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\title{Role of Poly(ADP-ribose) polymerase (PARP1)~ in viral infection and its
implication in SARS-CoV-2 pathogenesis~~~~~~~~~~~~}



\author[1]{Jyotika Rajawat}%
\author[2]{Abhishek Chandra}%
\affil[1]{University of Lucknow}%
\affil[2]{Mayo Clinic}%


\vspace{-1em}



  
  \date{April 26, 2026}


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\selectlanguage{english}
\begin{abstract}
Poly (ADP-ribose) polymerase 1 (PARP1) is a post-translational modifying
enzyme and is also known to act as transcription factor and
co-activator. PARP1 has been shown to be involved with diseases
resulting in increased inflammation and several viral diseases have also
been associated with PARP1 activation. PARP1 facilitates influenza A
virus entry in host cells by degrading interferon receptor type I. PARP1
regulates expression of NFkB and downstream cytokine production and its
inhibition is known to attenuate the expression of inflammatory
cytokines. Thus, PARP1 plays an important role in host-pathogen
interactions and pathogenesis. Moreover, pre-clinical and in vitro
studies have shown that PARP1 inhibition may affect viability of several
viruses including affecting replication of the SARS-CoV virus, a distant
relative of the SARS-CoV-2 virus, the one which caused the SARS epidemic
of 2002. Covid-19 has been declared a global pandemic; with symptoms of
the disease now not limited to respiratory distress alone. Severe
inflammation is observed in the lungs leading to a surge of cytokine
release systemically, affecting heart function, ischemia and stroke.
Inflammatory cytokines which are associated with severe comorbidities
and mortalities due to chronic diseases are being upregulated in an
acute fashion. There is no immediate treatment, and only palliative care
is being provided. The current review will discuss mechanisms of PARP1
activation during viral infection, inflammatory diseases, cytokine
expression and possibility of PARP1 in regulating cytokine storm and
hyper-inflammation seen with Covid-19.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Covid-19 (\emph{Co}rona\emph{vi}rus \emph{d}isease of 20\emph{19} ) is
caused by severe acute respiratory syndrome Coronavirus (SARS-CoV-2)
infection, which causes acute respiratory distress and lung fibrosis and
has resulted in more than \textasciitilde{}10 million reported cases and
more than \textasciitilde{}500,000 deaths worldwide as of 28th June 2020
(https://coronavirus.jhu.edu/map.html). The extent of the severity of
disease is still to be assessed with reasons for mortality linked with
Covid-19, being an evolving process with plethora of pathological
conditions being reported in an acute period. Epidemiological and cross
disciplinary aspect of the virus has been studied (Sun et al., 2020). A
retrospective study reported from Wuhan reported that 100\% of the
patients suffered from acute respiratory distress syndrome and sepsis,
more than 50\% patients with type I respiratory failure, acute cardiac
injury and heart failure, with some cases of kidney injury and hypoxic
encephalopathy (Chen et al., 2020). The disease is fatal with seniors
and people with comorbidities such as diabetes, obesity (Petrakis et
al., 2020), asthma, cardiovascular risks (Cheng et al., 2020) etc.
Moreover more recent reports suggest that the disease is not sparing
people of younger age groups, with symptoms of acute inflammation and
thrombosis leading to large vessel ischemic strokes becoming another
reason for mortality in Covid-19 patients (Oxley et al., 2020). Vaccines
and new drugs are being developed targeting various mechanisms through
which SARS-CoV-2 may be affecting different biological pathways and
organ failures, with an absolute cure still elusive.

To effectively target SARS-CoV-2, understanding the mechanisms of the
CoV-family may be important. Before the Covid-19, similar zoonotic
outbreaks occurred with the SARS-CoV outbreak in 2002 (Drosten et al.,
2003) and the MERS-CoV outbreak in 2012 . Prior to that human
coronaviruses, HCoV-229E and HCoV-OC43, have existed and caused common
cold (Malik, 2020). Interestingly SARS-CoV2 is not a direct descendent
of SARS-CoV however both belong to order \emph{Nidovirales} . This
uniqueness in the SARS-CoV-2 or Covid-19 could explain why it may be so
much more deadly than the viruses from the same genome order. Due to
these similarities and uniqueness, often targeting the virus itself may
become complicated. However, with more reports of pathological mode of
action on cells and organs, various treatments are directed towards the
pathogenesis of Covid-19.

Pathogenesis of Covid-19 mainly includes release of pro-inflammatory
proteins also referred as a ``cytokine storm'', oxidative stress, cell
death, activation of renin-angiotensin pathway and endothelial
dysfunction which ultimately lead to lung injury. Identification of any
drug or inhibitor beneficial in treating these pathogenesis, pulmonary
symptoms or thrombosis would prove to be lifesaving at this time for
Covid-19.

