The Influence of Viral Infections on Iron Homeostasis and the Potential for Lactoferrin as a Therapeutic in the Age of the SARS-CoV-2 Pandemic

Abstract

The association of hyperinflammation and hyperferritinemia with adverse outcomes in SARS-CoV-2-infected patients suggests an integral role for iron homeostasis in pathogenesis, a commonly described symptom of respiratory viral infections. This dysregulated iron homeostasis results in viral-induced lung injury, often lasting long after the acute viral infection; however, much remains to be understood mechanistically. Lactoferrin is a multipurpose glycoprotein with key immunomodulatory, antimicrobial, and antiviral functions, which can be found in various secreted fluids, but is most abundantly characterized in milk from all mammalian species. Lactoferrin is found at its highest concentrations in primate colostrum; however, the abundant availability of bovine-dairy-derived lactoferrin (bLf) has led to the use of bLf as a functional food. The recent research has demonstrated the potential value of bovine lactoferrin as a therapeutic adjuvant against SARS-CoV-2, and herein this research is reviewed and the potential mechanisms of therapeutic targeting are considered.

Bovine lactoferrin inhibits SARS‐CoV‐2 and SARS‐CoV‐1 by targeting the RdRp complex and alleviates viral infection in the hamster model

“…Wotring et al 45 reported that bLf showed potent efficacy on different SARS‐CoV‐2 variants, but the underlying mechanisms were not explored. Ward et al 46 and Shafqat et al 47 summarized the role of Lf against SARS‐CoV‐2, including blocking viral attachment between HSPGs and viral particles and modulating the expression of immune‐related genes. Although most studies have demonstrated that Lf inhibits viral infection primarily by interfering with cell entry, few studies have suggested that the post‐infection addition of Lf could also reduce infection 36 .…”

Iron Chelation as a Potential Therapeutic Approach in Acute Lung Injury

“…Second, lipid damage catalyzed by iron overload can exert a direct causative effect on ferroptosis, which is more likely to amplify cell death and trigger a series of other inflammatory-related immune regulatory responses [61] (Figure 3). confirmed that levels of lactoferrin correlate with the severity of infectious pneumonia and sepsis induced by bacteria and viruses [12,66]. NRAMP1, as a divalent metal transporter and a vital player in the host-pathogen battle for phagolysosomal iron, may have a broader role in regulating macrophage iron homeostasis through the hepcidin-Nramp1 axis [67] (Figure 3).…”

Association between iron metabolism and SARS-COV-2 infection, determined by ferritin, hephaestin and hypoxia-induced factor-1 alpha levels in COVID-19 patients

“…The microcytic anemia of the sla mouse was attributed to defective export of iron from enterocytes, indicating that decreased or defective hephaestin can lead to iron deficiency [ 7 – 9 ]. Infection of enterocytes with SARS-CoV-2 can induce down-regulation of ferroportin and hephaestin [ 10 ] and it was of interest to see if changes in serum hephaestin could correlate with COVID-19.…”