Iron metabolism in infections: Focus on COVID-19

Abstract

Iron is a micronutrient essential for a wide range of metabolic processes in virtually all living organisms. During infections, a battle for iron takes place between the human host and the invading pathogens. The liver peptide hepcidin, which is phylogenetically and structurally linked to defensins (antimicrobial peptides of the innate immunity), plays a pivotal role by subtracting iron to pathogens through its sequestration into host cells, mainly macrophages. While this phenomenon is well studied in certain bacterial infections, much less is known regarding viral infections. Iron metabolism also has implications on the functionality of cells of the immune system. Once primed by the contact with antigen presenting cells, lymphocytes need iron to sustain the metabolic burst required for mounting an effective cellular and humoral response. The COVID-19 pandemic has boosted an amount of clinical and translational research over the possible influences of nutrients on SARS-CoV-2 infection, in terms of either susceptibility or clinical course. Here we review the intersections between iron metabolism and COVID-19, belonging to the wider domain of the so-called "nutritional immunity". A better understanding of such connections has potential broad implications, either from a mechanistic standpoint, or for the development of more effective strategies for managing COVID-19 and possible future pandemics.

Keywords: COVID-19; Ferritin; Hepcidin; Immunity; Iron.

Fig. 1

Intersections between iron metabolism and severe COVID-19, according to suggestions from studies described and referenced in the text. Marked hypoferremia has been consistently reported in severe COVID-19, and might play a substantial role as contributing factor to a worsening clinical course. Hypoferremia is associated to the marked increase of pro-inflammatory cytokines, including IL-6 which is a major stimulator of hepcidin production by the liver. Hepcidin contribute to hypoferremia by inhibiting iron export from macrophages due to ferroportin internalization and degradation. Other still unknown mechanisms could contribute to hepcidin-independent hypoferremia. Activation of macrophages can mimic hemophagocytic syndromes with marked hyperferritinemia and further contribute to the cytokine storm. The functional iron deficiency in turn is a major determinant of the anemia of inflammation, and can alter either oxygen sensing and lymphocyte function. Altogether these mechanisms could contribute to disease severity.