Poly (ADP-ribose) polymerase 1 (PARP1) is a polymerase enzyme with
multifunctional role to play in a cell (Hassa, 2009; Rajawat et al.,
2017a; Rajawat et al., 2017b), primarily maintaining genomic integrity
and cell survival being the distinct feature. PARP1 regulates several
genes either directly as transcription factors or as coactivator or
inhibitor. Additionally, PARP1 has been reported to be involved in
cytokine regulation, inflammation, pulmonary diseases and strokes.
Therefore, PARP1 inhibition has emerged as a powerful tool to control
inflammation in several organ injuries and diseases. PARP inhibitors are
such compounds which are significantly beneficial in preventing or
inhibiting inflammation, pulmonary disease symptoms, cardiovascular
disease and stroke. Several PARP inhibitors are in clinical trial for
cancer, neurodegenerative diseases and stroke. Some have been approved
by FDA already; therefore, use of PARP inhibitors would be safe too.
PARP1 has been shown to play a key role in the pathogenesis of several
viral diseases (Grady et al., 2012; Hassumi-Fukasawa et al., 2012;
Lupey-Green et al., 2018; Na et al., 2016; Xia et al., 2020). Moreover,
PARP1 and other members of PARP family are known to exhibit either
antiviral or pro-viral activities against various viruses.

In this review we have discussed the role PARP plays in regulating viral
infection or virulence, pulmonary diseases, inflammatory diseases,
cardiovascular diseases and in regulating cytokine storm. We also
explore the role of PARP1 which may result in symptoms that has been
observed in Covid-19 patients and hence the potential of PARP inhibitors
to be used for reducing the SARS-CoV-2 mediated pathogenesis.

\textbf{PARP1 and Viral infection}

Several members of PARP family are reported to play varied roles in
viral infections. PARP activity or PARylation can function as both
enhancer and repressor of virus replication (Ko et al., 2013;
Lupey-Green et al., 2017). PARP7, 10 and 12 reportedly inhibits
replication of Venezuelan equine encephalitis virus (VEEV) (Atasheva et
al., 2012; Atasheva et al., 2014). PARP1 is observed to be a facilitator
of influenza A virus (IAV) infection through regulation of RNA dependent
RNA polymerase (Rdrp polymerase) of influenza A virus. However,
endogenous PARylation inhibited Rdrp assembly (Westera et al., 2019).
Host protein PARP1 is reported to facilitate propagation of influenza A
virus through degradation of interferon receptor type I (IFNAR) (Xia et
al., 2020). This novel role of PARP1 could be utilized to design
antivirals for influenza treatment and such study can also be expanded
to other viruses which utilizes same receptor for entry in host.
Furthermore, PARP1 is required for HIV-1 infection and integration in
cells(Ha et al., 2001) and PARP1 activity is also required for
transcriptional activation of HIV-1(Yu et al., 2018) . In addition to
aforementioned studies, PARP1 inhibition has been found to be effective
in management of HIV infection and replication \emph{in vitro} (Rom et
al., 2015). Although some contradictory reports are also there in
context to HIV-1 infection but still PARP1 inhibition can be an
effective strategy for viral disease management. Recent study has
proposed the role of PARP1 in regulating the NK cell migration to the
site of viral infection through production of CCL2 and further CCL2-CCR
axis regulates the migration of NK cells (Shou et al., 2019). Another
instance where interaction with PARP1 was found important for viral
biology was Porcine reproductive and respiratory syndrome virus (PRRSV)
(Liu et al., 2015), indicating that targeting PARP1 could be a viable
option to inhibit virus proliferation.

Interestingly, few studies have recently been carried out to identify
PARPs relationship with coronavirus infection and replication in
mammalian cells. ADP-ribosylation of coronavirus nucleocapsid protein (N
protein) was identified as a novel post translational modification
(Grunewald et al., 2018). Several family of virus including
Coronaviridae possess a macrodomain with poly(ADP-ribose) glycohydrolase
activity. There are reports of a coronavirus macrodomain binding to
ADP-ribose and further removal of mono ADP-ribose from proteins thus
facilitates virus to replicate. These macrodomains are reported to
counteract the antiviral ADP-ribosylation of PARP during infection.
Although it has not been clear whether PARP1 is involved in inhibition
of coronavirus replication but role of PARP-12 and -14 has been
identified in enhancement of interferon production and coronavirus
inhibition (Grunewald et al., 2019). Thus, PARP either promotes or
inhibits the replication of viruses and their pathogenesis (Fehr et al.,
2020). Further analysis of macrodomain of SARS-CoV-2 could highlight the
use of PARP inhibitors for treatment of Covid-19.Interestingly, few
studies have recently been carried out to identify PARPs relationship
with coronavirus infection and replication in mammalian cells.
ADP-ribosylation of coronavirus nucleocapsid protein (N protein) was
identified as a novel post translational modification (Grunewald et al.,
2018). Several family of virus including Coronaviridae possess a
macrodomain with poly(ADP-ribose) glycohydrolase activity. There are
reports of a coronavirus macrodomain binding to ADP-ribose and further
removal of mono ADP-ribose from proteins thus facilitates virus to
replicate. These macrodomains are reported to counteract the antiviral
ADP-ribosylation of PARP during infection. Although it has not been
clear whether PARP1 is involved in inhibition of coronavirus replication
but role of PARP-12 and -14 has been identified in enhancement of
interferon production and coronavirus inhibition (Grunewald et al.,
2019). Thus, PARP either promotes or inhibits the replication of viruses
and their pathogenesis (Fehr et al., 2020). Further analysis of
macrodomain of SARS-CoV-2 could highlight the use of PARP inhibitors for
treatment of Covid-19.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1. PARP role in viral infection.} (A) ADP-ribosylation of
macrodomain protein of Coronavirus. (B) PARP1 mediated inflammatory
response to viral infection.

