How the Interaction of SARS-Cov-2 with the Interleukin-17A Receptor May Contribute to Neuropathology
Nils Lannes, Alexey Larionov, Smart I Mbagwu and Luis Filgueira*
Anatomy, Department of Oncology, Microbiology and Immunology, University of Fribourg, Switzerland
Submission: December 15, 2020; Published: January 20, 2021
*Corresponding author: Luis Filgueira, Chair of Anatomy, University of Fribourg, Route Albert Gockel 1, CH-1700 Fribourg, Switzerland
How to cite this article: Nils L, Alexey L, Smart I M, Luis F. How the Interaction of SARS-Cov-2 with the Interleukin-17A Receptor May Contribute to Neuropathology. Open Access J Neurol Neurosurg 2021; 14(5): 555896 DOI: 10.19080/OAJNN.2021.14.555896.
The inflammatory response in the context of SARS-CoV-2 infection has been implicated in corresponding neurological and neuropsychiatric manifestations. Severe coronavirus disease coincides with substantial serum concentrations of interleukin-17. Previous clinical studies and reports have indicated that inteleukin-17 may contribute to various neurological and neuropsychiatric conditions, as well as to severe disease in the course of SARS-CoV-2 infection. Interestingly, the viral ORF-8 protein, that is unique to SARS-CoV-2 and contributes to severity of COVID-19, interacts with the interleukin-17A receptor. This review will elucidate the possible role of interleukin-17 in brain conditions and how, together with SARS-CoV-2, it may interfere and enhance coronavirus disease of the brain.
Clinical manifestation of the brain has been well documented in the context of severe COVID-19 (coronavirus disease of 2019) that is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection (for review [1-3]). All brain regions can be affected by COVID-19 [4-12], resulting in complex acute symptoms and syndromes [13-19], as well as chronic complications and residual damage [20-23]. Besides various neurological and neuropsychiatric manifestations related to neuronal and glial infection with SARS-CoV-2, COVID-19 related cerebrovascular thrombosis [24,25] and stroke [26,27] have also been reported as COVID-19 is associated with endothelial cell infection, endotheliopathy and coagulopathy [13,28]. To date, various neuropathological mechanisms have been considered . There is published evidence that brain cells , including neurons [31-33]), astrocytes [34, 35], microglia , cells of the choroid plexus  and endothelial cells [37-40] can be infected by SARS-CoV-2 . Susceptible cells need to express the ACE2 (angiotensin‑converting enzyme 2) membrane protein  for binding of SARS-CoV-2 through its spike proteins [33,43,44], as well as one of the two membrane proteins, either TMPRSS2 (transmembrane protease serin sub
type 2) ) or neuropilin-1  as co-receptors for entry into the cell. Infected cells may die through cytopathic effects of the virus ) or they may be eliminated by the cytotoxic immune response against the virus [48,49]. Either way, cell death of neurons and glia cells results in disruption of cellular function in neuronal networks, whereas damage to endothelial cells leads to local coagulopathy with thrombosis and stroke . Interestingly, endothelial von Willebrand factor may play a crucial role in infected and activated endothelial cells , whereby its expression pattern in endothelial cells varies substantially between different brain regions , providing a possible explanation for focal lesions and consequently for enhanced thrombosis and stroke in certain brain regions. In summary, SARS-CoV-2 infects neurons, glia cells and endothelial cells resulting in COVID-19 manifestations of the brain.
Interleukin-17 Effects on the Nervous System
The inflammatory cytokine interleukin-17 (IL-17) contributes substantially to severe COVID-19 [53,54]. IL-17 is produced by activated gamma-delta T lymphocytes , T helper 17 lymAbstract phocytes (TH17) , astrocytes  and microglia [58,59]. In
addition to exhibiting neuropathological effects that are explained
in this paragraph, IL-17 is a versatile cytokine supporting diverse
physiological functions, including efficient immune defence
against certain bacteria and fungi, as well as tissue repair and
regeneration . IL-17 binds to and signals through its unique
interleukin-17 receptor 17A (IL-17RA) (for review of IL-17 and
its receptor see ). In the central nervous system, the IL-17RA
is expressed by astrocytes [60,62], microglia [62,63] and neurons
[64-66]. Interestingly, infection with neurotropic viruses and corresponding
encephalitis increases expression of IL-17RA in the
brain [67,68]. Locally produced IL-17 may physiologically contribute
to brain development, regeneration, and remodelling .
