Bovine Lactoferrin Inhibits Coronavirus at the Initial Viral Attachment Stage Among Suspects, Vulnerable, And Confirmed COVID-19 Cases: A Narrative Review

Role of lactoferrin on coronavirus

By boosting natural killer (NK) cell activity and promoting neutrophil aggregation and adhesion, LF during SARSCoronavirus (CoV) invasion has presented to the host immune response. LF prevents infection with the SARS pseudo-virus in a dose-dependent way. The fact that LF could prevent the spiky protein from attaching to host cells suggests that LF showcased the inhibitory effect during the early viral attachment stage. The spike protein interactions with the active SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2), were not affected by LF. Previous research has demonstrated that abundant cell-surface heparan sulfate proteoglycans (HSPGs) colocalize with LF. Heparinase or exogenous heparin treatment of the cells exhibited that HSPGs supply the sites of binding for the invasion of SARSCoV at early stages of the attachment phase by inhibiting spike protein binding to host cells and preventing SARS-CoV infection. By attaching HSPGs and preventing the initial interaction between SARS-CoV and host cells, LF may help the host fight off SARS-CoV infection.^[17]

Studies in favor of lactoferrin's usage as an antiviral

A study titled “Antiviral Properties of Lactoferrin, a Natural Immunity Molecule” by Francesca Berlutti, Fabrizio Berlutti F, et al. claims that to inhibit microbial and viral adhesion and penetration into host cells, lactoferrin interacts with the surfaces of microbial, viral, and host cells. In addition to being a key defense mechanism against mucosal infections, lactoferrin functions as a multifunctional regulator that interacts with viral infectious processes. It has been shown to have an antiviral effect against both enveloped and naked viruses in the early stages of infection, blocking virus entry into the host cell. This action is induced by attachment to viral particles, to cell receptors for heparin sulfate glycosaminoglycans, or to both. Despite widespread in vitro evidence of lactoferrin's antiviral effects, few clinical trials have been conducted, and the underlying mechanism of action remains under debate. According to the nuclear localization of lactoferrin in a number of human epithelial cells, it has intracellular antiviral effects and acts during the initial stage of virus-cell surface interactions. The indication that lactoferrin is an essential component of the mucosal wall is effective against viral attacks, and that it could be practically applied as a novel strategy in treating viral infections is strengthened by the fact that lactoferrin can display antiviral activity through its attachment to host cells as well as viral particles and its nuclear localization.^[18]

Similarly, Valenti published a study titled “Lactoferrin: An important host defense against microbial and viral attack,” published in PubMed. P and Antonini summarize that LF inhibits adhesion of bacteria on abiotic surfaces by ionic binding to the biomaterials as well as specific binding to the structures of bacteria, or both. LF binding to bacteria or host cells is necessary to limit bacterial adherence to host cells. By attaching to the proteins of bacteria and glycosaminoglycans, which can both be broken down by LF-mediated proteolysis, it can prevent internalization of the microbes. Additionally, through regulating gene expression, LF localization to the cell nuclei of the host may influence bacterial ingress into cells. Last but not least, the fact that LF can exert antiviral action by binding to the host cells or viral particles aids the notion that it is a crucial component of the mucosal wall, protecting against attacks by microbes and viruses.^[19]

According to a review study written by Silva et al.^[20] and published in the 2019 Food Science and Technology issue, in vitro research indicates that LF exhibits an inhibitory effect towards many viruses. It treats the common cold, influenza, viral gastroenteritis, and herpes in animals and people when given orally (Wakabayashi et al., 2014).^[21]Lactoferrin demonstrated a cytotoxic effect against cancer cells in experiments carried out in vivo and in vitro by Silva et al. (2002), significantly reducing the number of tumors.^[20]According to a study by Hiroyuki Wakabayashi et al. in the Journal of Infection and Chemotherapy, numerous studies have demonstrated lactoferrin's in vitro antiviral activity against viral pathogens that cause common infections like the common cold, influenza, gastroenteritis, summer cold, and herpes, where lactoferrin primarily inhibits viral attachment to the target cells. Studies showing the oral administration of lactoferrin has protective benefits in vivo against common viral infections have grown recently. For instance, lactoferrin may target norovirus, a significant new human pathogen that accounts for most gastroenteritis outbreaks globally. In a pilot study, ingestion of lactoferrin decreased the frequency of noroviral gastroenteritis in children and had a similar impact over a broad age range. A recent in vitro study shows that lactoferrin prevents both cellular attachment and viral reproduction in cells of murine norovirus, which is a virus that is closely related to the human norovirus. This is done by generating the antiviral cytokines interferon (IFN)-a/b. Additionally, taking lactoferrin increases Th1 cytokine production and NK cell activity, helping to protect against viral infections. In supposition, taking lactoferrin may shield the host from viral infections by inhibiting viral attachment to cells, preventing viral multiplication within cells, and boosting systemic immune responses.^[21]

Although for severe acute respiratory syndrome coronavirus infection, lactoferrin is a functional receptor,^[22] several reports have indicated that Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), Liver/Lymph node-Specific ICAM-3 Grabbing Non-integrin (L-SIGN) (known as CD209L, which is specific to liver/lymph node), and heparan sulfate^[17] are also involved. This is according to Haiyan Sun and Harvard Jenssen's book “Milk Derived Peptides with Immune Stimulating Antiviral Properties”. Due to its interactions with DC-SIGN or heparin sulfate receptors, lactoferrin may be able to stop the transmission of the coronavirus, causing severe acute respiratory syndrome in the host, using the same mechanism as that for human immunodeficiency virus (HIV). Recently, Lang et al.^[17] reported that lactoferrin's binding to heparan sulfate prevented the severe acute respiratory syndrome coronavirus from infecting HEK293E/angiotensin-converting enzyme 2-Myc cells.^{[17, 23-27]}