\par\null\par\null

\textbf{PARP1 and inflammatory disease}

PARP1 activation is observed in both infectious and non-infectious
diseases, simultaneous to inflammatory responses. Hyper-activation of
PARP1 in response to DNA damage causes NAD and ATP depletion and
consequently necrosis (Rajawat et al., 2007) , leading to inflammatory
state in many diseases. PARP1 also plays an important role in regulating
pro-inflammatory gene expression and subsequently cell death in the
damaged tissues (Beneke \& Burkle, 2007; Jagtap \& Szabo, 2005). Several
evidences reflect the role of PARP1 in activation of transcription
factors like NF\selectlanguage{russian}кB, AP-1, heat shock proteins, adhesion molecules in
promoting inflammation. PARP1 is known to be a coactivator of AP-1 and
NFкB and hence regulates their expression during chronic inflammation.
PARP1- NFкB interaction then induces downstream signalling by inducing
the expression of pro-inflammatory cytokines including IL-1, TNF-\selectlanguage{greek}α, \selectlanguage{english}IFN\selectlanguage{greek}γ
\selectlanguage{english}and iNOS activation (Ba \& Garg, 2011). Implication of PARP1 was also
observed in renin-angiotensin system (RAS) that responds to inflammation
(Reinemund et al., 2009). RAS signalling promotes viral entry and
simultaneously inhibits or regulates severe lung injury and inflammation
(Fung \& Liu, 2019). PARP1 deletion or inhibition was beneficial in
lipopolysaccharides (LPS) induced pulmonary inflammation (Liaudet et
al., 2002; Zerfaoui et al., 2009). Similarly, PARP1 inhibition delayed
the gut inflammation during enterocolitis caused by Salmonella
typhimurium (Altmeyer et al., 2010). Additionally, massive DNA damage
induced PARP activation aggravates inflammatory response in ventilator
induced lung injury (Kim et al., 2008; Vaschetto et al., 2008). Thus,
PARP inhibition is anti-inflammatory and can control hyper-inflammation
induced during several pathologies. Moreover, PARP1 also controls the
immune function by destabilizing the Foxp3 in regulatory T cells (Treg)
(Hori et al., 2017). PARP1 is known to destabilize Foxp3 by
ADP-ribosylation, while, PARP inhibition stabilizes Foxp3 and
subsequently downstream gene expression involved in Treg immune
suppressive function (Luo et al., 2015).

Cytokine storm, which is represented by a dysregulated
cytokine/chemokine response, has been shown to be one of the key
biological manifestation during the SARS-CoV pandemic (Channappanavar \&
Perlman, 2017). While the cell types infected by the SARS-CoV-2 are
still under investigation, the cytokine storm they may entail may be
more varied and detrimental for the healthy cells, apart from the viral
infection itself. Cytokine storm leads to hyper-inflammation that could
be a major cause for mortality (Mehta et al., 2020). Hyper-inflammation
can be curbed by inhibiting PARP with nicotinamide, as this might lead
to inhibition of iNOS and downstream pro-inflammatory gene response.
Furthermore, NAD and niacin supplementation could also prove to be
beneficial in suppressing inflammation and oxidative stress induced cell
death (Gharote, 2020). There are reports of the association of
senescence with chronic obstructive pulmonary disorder (COPD). These
senescent cells are also known to secrete pro-inflammatory cytokines
such as IL-6, IL-8 and plasminogen activator inhibitor-I (PAI) (Kumar et
al., 2014). Thus, senescence and senescence associated secretory
phenotype (SASP) during viral infection cannot be neglected.

Table 1: PARP inhibitors in inflammatory diseases:\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
SNo. & Disease/ pathology & PARP inhibitors & Model & Ref\tabularnewline
\midrule
\endhead
1. & Ischemia/ reperfusion & PJ-34 & Mouse & (Black et al.,
2006)\tabularnewline
2. & Ischemic stroke & PJ-34 & Rat & (Kauppinen et al.,
2009)\tabularnewline
3. & Cerebral ischemia & NU1025 & Rat & (Kaundal et al.,
2006)\tabularnewline
4. & Heat stroke & PJ-34 & Mouse & (Mota et al., 2008)\tabularnewline
5. & Induced atherosclerosis & TIQ-A & Mouse & (Hans et al.,
2009)\tabularnewline
6. & Endothelial dysfunction & INO-1001 & Mouse & (Benko et al.,
2004)\tabularnewline
7. & Airway inflammation & TIQ-A & Mouse & (Naura et al.,
2008)\tabularnewline
\bottomrule
\end{longtable}

\textbf{PARP1 and pulmonary disease}

Fibrotic disease of the lungs idiopathic pulmonary interstitial fibrosis
(IPF) is a result of enhanced fibroblasts proliferation and accumulation
of collagen and extracellular matrix. This leads to alveolar injury,
stiffening of airways, blood membrane thickening, chronic inflammation,
damaged lungs and ultimately respiratory failure (Coultas et al., 1994;
King et al., 2011). PARP1 enzyme is known to play critical role in many
fibrotic disorders including heart (Gero et al., 2014), vessels
(Abdallah et al., 2007), lungs (Genovese et al., 2005) and liver
(Mukhopadhyay et al., 2014). Key observation of increased PARylation was
reported in lung fibroblasts of IPF patients (Hu et al., 2013). PARP
inhibitors are now reported to inhibit fibrosis and reduce collagen
accumulation in liver. PARP1 inhibitor, HYDAMTIQ reduces the progression
of bleomycin induced lung fibrosis by inhibiting the TGF\selectlanguage{greek}β/\selectlanguage{english}SMAD
signalling pathway (Lucarini et al., 2017).

