COVID-19: патогенез
Severe coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the Spike (S) protein to
engage with its receptors and infect host cells. To date, it is still not known whether heart vascular
pericytes (PCs) are infected by SARS-CoV-2, and if the S protein alone provokes PC dysfunction. Here,
we aimed to investigate the effects of the S protein on primary human cardiac PC signalling and
function. Results show, for the first time, that cardiac PCs are not permissive to SARS-CoV-2 infection
in vitro, whilst a recombinant S protein alone elicits functional alterations in PCs. This was documented
as: (1)
increased migration, (2) reduced ability to support endothelial cell (EC) network formation on
Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine stormand (4)
production of pro-apoptotic factors responsible for EC death. Next, adopting a blocking strategy against
the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S
protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2
(ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using
a blocking antibody or mRNA silencing, reduced ERK1/2 activation and rescued PC function in the
presence of the S protein. In conclusion, our findings suggest that circulating S protein prompts vascular
PC dysfunction, potentially contributing to establishing microvascular injury in organs distant from the
site of infection. This mechanism may have clinical and therapeutic implications.
Ещё один механизм патогенности спайк-протеина.
via 
Viking700: Potent SARS-CoV-2-Specific T Cell Immunity and Low Anaphylatoxin Levels Correlate With Mild Disease Progression in COVID-19 Patients и Uni Innsbruck: Schwere Verläufe bei hohen Antikörpertitern, leichte bei guter T-Zell-Aktivität
Die Studie der Medizinischen Universität Innsbruck an Geweben von COVID-19 Patienten liefert überraschende Einsichten in den Verlauf von Corona-Infektionen. Die Daten belegen, dass hohe SARS-CoV-2-Antikörpertiter mit einem schweren Krankheitsverlauf verbunden sind. Eine robuste T-Zell-Aktivität hingegen korreliert signifikant mit leichten Symptomen. Die Ergebnisse sind auch für andere respiratorische Erkrankungen relevant.
T cells play a fundamental role in the early control and clearance of
many viral infections of the respiratory system. In SARS-CoV-2-infected
individuals, lymphopenia with drastically reduced CD4+ and CD8+
T cells correlates with Coronavirus disease 2019 (COVID-19)-associated
disease severity and mortality. In this study, we characterized cellular
and humoral immune responses induced in patients with mild, severe and
critical COVID-19. Peripheral blood mononuclear cells of 37 patients
with mild, severe and critical COVID-19 and 10 healthy individuals were
analyzed by IFNγ ELISpot and multi-color flow cytometry upon stimulation
with peptide pools covering complete immunodominant SARS-CoV-2 matrix,
nucleocapsid and spike proteins. In addition SARS-CoV-2 antibody levels,
neutralization abilities and anaphylatoxin levels were evaluated by
various commercially available ELISA platforms. Our data clearly
demonstrates a significantly stronger induction of SARS-CoV-2 specific
CD8+ T lymphocytes and higher IFNγ production in patients
with mild compared to patients with severe or critical COVID-19. In all
patients SARS-CoV-2-specific antibodies with similar neutralizing
activity were detected, but highest titers of total IgGs were observed
in critical patients. Finally, elevated anaphylatoxin C3a and C5a levels
were identified in severe and critical COVID-19 patients probably
caused by aberrant immune complex formation due to elevated antibody
titers in these patients. Crucially, we provide a full picture of
cellular and humoral immune responses of COVID-19 patients and prove
that robust polyfunctional CD8+ T cell responses concomitant
with low anaphylatoxin levels correlate with mild infections. In
addition, our data indicates that high SARS-CoV-2 antibody titers are
associated with severe disease progression.
We hypothesized that these vascular symptoms might be associated with
disrupted endothelial barrier integrity. This was investigated in vitro
using endothelial cell culture and recombinant SARS-CoV-2 spike protein
S1 Receptor-Binding Domain (Spike). Mouse brain microvascular
endothelial cells from normal (C57BL/6 mice) and diabetic (db/db) mice
were used. An endothelial transwell permeability assay revealed
increased permeability in diabetic cells as well as after Spike
treatment. The expression of VE-Cadherin, an endothelial adherens
junction protein, JAM-A, a tight junctional protein, Connexin-43, a gap
junctional protein, and PECAM-1, were all decreased significantly after
Spike treatment in control and to a greater extent, in diabetic cells.
In control cells, Spike treatment increased association of endothelial
junctional proteins with Rab5a, a mediator of the endocytic trafficking
compartment. In cerebral arteries isolated from control and diabetic
animals, Spike protein had a greater effect in downregulating expression
of endothelial junctional proteins in arteries from diabetic animals
than from control animals. In conclusion, these experiments reveal that
Spike-induced degradation of endothelial junctional proteins affects
endothelial barrier function and is the likely cause of vascular damage
observed in COVID-19 affected individuals.
COVID-19: Up to 82% critically ill patients had low Vitamin C values
Это кстати интересно в плане того, что веганское питание заметно снижает риск серьёзного течения ковида - оно, среди прочего, обеспечивает заметно более высокий уровень витамина С.