7-4- Nrf2 and COVID-19
A putative mechanism may be proposed (Figure 5). SARS-CoV-2
downregulates ACE2 inducing an increased insulin resistance associated
with oxidative stress through the AT1R pathway. This may
explain risk factors for severe COVID-19.
Fermented vegetables are often made from cruciferous (Brassica)
vegetables that release glucoraphanin converted by the plant or by the
gut microbiome into sulforaphane which activates Nrf2 and subsequently
reduces insulin intolerance by its potent antioxidant activities.
Fermented vegetables contain a high content of Lactobacillus that
can activate Nrf2 and impact on the microbiome. 114Sulforaphane and LAB both therefore have the ability to reduce insulin
resistance.
Other putative actions on COVID-19 severity may be postulated. The
down-regulation of ACE2 reduces the Ang-1,7 anti-oxidant activity that
was found to activate Nrf2. 115,116 Nrf2 protects
against hallmarks of severe COVID-19. It has anti-fibrotic effects on
various organs including the lungs, 117 protects
against lung injury and acute respiratory distress syndrome,118 and endothelial damage, 75 .
Finally, Nrf2 can block IL-6 in different models of inflammation119 and might play a role in the COVID-19 cytokine
storm.
These different mechanisms may explain the importance of fermented
cabbage in preventing the severity of COVID-19. It is clear that other
nutrients, vitamin D 120 and many different foods act
on NRF2 and that mechanisms other than Nrf2 may be operative.
It is not yet known whether sulforaphane and/or LAB may act on the
infectivity of SARS-CoV-2. Disulfide bonds can be formed under oxidizing
conditions and play an important role in the folding and stability of
some proteins. The receptor-binding domain of the viral spike proteins
and ACE2 have several cysteine residues. Using molecular dynamics
simulations, the binding affinity was significantly impaired when all of
the disulfide bonds of both ACE2 and SARS-CoV/CoV-2 spike proteins were
reduced to thiol groups. This computational finding possibly provides a
molecular basis for the differential COVID-19 cellular recognition due
to the oxidative stress.121
It is likely that foods with anti-oxidant activity can interact with
COVID-19 and that fermented or cruciferous vegetables represent
one of the possible foods involved. If some foods are found to be
associated with a prevention of COVID-19 prevalence or severity, it may
be of interest to study their LAB and/or sulforaphane composition in
order to eventually find some common mechanisms and targets for therapy.
May dietary modifications change the course of COVID-19?