The characteristic feature of chronic obstructive pulmonary disorder
(COPD) is airway inflammation, which could be due to reactive oxygen
species (ROS) i.e. oxidative injury (MacNee, 2001). ROS induces PARP1
activation, although PARP role is to maintain genomic integrity, but
excessive DNA damage could lead to PARP1 over-activation and finally
cell death. One such study observed PARP1 activation in COPD via ROS and
pharmacological inhibition of PARP1 or knockout has prevented epithelial
cell injury and inflammation of airway (Boulares et al., 2003). It is
interesting to note that oxidative stress, PARP1 and NF\selectlanguage{russian}кB axis is
connected to the inflammation observed in COPD, asthma and acute lung
injury. Another study examined the requirement of PARP1 for induction of
iNOS under oxidative stress during allergen induced eosinophilia (Naura
et al., 2008). Allergen exposure may activate PARP1 that subsequently
induces iNOS expression through NFкB. Moreover, PARP1 also regulates
IL-5 production which in addition with other cytokines promotes
eosinophil recruitment and promotes inflammation in lungs. iNOS
reciprocally regulates PARP1 activity and thereby try to inhibit
inflammatory response (Naura et al., 2008). Inhibition of PARP1
prevented the airway infiltration of eosinophils through IL-5
suppression (Oumouna et al., 2006). PARP1 is also known to modulate the
Th2 cytokine (Oumouna et al., 2006) and ICAM-1 (Zerfaoui et al., 2009)
expression in airways and hence regulates the eosinophil recruitment in
lung airways. It has also been identified that PARP1 activation is a
prerequisite for STAT6 expression which regulates the expression of IL-5
and GATA3 (Datta et al., 2011).

Preclinical analysis of PARP inhibition in dust mite exposed mice
resulted in blocking asthma like traits. Furthermore, clinical analysis
of the lung specimens and PBMCs derived from asthmatic patients
presented activation of PARP1 in such patients (Ghonim et al., 2015).
Moreover, PARP1 also contributes in epithelial-mesenchymal transition in
airway remodelling in chronic asthma by formation of ternary complex
through TGF\selectlanguage{greek}β \selectlanguage{english}and NFkB (Stanisavljevic et al., 2011). Thus, PARP1 has
multifaceted role in lung diseases and hence could be a probable target
for targeting symptomatic treatment in Covid-19 patients.

\textbf{PARP1 and cardiovascular disorders (stroke)}

Accumulating evidences have reported PARP activation in oxidative stress
related pathologies including cardiovascular disorders and stroke. Role
of PARP1 in regulating the pathological stress in cardiovascular disease
can be predicted by its interaction with Kruppel like factor 5 (KLF5)
transcription factor (Suzuki et al., 2007). HYDAMTIQ, a PARP1 inhibitor
has been illustrated to confer neuroprotection post stroke (Moroni et
al., 2012). The reason for morbidity in multiple sclerosis, trauma and
stroke is dysfunction of blood brain barrier and subsequently leukocyte
infiltration and neuro-inflammation. Recent evidences have suggested
PARP inhibition diminishes inflammation in leukocytes via attenuation of
adhesion and migration (Rom et al., 2016).

The only approved treatment for thrombolysis in ischemic stroke is
recombinant tissue plasminogen activator (rtPA), but at certain dose and
in some conditions, it can aggravate the risk of haemorrhage. rtPA is
reported to increase PARP1 activity and inhibition of PARP1 prevents the
vascular toxicity of rtPA on brain (Teng et al., 2013). Thus,
co-treatment of PARP inhibitor with rtPA seems to be a promising
approach for handling thrombolysis effects. PARP1 inhibition has been
shown to suppress inflammation-related plaque formation, another reason
for ischemia (von Lukowicz et al., 2008).

\textbf{Potential implication of PARP inhibitors in Covid-19}

Several evidences have supported the involvement of PARP1 in oxidative
stress mediated response, inflammation and various diseases. PARP-1
mediated inflammatory response caused by bacteria and other pathogenic
agents like parasite and fungi has been elucidated. PARP1 is also known
to regulate cytokine production and the string analysis also depict
direct PARP1 interaction with some cytokines and indirect with few other
cytokines known to be involved in Covid-19 (Fig 1). Although there are
reports of PARP1 regulation of virus-host interaction and virus
infection, but detailed mechanistic studies are required as PARP1
involvement in virus mediated inflammation is not elucidated fully.
PARP1 mediated inflammation during fibrosis, ischaemia and stroke and
its relationship with viruses, inspired us to think about probability of
role of PARP1 in SARS-CoV-2 mediated inflammation. Further work is
required to identify the link between SARS-CoV-2 virus infection and
PARP1 mediated inflammation.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2.} String analysis of PARP1 interaction with cytokines.

