms that contribute to the pathogenesis of
coronavirus infections, will set the foundation for development of new
treatments for coronavirus infections.
Author contributions
CG, SiS, TA, and TK wrote the manuscript, reviewed the literature,
and collected the information. SaS revised the manuscript. All authors
contributed to the article and approved the submitted version.
Funding
is work was supported in part by National Institute of Health
grant R01AG059501 (TK), National Institute of Health grant
R01AG059502 04S1 (TK), and California HIV/AIDS Research Program
grant OS17-LA-002 (TK).
Conflict of interest
e authors declare that the research was conducted in the absence
of any commercial or nancial relationships that could beconstrued as
a potential conict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and
do not necessarily represent those of their aliated organizations, or
those of the publisher, the editors and the reviewers. Any product that
may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
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