Introduction
On January 30th, 2020, the World Health Organization declared an
International Health Emergency in connection with a coronavirus disease
2019 (COVID-19), caused by a mutated RNA coronavirus named Severe Acute
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (Sohrabi et al., 2020).
As of June 2023, more than 767 million cases have been identified with
over 6.9 million deaths. Despite active vaccination, the virus continues
to mutate and cause new infections, the most severe of which result in
Acute Respiratory Distress Syndrome (ARDS). The acute stage of ARDS is
characterized by increased vascular permeability, vascular leak, diffuse
alveolar infiltrates, and loss of aerated alveolar surfaces, leading to
reduced lung compliance and hypoxemia (Hussain et al., 2021). Although a
few potential therapeutics are under investigation (Horie et al., 2020),
the only FDA-approved interventions are methylprednisolone (Ranjbar et
al., 2021), the antiviral drug remdesivir (Veklury) and the immune
modulator baricitinib (Olumiant). Thus, there continues to be a
significant need to identify new therapeutic targets for COVID-19
related ARDS.
We recently established an animal model of COVID-19-related ARDS by
exposing K18–human ACE2 (K18-hACE2) transgenic mice to the surface
elements, i.e., the Spike Protein (SP), of SARS-CoV-2 (Colunga
Biancatelli et al., 2021). The SP is responsible for the binding to the
Angiotensin Converting Enzyme 2 (ACE2) receptor and the internalization
of the viral material into the cell (Ni et al., 2020). During this
process, the SP undergoes two cleavage processes, mediated by furin and
furin-like proteases, that results in the release of the subunit 1 of
the Spike Protein (S1SP), while the subunit 2 mediates membrane fusion
(Peacock et al., 2021). Up to 45% of the S1SP monomers can be found in
the extracellular medium, vascular compartment or alveolar structures
after viral internalization, where they can exert pathologically
relevant functions (Ke et al., 2020). COVID-19 vaccines also increase
the S protein content in blood named “Spike effect” of vaccination
(Angeli et al., 2022; Cognetti & Miller, 2021; Solopov, 2023). Besides
the ACE2 receptor, other cell proteins can interact with the S protein,
including, CORO1C, STON2, the neuropilin-1 (NRP1) receptor and the
transmembrane glycoprotein, CD147 (Zhou et al., 2023).
We hypothesized that S1SP exerts a direct role in lung injury and
intratracheally instilled it in K18-hACE2 transgenic mice. Three days
after exposure, mice displayed histological evidence of lung injury and
strong alveolar inflammation reminiscent of cytokine storm including the
activation of two main inflammatory pathways, Signal Transducer and
Activator of Transcription 3 (STAT3) and Nuclear Factor
Kappa-light-chain-enhancer of activated B cells (NF-kB) (Colunga
Biancatelli et al., 2021).
In this study, we tested whether a novel Protein Tyrosine Phosphatase
4A3 (PTP4A3) inhibitor, KVX-053, also known as JMS-053 (Salamoun et al.,
2016), could prevent SARS-CoV-2 S1SP-induced ARDS. PTP4A3 (also known as
PRL3) is a prenylated dual-specificity phosphatase that regulates
vascular barrier function (McQueeney et al., 2017) and mediates the
release of cytokines TNF-α, IL-1α, IL-1β, MCP-1, MCP-2 and VEGF in
LPS-challenged mice (Tang et al., 2010). Furthermore, VEGF-mediated
vascular permeability, in vivo, was significantly attenuated in
PTP4A3-deficient mice (Zimmerman et al., 2014). The PTP4A3 inhibitor
KVX-053 displays a potent, selective, allosteric inhibitory activity in
vitro [13,14], as well as anti-tumor activity in in vivo models of
ovarian cancer (Lazo et al., 2021). Importantly, PTP4A3 is involved in
STAT3 activation and NF-κB nuclear translocation, suggesting that its
inhibition could be beneficial in inflammatory diseases (Angeli et al.,
2022). We previously have demonstrated that KVX-053 reduced VEGF- and
LPS-induced endothelial dysfunction and vascular permeability (McQueeney
et al., 2017).
Here, we show how KVX-053 exerts a strong therapeutic effect against
SARS-CoV-2 S1SP-induced lung injury, local and systemic inflammation,
vascular permeability, and lung dysfunction. These results support
further studies on the potential use of KVX-053 for therapeutic
intervention against SARS-CoV-2 and future coronavirus diseases.