Multiple FDA approved PARP inhibitors are in clinical trials for cancer
and other pathologies. Protective effects of PARP inhibitors have been
demonstrated in \emph{in vivo} models of non-oncological diseases.
Recently \emph{in silico} and \emph{in vitro} analysis indicated that
PARP inhibitor, a cancer drug Mefuparib (CVL218) exhibits antiviral
activity against SAR-CoV-2. CVL218 was also shown to suppress the IL-6
production in PBMCs proposing its beneficial effect in SARS-CoV-2
induced immunopathology. The antiviral activity of CVL218 was more
potent as compared to Remdesivir (Ge et al., 2020). Curtin and
colleagues have also suggested the importance of repositioning of PARP
inhibitors as a multi-pronged therapy for Covid-19 (Curtin et al.,
2020). Based on these reports another PARP inhibitor, 2X-121 (former
name E7449) has entered in preclinical study to assess its efficacy in
Covid-19. 2X-121 is currently under Phase 2 for treatment of advanced
ovarian cancer and metastatic breast cancer
(\url{https://clinicaltrials.gov/ct2/show/NCT03562832}). These
approaches have opened a new paradigm of inhibitors to be used against
SARS-CoV-2 infection either directly or after repurposing. To explore a
potential therapeutic for Covid-19, PARP inhibitors appear to be a
promising approach.

\par\null

\textbf{Graphical Abstract}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.42\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Acknowledgement}

JR acknowledges Department of Science \& Technology (DST) for awarding
DST-WOS-A fellowship (No. SR/WOS-A/LS-161/2018 (G)), and JR thanks Prof.
Monisha~ \textbf{~}Banerjee (Molecular and Human Genetics Lab),
Department of Zoology and University of Lucknow for infrastructural
support.~ \textbf{~}~AC thanks Mayo Clinic CTSA grant number UL1TR002377
from the National Center for Advancing Translational Sciences (NCATS), a
component of the National Institutes of Health (NIH).

\textbf{Conflict of Interest}

Authors declare No conflict of interest.

\textbf{References}

Abdallah Y, Gligorievski D, Kasseckert SA, Dieterich L, Schafer M,
Kuhlmann CR\emph{, et al.} (2007). The role of poly(ADP-ribose)
polymerase (PARP) in the autonomous proliferative response of
endothelial cells to hypoxia. Cardiovasc Res 73\textbf{:} 568-574.

Altmeyer M, Barthel M, Eberhard M, Rehrauer H, Hardt WD, \& Hottiger MO
(2010). Absence of poly(ADP-ribose) polymerase 1 delays the onset of
Salmonella enterica serovar Typhimurium-induced gut inflammation. Infect
Immun 78\textbf{:} 3420-3431.

Atasheva S, Akhrymuk M, Frolova EI, \& Frolov I (2012). New PARP gene
with an anti-alphavirus function. J Virol 86\textbf{:} 8147-8160.

Atasheva S, Frolova EI, \& Frolov I (2014). Interferon-stimulated
poly(ADP-Ribose) polymerases are potent inhibitors of cellular
translation and virus replication. J Virol 88\textbf{:} 2116-2130.

Ba X, \& Garg NJ (2011). Signaling mechanism of poly(ADP-ribose)
polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol
178\textbf{:} 946-955.

Beneke S, \& Burkle A (2007). Poly(ADP-ribosyl)ation in mammalian
ageing. Nucleic Acids Res 35\textbf{:} 7456-7465.

Benko R, Pacher P, Vaslin A, Kollai M, \& Szabo C (2004). Restoration of
the endothelial function in the aortic rings of apolipoprotein E
deficient mice by pharmacological inhibition of the nuclear enzyme
poly(ADP-ribose) polymerase. Life Sci 75\textbf{:} 1255-1261.

Black JH, Casey PJ, Albadawi H, Cambria RP, \& Watkins MT (2006). Poly
adenosine diphosphate-ribose polymerase inhibitor PJ34 abolishes
systemic proinflammatory responses to thoracic aortic ischemia and
reperfusion. J Am Coll Surg 203\textbf{:} 44-53.

Boulares AH, Zoltoski AJ, Sherif ZA, Jolly P, Massaro D, \& Smulson ME
(2003). Gene knockout or pharmacological inhibition of poly(ADP-ribose)
polymerase-1 prevents lung inflammation in a murine model of asthma. Am
J Respir Cell Mol Biol 28\textbf{:} 322-329.

Channappanavar R, \& Perlman S (2017). Pathogenic human coronavirus
infections: causes and consequences of cytokine storm and
immunopathology. Semin Immunopathol 39\textbf{:} 529-539.

Chen T, Wu D, Chen H, Yan W, Yang D, Chen G\emph{, et al.} (2020).
Clinical characteristics of 113 deceased patients with coronavirus
disease 2019: retrospective study. BMJ 368\textbf{:} m1091.

Cheng P, Zhu H, Witteles RM, Wu JC, Quertermous T, Wu SM\emph{, et
al.}(2020). Cardiovascular Risks in Patients with COVID-19: Potential
Mechanisms and Areas of Uncertainty. Curr Cardiol Rep 22\textbf{:} 34.

Coultas DB, Zumwalt RE, Black WC, \& Sobonya RE (1994). The epidemiology
of interstitial lung diseases. Am J Respir Crit Care Med
150\textbf{:}967-972.

Curtin N, Banyai K, Thaventhiran J, Le Quesne J, Helyes Z, \& Bai P
(2020). Repositioning PARP inhibitors for SARS-CoV-2
infection(COVID-19); a new multi-pronged therapy for acute respiratory
distress syndrome? Br J Pharmacol.

