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.⁠