2.3 LF as potential preventative and treatment of COVID-19
Lf has been found to experimentally inhibit viral entry via binding to
host cell surface HSPGs in murine coronavirus (de Haan et al., 2005),
and human coronaviruses hCOV-NL63 (Milewska et al., 2014) and
pseudotyped SARS-CoV (Lang et al., 2011). There are as yet no published
studies on Lf effects on SARS-CoV-2 and its entry into host cells.
Nevertheless, given the currently accepted ’viral surfing’ model for the
role of cell surface HSPGs (Burckhardt & Greber, 2009), that the
invading virion particles ’surf’ from low affinity HSPG anchoring sites
to high affinity entry receptors in an invasion, together with the
homology of SARS-CoV and SARS-CoV-2 spike protein structures, as well as
both viruses depending on the same ACE2 receptor for cell entry
(Hoffmann et al., 2020), we feel safe to postulate a similar mechanism
whereby HSPGs serve as SARS-CoV-2 attachment sites that congregate the
virus on the cell surface and facilitate specific entry receptors such
as ACE2. It is thus likely that Lf can inhibit SARS-CoV-2 invasion at
micromolar concentrations and in a dose dependent manner just as in the
case of SARS-CoV (Lang et al., 2011).
Another major aspect of Lf bioactivity relates to its immunomodulatory
and anti-inflammatory functions. In the case of viral infections in
particular, it is often the magnitude of immune response and
inflammation which contributes to disease severity, and this is
particularly relevant for COVID-19.
Current thinking suggests that mortality from COVID-19 is not simply due
to viral infection but is a result of a cytokine storm syndrome in
select patients associated with hyper-inflammation leading to acute
respiratory distress and subsequent mortality (Mehta et al., 2020). A
cytokine profile in severe COVID-19 cases is characterized by increases
in cytokines and acute phase reactants such as interleukin IL-6, tumor
necrosis factor-α (TNFα) and ferritin. In this regard, Lf is
demonstrated to reduce IL-6, TNFα (Zimecki et al., 1998), and
downregulate ferritin (Rosa et al., 2017) in experimental settings
simulating sepsis. If the hypothesis that Lf can modulate an overactive
immune and inflammatory response to viral infection is correct, then Lf
could be a candidate adjunct treatment for more severe cases of
COVID-19.
3.
Discussion
Lf can be recombinant or naturally derived from bovine or mammalian
sources, and is considered by the FDA as ’generally regarded to be
safe” (GRAS) with no contraindications. It is widely used as a
nutritional additive in infant formulas and clinical studies employed Lf
doses ranging from 100 mg to 4.5g a day for various indications without
apparent toxicities. Newer formulations of Lf including encapsulation
and liposomalization have been explored (Ishikado et al., 2005),
and Lf derivatives and related peptides such as lactoferricin and
lactoferrampin with more potent antiviral properties are being explored
and developed (Bruni et al., 2016).
One observation regarding the clinical epidemiology of the current
COVID-19 pandemic that may be relevant to Lf was the relatively low
incidence of the infection in children. Indeed, it has been reported
that the incidence of COVID-19 in children aged 0-10 was only 0.9% in
the Chinese cases reported (Hong et al., 2020). COVID-19 cases were
rarer still in neonates and infants with a total of only 9 infected and
hospitalized cases in China between December 8 2019 and February 6 2020
out of a total 31,211 reported cases nationwide (Wei et al., 2020).
Moreover the course in infants was mild even upon infection with none of
the 9 reported cases above requiring ICU stay or ventilation support,
with infection rarely progressing to lower respiratory tract infections
(Hong et al., 2020). We postulate that breast feeding or wide use of Lf
containing infant formula in this population may account for the above
observation (Chang & Sun, 2020) but this remains to be validated.
Another interesting observation is that zinc saturated lactoferrin can
apparently exert a more potent antiviral effect. In experiments with
polio virus, it was observed that only zinc lactoferrin, and not iron
inhibited viral infection when incubated with the cells after viral
attachment, and the inhibition directly correlated with the degree of
zinc saturation (Marchetti et al., 1999). This is of particular
relevance in COVID-19 as zinc supplementation has been proposed as a
possible supplemental intervention for the disease (Zhang & Liu,
2020).
As there is currently neither established treatment regimen for COVID-19
nor established preventative for SARS-CoV-2, one can contemplate the use
of Lf both as a non-toxic health supplement to prevent as well as an
adjunct treatment for those who have developed COVID-19. Its successful
combined use to enhance conventional antiviral drug treatment in viral
disease has been demonstrated against HCV (Kaito et al., 2007) and its
potential to reduce mortality due to cytokine induced inflammation and
respiratory failure in severe COVID-19 is also suggested by laboratory,
animal and clinical studies.