Datta R, Naura AS, Zerfaoui M, Errami Y, Oumouna M, Kim H\emph{, et
al.}(2011). PARP-1 deficiency blocks IL-5 expression through
calpain-dependent degradation of STAT-6 in a murine asthma model.
Allergy 66\textbf{:} 853-861.

Drosten C, Preiser W, Gunther S, Schmitz H, \& Doerr HW (2003). Severe
acute respiratory syndrome: identification of the etiological agent.
Trends Mol Med 9\textbf{:} 325-327.

Fehr AR, Singh SA, Kerr CM, Mukai S, Higashi H, \& Aikawa M (2020). The
impact of PARPs and ADP-ribosylation on inflammation and host-pathogen
interactions. Genes Dev 34\textbf{:} 341-359.

Fung TS, \& Liu DX (2019). Human Coronavirus: Host-Pathogen Interaction.
Annu Rev Microbiol 73\textbf{:} 529-557.

Ge Y, Tian T, Huang S, Wan F, Li J, Li S\emph{, et al.} (2020). A
data-driven drug repositioning framework discovered a potential
therapeutic agent targeting COVID-19.

Genovese T, Mazzon E, Di Paola R, Muia C, Threadgill MD, Caputi
AP\emph{, et al.} (2005). Inhibitors of poly(ADP-ribose) polymerase
modulate signal transduction pathways and the development of
bleomycin-induced lung injury. J Pharmacol Exp Ther
313\textbf{:}529-538.

Gero D, Szoleczky P, Chatzianastasiou A, Papapetropoulos A, \& Szabo C
(2014). Modulation of poly(ADP-ribose) polymerase-1 (PARP-1)-mediated
oxidative cell injury by ring finger protein 146 (RNF146) in cardiac
myocytes. Mol Med 20\textbf{:} 313-328.

Gharote M (2020). Role of PARP-1 inhibition by nicotinamide to modulate
host immune response and prevention of cytokine storm in COVID-19.
Indian Journal of Medical Sciences 72\textbf{:} 21-24.

Ghonim MA, Pyakurel K, Ibba SV, Wang J, Rodriguez P, Al-Khami AA\emph{,
et al.} (2015). PARP is activated in human asthma and its inhibition by
olaparib blocks house dust mite-induced disease in mice. Clin Sci (Lond)
129\textbf{:} 951-962.

Grady SL, Hwang J, Vastag L, Rabinowitz JD, \& Shenk T (2012). Herpes
simplex virus 1 infection activates poly(ADP-ribose) polymerase and
triggers the degradation of poly(ADP-ribose) glycohydrolase. J Virol
86\textbf{:} 8259-8268.

Grunewald ME, Chen Y, Kuny C, Maejima T, Lease R, Ferraris D\emph{, et
al.} (2019). The coronavirus macrodomain is required to prevent
PARP-mediated inhibition of virus replication and enhancement of IFN
expression. PLoS Pathog 15\textbf{:} e1007756.

Grunewald ME, Fehr AR, Athmer J, \& Perlman S (2018). The coronavirus
nucleocapsid protein is ADP-ribosylated. Virology 517\textbf{:} 62-68.

Ha HC, Juluri K, Zhou Y, Leung S, Hermankova M, \& Snyder SH (2001).
Poly(ADP-ribose) polymerase-1 is required for efficient HIV-1
integration. Proc Natl Acad Sci U S A 98\textbf{:} 3364-3368.

Hans CP, Zerfaoui M, Naura AS, Troxclair D, Strong JP, Matrougui
K\emph{, et al.} (2009). Thieno{[}2,3-c{]}isoquinolin-5-one, a potent
poly(ADP-ribose) polymerase inhibitor, promotes atherosclerotic plaque
regression in high-fat diet-fed apolipoprotein E-deficient mice: effects
on inflammatory markers and lipid content. J Pharmacol Exp Ther
329\textbf{:} 150-158.

Hassa PO (2009). The molecular ''Jekyll and Hyde'' duality of PARP1 in
cell death and cell survival. Front Biosci (Landmark Ed)
14\textbf{:}72-111.

Hassumi-Fukasawa MK, Miranda-Camargo FA, Zanetti BR, Galano DF,
Ribeiro-Silva A, \& Soares EG (2012). Expression of BAG-1 and PARP-1 in
precursor lesions and invasive cervical cancer associated with human
papillomavirus (HPV). Pathol Oncol Res 18\textbf{:} 929-937.

Hori S, Nomura T, \& Sakaguchi S (2017). Pillars Article: Control of
Regulatory T Cell Development by the Transcription Factor Foxp3. Science
2003. 299: 1057-1061. J Immunol 198\textbf{:} 981-985.

Hu B, Wu Z, Hergert P, Henke CA, Bitterman PB, \& Phan SH (2013).
Regulation of myofibroblast differentiation by poly(ADP-ribose)
polymerase 1. Am J Pathol 182\textbf{:} 71-83.

Jagtap P, \& Szabo C (2005). Poly(ADP-ribose) polymerase and the
therapeutic effects of its inhibitors. Nat Rev Drug Discov
4\textbf{:}421-440.

Kaundal RK, Shah KK, \& Sharma SS (2006). Neuroprotective effects of
NU1025, a PARP inhibitor in cerebral ischemia are mediated through
reduction in NAD depletion and DNA fragmentation. Life Sci
79\textbf{:}2293-2302.