IL-17 certainly contributes to anti-viral immune defence in the
brain. However, out of balance production of IL-17 causes encephalitis
[67,69], as well as neurocognitive disorders . However,
IL-17 actions on the brain are best known for its corresponding
chronic inflammatory effects (for review see ), many of them
reminding chronic COVID-19 complications. Il-17 contributes to
various neurological and neuropsychiatric conditions, including
depression , cognitive impairment , multiple sclerosis
, schizophrenia [75,76] and Parkinson’s disease . Most
important, however, is the contribution of IL-17 in the context of
cerebrovascular events (for review see ), especially in poststroke
neurodegeneration [79,80], relevant acute manifestation
of severe COVID-19. IL-17 acts on endothelial cells affecting the
blood-brain barrier [70,81,82], infiltration of immune cells into
the brain tissue  and thrombosis [80,84], also by releasing
von Willebrand factor [52,84,85]. Cerebrovascular thrombosis
may then also be enhanced by IL17 acting on platelets , as
they express IL-17RA , as well as ACE2 allowing binding of
SARS-CoV-2 and subsequent thrombotic activation . Summarizing,
IL-17 and its receptor are key players in COVID-19 and they
contribute substantially to complications of the brain. The question
now is, whether it is possible to interfere with IL-17 effects.
Various IL-17 and IL-17RA antagonist or inhibitors have been
developed and explored in recent years in the context of severe
autoimmune-related diseases where IL-17 play a major role [89,
90]. Consequently, IL-17 inhibitors have been proposed to treat
patients with severe COVID-19 [91, 92]. However, clinical trials
would be needed to explore the benefit of IL-17 inhibitors in patients
with neurological manifestations due to COVID-19.
The role of SARS-CoV-2 ORF8 Protein in IL-17 Neuropathology
ORF8 (open reading frame 8) protein of SARS-CoV-2 is unique
to this virus and not present in the other coronaviruses [93-95].
ORF8 somehow influences the immune response [96,97]. ORF8
modifications or deletion, which happen naturally along the evolution
of the virus, as well as experimentally in research laboratories,
indicate that variations of ORF8 correlate with severity
of COVID-19 . Interestingly, it has recently been shown that
ORF8 protein forms a complex with IL-17RA , which may
modify or influence the IL-17 cellular response. The interaction of
ORF8 protein with IL-17RA enhances SARS-Cov-2 production in
the infected cell. However, IL-17 binding to the receptor does not
influence viral reproduction, but the wild-type version of ORF8
associated with severe COVID-19 increases substantially IL-17
serum concentration . In the context of brain cells infected
with SARS-CoV-2 and expression of IL-17RA, the interaction of
ORF8 protein with IL17-RA may enhance virus production and
thus spread the virus locally which may increase local immune response
and tissue damage. In addition, in brain cells that also produce
IL-17, the interaction between the ORF8 protein and IL-17RA
may dysregulate IL-17 feedback and cellular response, resulting
in uncontrolled continuous secretion of IL-17 and subsequent local
neuropathological and cardiovascular effects, described in the
previous paragraph. The most reasonable way to interfere with
SARS-CoV2 and IL-17 effects on the brain might be to develop new
small molecules that disrupt specifically the interaction between
ORF8 and the IL-17RA for prevention of major neuropathologies
early in SARS-CoV-2 infection.
The inflammatory cytokine IL-17 plays a major role in severe
COVID-19 and may have a substantial contribution to corresponding
neurological and neuropsychiatric acute and chronic manifestations.
IL-17 related neuropathological effects may be enhanced
by the interaction of SARS-CoV-2 ORF8 protein with the IL-17RA
in brain cells. COVID-19 patients may benefit from treatment with
already available IL-17 inhibitors in the early stage of the infection.
In addition, new inhibitory small molecules ought to be developed
that interfere with the complex formation of the ORF8 protein and
the IL-17RA for decreasing or blocking viral reproduction and for
preventing COVID-19 related neuropathologies.
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