In December, 2019, an outbreak of pneumonia with unknown cause occurred in Wuhan city, in
China. On January 7th, the scientists succeeded to isolate a novel coronavirus, severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2). WHO nominated it as coronavirus disease 2019
(COVID-19) in February, 2020. COVID-19 has a wide clinical spectrum ranging between
asymptomatic infection, mild upper respiratory tract symptoms, and severe viral pneumonia
that may result in respiratory failure and finally death. There is currently no clinically
proven specific antiviral agent available for SARS-CoV-2 infection. Supportive treatment,
including oxygen therapy, conservation fluid management, and broad-spectrum antibiotics to
cover secondary bacterial infection, remains the most important management strategy.

Lactoferrin is a highly conserved pleiotropic iron-binding 80-kDa glycoprotein of the
transferrin family that is expressed and secreted by glandular cells and found in most body
fluids with especially high concentrations in mammalian milk. Since its discovery,
lactoferrin and its related peptides are mainly considered to be important non-specific host
defense molecules against a broad range of viruses including SARS-CoV, which is closely
related to SARS-CoV-2 that causes COVID-19. Lactoferrin has been found to experimentally
inhibit viral entry in murine coronavirus, and human coronaviruses hCOV-NL63 and pseudotyped
SARS-CoV. Given 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, it is likely that
lactoferrin can inhibit SARS-CoV-2 invasion as in the case of SARS-CoV. Besides reducing
viral entry, lactoferrin can also suppress virus replication after the viral entry as in the
case of HIV.

Another major aspect of lactoferrin bioactivity relates to its immunomodulatory and
anti-inflammatory functions. Current thinking suggests that mortality from COVID-19 is not
simply due to viral infection but is a result of a cytokine storm associated with
hyper-inflammation leading to acute respiratory distress and subsequent mortality. 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-a (TNFa) and ferritin. In this
regard, lactoferrin was demonstrated to reduce IL-6, TNF a, and downregulate ferritin in
experimental settings simulating sepsis.

In this study, we aim to study the antiviral properties and immunomodulatory mechanisms of
lactoferrin within the context of its potential applications against SARS-CoV-2 and propose
the possibility of supplemental lactoferrin as a potential preventive agent for COVID-19.