Kauppinen TM, Suh SW, Berman AE, Hamby AM, \& Swanson RA (2009).
Inhibition of poly(ADP-ribose) polymerase suppresses inflammation and
promotes recovery after ischemic injury. J Cereb Blood Flow Metab
29\textbf{:} 820-829.

Kim JH, Suk MH, Yoon DW, Kim HY, Jung KH, Kang EH\emph{, et al.} (2008).
Inflammatory and transcriptional roles of poly (ADP-ribose) polymerase
in ventilator-induced lung injury. Crit Care 12\textbf{:} R108.

King TE, Jr., Pardo A, \& Selman M (2011). Idiopathic pulmonary
fibrosis. Lancet 378\textbf{:} 1949-1961.

Ko HL, Ng HJ, Goh EH, \& Ren EC (2013). Reduced ADP-ribosylation by
PARP1 natural polymorphism V762A and by PARP1 inhibitors enhance
Hepatitis B virus replication. J Viral Hepat 20\textbf{:} 658-665.

Kumar M, Seeger W, \& Voswinckel R (2014). Senescence-associated
secretory phenotype and its possible role in chronic obstructive
pulmonary disease. Am J Respir Cell Mol Biol 51\textbf{:} 323-333.

Liaudet L, Pacher P, Mabley JG, Virag L, Soriano FG, Hasko G\emph{, et
al.} (2002). Activation of poly(ADP-Ribose) polymerase-1 is a central
mechanism of lipopolysaccharide-induced acute lung inflammation. Am J
Respir Crit Care Med 165\textbf{:} 372-377.

Liu L, Lear Z, Hughes DJ, Wu W, Zhou EM, Whitehouse A\emph{, et
al.}(2015). Resolution of the cellular proteome of the nucleocapsid
protein from a highly pathogenic isolate of porcine reproductive and
respiratory syndrome virus identifies PARP-1 as a cellular target whose
interaction is critical for virus biology. Vet Microbiol 176\textbf{:}
109-119.

Lucarini L, Durante M, Lanzi C, Pini A, Boccalini G, Calosi L\emph{, et
al.} (2017). HYDAMTIQ, a selective PARP-1 inhibitor, improves
bleomycin-induced lung fibrosis by dampening the TGF-beta/SMAD
signalling pathway. J Cell Mol Med 21\textbf{:} 324-335.

Luo X, Nie J, Wang S, Chen Z, Chen W, Li D\emph{, et al.} (2015).
Poly(ADP-ribosyl)ation of FOXP3 Protein Mediated by PARP-1 Protein
Regulates the Function of Regulatory T Cells. J Biol Chem
290\textbf{:}28675-28682.

Lupey-Green LN, Caruso LB, Madzo J, Martin KA, Tan Y, Hulse M\emph{, et
al.} (2018). PARP1 Stabilizes CTCF Binding and Chromatin Structure To
Maintain Epstein-Barr Virus Latency Type. J Virol 92.

Lupey-Green LN, Moquin SA, Martin KA, McDevitt SM, Hulse M, Caruso
LB\emph{, et al.} (2017). PARP1 restricts Epstein Barr Virus lytic
reactivation by binding the BZLF1 promoter. Virology
507\textbf{:}220-230.

MacNee W (2001). Oxidative stress and lung inflammation in airways
disease. Eur J Pharmacol 429\textbf{:} 195-207.

Malik YA (2020). Properties of Coronavirus and SARS-CoV-2. Malays J
Pathol 42\textbf{:} 3-11.

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ\emph{,
et al.} (2020). COVID-19: consider cytokine storm syndromes and
immunosuppression. Lancet 395\textbf{:} 1033-1034.

Moroni F, Cozzi A, Chiarugi A, Formentini L, Camaioni E,
Pellegrini-Giampietro DE\emph{, et al.} (2012). Long-lasting
neuroprotection and neurological improvement in stroke models with new,
potent and brain permeable inhibitors of poly(ADP-ribose) polymerase. Br
J Pharmacol 165\textbf{:} 1487-1500.

Mota RA, Hernandez-Espinosa D, Galbis-Martinez L, Ordonez A, Minano A,
Parrilla P\emph{, et al.} (2008). Poly(ADP-ribose) polymerase-1
inhibition increases expression of heat shock proteins and attenuates
heat stroke-induced liver injury. Crit Care Med 36\textbf{:} 526-534.

Mukhopadhyay P, Rajesh M, Cao Z, Horvath B, Park O, Wang H\emph{, et
al.} (2014). Poly (ADP-ribose) polymerase-1 is a key mediator of liver
inflammation and fibrosis. Hepatology 59\textbf{:} 1998-2009.

Na TY, Ka NL, Rhee H, Kyeong D, Kim MH, Seong JK\emph{, et al.} (2016).
Interaction of hepatitis B virus X protein with PARP1 results in
inhibition of DNA repair in hepatocellular carcinoma. Oncogene
35\textbf{:} 5435-5445.

Naura AS, Hans CP, Zerfaoui M, You D, Cormier SA, Oumouna M\emph{, et
al.} (2008). Post-allergen challenge inhibition of poly(ADP-ribose)
polymerase harbors therapeutic potential for treatment of allergic
airway inflammation. Clin Exp Allergy 38\textbf{:} 839-846.

Oumouna M, Datta R, Oumouna-Benachour K, Suzuki Y, Hans C, Matthews
K\emph{, et al.} (2006). Poly(ADP-ribose) polymerase-1 inhibition
prevents eosinophil recruitment by modulating Th2 cytokines in a murine
model of allergic airway inflammation: a potential specific effect on
IL-5. J Immunol 177\textbf{:} 6489-6496.

Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP\emph{, et
al.} (2020). Large-Vessel Stroke as a Presenting Feature of Covid-19 in
the Young. N Engl J Med.

Petrakis D, Margina D, Tsarouhas K, Tekos F, Stan M, Nikitovic D\emph{,
et al.} (2020). Obesity a risk factor for increased COVID19 prevalence,
severity and lethality (Review). Mol Med Rep.

Rajawat J, Shukla N, \& Mishra DP (2017a). Poly(ADP-Ribose) polymerase
1: a therapeutic hope in gynecologic cancers. Front Biosci (Schol Ed)
9\textbf{:} 343-356.

Rajawat J, Shukla N, \& Mishra DP (2017b). Therapeutic Targeting of
Poly(ADP-Ribose) Polymerase-1 (PARP1) in Cancer: Current Developments,
Therapeutic Strategies, and Future Opportunities. Med Res Rev
37\textbf{:} 1461-1491.

Rajawat J, Vohra I, Mir HA, Gohel D, \& Begum R (2007). Effect of
oxidative stress and involvement of poly(ADP-ribose) polymerase (PARP)
in Dictyostelium discoideum development. FEBS J 274\textbf{:} 5611-5618.

Reinemund J, Seidel K, Steckelings UM, Zaade D, Klare S, Rompe F\emph{,
et al.} (2009). Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally
regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein
(ATBP) genes. Biochem Pharmacol 77\textbf{:} 1795-1805.

Rom S, Reichenbach NL, Dykstra H, \& Persidsky Y (2015). The dual action
of poly(ADP-ribose) polymerase -1 (PARP-1) inhibition in HIV-1
infection: HIV-1 LTR inhibition and diminution in Rho GTPase activity.
Front Microbiol 6\textbf{:} 878.

Rom S, Zuluaga-Ramirez V, Reichenbach NL, Dykstra H, Gajghate S, Pacher
P\emph{, et al.} (2016). PARP inhibition in leukocytes diminishes
inflammation via effects on integrins/cytoskeleton and protects the
blood-brain barrier. J Neuroinflammation 13\textbf{:} 254.

Shou Q, Fu H, Huang X, \& Yang Y (2019). PARP-1 controls NK cell
recruitment to the site of viral infection. JCI Insight 4.

Stanisavljevic J, Porta-de-la-Riva M, Batlle R, de Herreros AG, \&
Baulida J (2011). The p65 subunit of NF-kappaB and PARP1 assist Snail1
in activating fibronectin transcription. J Cell Sci
124\textbf{:}4161-4171.

Sun J, He WT, Wang L, Lai A, Ji X, Zhai X\emph{, et al.} (2020).
COVID-19: Epidemiology, Evolution, and Cross-Disciplinary Perspectives.
Trends Mol Med 26\textbf{:} 483-495.

Suzuki T, Nishi T, Nagino T, Sasaki K, Aizawa K, Kada N\emph{, et
al.}(2007). Functional interaction between the transcription factor
Kruppel-like factor 5 and poly(ADP-ribose) polymerase-1 in
cardiovascular apoptosis. J Biol Chem 282\textbf{:} 9895-9901.

Teng F, Beray-Berthat V, Coqueran B, Lesbats C, Kuntz M, Palmier
B\emph{, et al.} (2013). Prevention of rt-PA induced blood-brain barrier
component degradation by the poly(ADP-ribose)polymerase inhibitor PJ34
after ischemic stroke in mice. Exp Neurol 248\textbf{:} 416-428.

Vaschetto R, Kuiper JW, Chiang SR, Haitsma JJ, Juco JW, Uhlig S\emph{,
et al.} (2008). Inhibition of poly(adenosine diphosphate-ribose)
polymerase attenuates ventilator-induced lung injury. Anesthesiology
108\textbf{:} 261-268.

von Lukowicz T, Hassa PO, Lohmann C, Boren J, Braunersreuther V, Mach
F\emph{, et al.} (2008). PARP1 is required for adhesion molecule
expression in atherogenesis. Cardiovasc Res 78\textbf{:} 158-166.

Westera L, Jennings AM, Maamary J, Schwemmle M, Garcia-Sastre A, \&
Bortz E (2019). Poly-ADP Ribosyl Polymerase 1 (PARP1) Regulates
Influenza A Virus Polymerase. Adv Virol 2019\textbf{:} 8512363.

Xia C, Wolf JJ, Sun C, Xu M, Studstill CJ, Chen J\emph{, et al.} (2020).
PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation
of Host Type I Interferon Receptor. J Virol 94.

Yu D, Liu R, Yang G, \& Zhou Q (2018). The PARP1-Siah1 Axis Controls
HIV-1 Transcription and Expression of Siah1 Substrates. Cell Rep
23\textbf{:} 3741-3749.

Zerfaoui M, Naura AS, Errami Y, Hans CP, Rezk BM, Park J\emph{, et
al.}(2009). Effects of PARP-1 deficiency on airway inflammatory cell
recruitment in response to LPS or TNF: differential effects on CXCR2
ligands and Duffy Antigen Receptor for Chemokines. J Leukoc Biol
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