Ambulatory COVID-19 Patients Treated with Lactoferrin as a Supplementary Antiviral Agent: A Preliminary Study
Luigi Rosa, Giovanni Tripepi, Enrico Naldi, Marina Aimati, Stefano Santangeli, Francesco Venditto, Marcello Caldarelli, Piera Valenti
Journal of Clinical Medicine, doi:10.3390/jcm10184276
SARS-CoV-2, an enveloped, single-stranded RNA virus causing COVID-19, exerts morbidity and mortality especially in elderly, obese individuals and those suffering from chronic conditions. In addition to the availability of vaccines and the limited efficacy of the first dose of vaccine against SARS-CoV-2 variants, there is an urgent requirement for the discovery and development of supplementary antiviral agents. Lactoferrin (Lf), a pleiotropic cationic glycoprotein of innate immunity, has been proposed as a safe treatment combined with other therapies in COVID-19 patients. Here, we present a small retrospective study on asymptomatic, paucisymptomatic, and moderate symptomatic COVID-19 Lf-treated versus Lf-untreated patients. The time required to achieve SARS-CoV-2 RNA negativization in Lf-treated patients (n = 82) was significantly lower (p < 0.001) compared to that observed in Lf-untreated ones (n = 39) (15 versus 24 days). A link among reduction in symptoms, age, and Lf treatment was found. The Lf antiviral activity could be explained through the interaction with SARS-CoV-2 spike, the binding with heparan sulfate proteoglycans of cells, and the anti-inflammatory activity associated with the restoration of iron homeostasis disorders, which favor viral infection/replication. Lf could be an important supplementary treatment in counteracting SARS-CoV-2 infection, as it is also safe and well-tolerated by all treated patients.
Conflicts of Interest: The authors declare no conflict of interest.
References
Bektas, Schurman, Sen, Ferrucci, Aging, inflammation and the environment, Exp. Gerontol
Berlutti, Pantanella, Natalizi, Frioni, Paesano et al., Antiviral properties of lactoferrin-A natural immunity molecule, Molecules,
doi:10.3390/molecules16086992Butowt, Bili Ńska, SARS-CoV-2: Olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection, ACS Chem. Neurosci,
doi:10.1021/acschemneuro.0c00172Cagno, Tseligka, Jones, Tapparel, Heparan sulfate proteoglycans and viral attachment: True receptors or adaptation bias?, Viruses,
doi:10.3390/v11070596Campione, Cosio, Rosa, Lanna, Di Girolamo et al., Lactoferrin as protective natural barrier of respiratory and intestinal mucosa against coronavirus infection and inflammation, Int. J. Mol. Sci
Campione, Lanna, Cosio, Rosa, Conte et al., Lactoferrin against SARS-CoV-2: In vitro and in silico evidences, Front. Pharmacol,
doi:10.3389/fphar.2021.666600Campione, Lanna, Cosio, Rosa, Conte et al., Pleiotropic effect of lactoferrin in the prevention and treatment of COVID-19 infection: Randomized clinical trial, in vitro and in silico preliminary evidences, bioRxiv,
doi:10.1101/2020.08.11.244996Clausen, Sandoval, Spliid, Pihl, Perrett et al., SARS-CoV-2 Infection depends on cellular heparan sulfate and ACE2, Cell
Cuervo, Grandvaux, ACE2: Evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities, eLife,
doi:10.7554/eLife.61390Cutone, Lepanto, Rosa, Scotti, Rossi et al., Aerosolized bovine lactoferrin counteracts infection, inflammation and iron dysbalance in a cystic fibrosis mouse model of pseudomonas aeruginosa chronic lung infection, Int. J. Mol. Sci,
doi:10.3390/ijms20092128Cutone, Rosa, Lepanto, Scotti, Berlutti et al., Lactoferrin Efficiently Counteracts the Inflammation-Induced Changes of the Iron Homeostasis System in Macrophages, Front. Immunol
Fda, GRN 000465 Cow's Milk-Derived Lactoferrin
Han, Ma, Li, Liu, Zhao et al., Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors, Emerg. Microbes Infect,
doi:10.1080/22221751.2020.1770129He, Zhang, Zhang, Zheng, Zhang et al., Neurological and psychiatric presentations associated with COVID-19, Eur. Arch. Psychiatry Clin. Neurosci,
doi:10.1007/s00406-021-01244-0Hoffmann, Kleine-Weber, Schroeder, Krüger, Herrler et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052Hu, Meng, Zhang, Xiang, Wang, The in vitro antiviral activity of lactoferrin against common human coronaviruses and SARS-CoV-2 is mediated by targeting the heparan sulfate co-receptor, Emerg. Microbes Infect,
doi:10.1080/22221751.2021.1888660Kıraç, Is ethics approval necessary for all trials? A clear but not certain process, Mol. Imaging Radionucl. Ther,
doi:10.4274/Mirt.80664Lan, Ge, Yu, Shan, Zhou et al., Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor, Nature,
doi:10.1038/s41586-020-2180-5Lang, Yang, Deng, Liu, Yang et al., Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans, PLoS ONE,
doi:10.1371/journal.pone.0023710Lee, Lockwood, Das, Wang, Grinspun et al., Self-reported anosmia and dysgeusia as key symptoms of coronavirus disease 2019, CJEM,
doi:10.1017/cem.2020.420Lepanto, Rosa, Cutone, Conte, Paesano et al., Efficacy of lactoferrin oral administration in the treatment of anemia and anemia of inflammation in pregnant and non-pregnant women: An interventional study, Front. Immunol,
doi:10.3389/fimmu.2018.02123Li, Li, Farzan, Harrison, Structure of SARS coronavirus spike receptor-binding domain complexed with receptor, Science,
doi:10.1126/science.1116480Li, Moore, Vasilieva, Sui, Wong et al., Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus, Nature,
doi:10.1038/nature02145Liu, Chopra, Li, Wolfert, Tompkins et al., SARS-CoV-2 spike protein binds heparan sulfate in a lengthand sequence-dependent manner, bioRxiv,
doi:10.1101/2020.05.10.087288Liu, Li, Xu, Wu, Luo et al., Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19, J. Clin. Virol,
doi:10.1016/j.jcv.2020.104370Liu, Ye, Liu, Liu, Singh, Stability during in vitro digestion of lactoferrin-loaded liposomes prepared from milk fat globule membrane-derived phospholipids, J. Dairy Sci,
doi:10.3168/jds.2012-6072Loganathan, Kuppusamy, Wankhar, Gurugubelli, Mahadevappa et al., Angiotensinconverting enzyme 2 (ACE2): COVID 19 gate way to multiple organ failure syndromes, Respir. Physiol. Neurobiol,
doi:10.1016/j.resp.2020.103548Mancinelli, Rosa, Cutone, Lepanto, Franchitto et al., Viral hepatitis and iron dysregulation: Molecular pathways and the role of lactoferrin, Molecules,
doi:10.3390/molecules25081997Miesbach, Makris, COVID-19: Coagulopathy, risk of thrombosis, and the rationale for anticoagulation, Clin. Appl. Thromb,
doi:10.1177/1076029620938149Miotto, Di Rienzo, Bò, Boffi, Ruocco et al., Molecular mechanisms behind anti SARS-CoV-2 action of lactoferrin, Front. Mol. Biosci,
doi:10.3389/fmolb.2021.607443Nai, Lorè, Pagani, De Lorenzo, Di Modica et al., Hepcidin levels predict Covid-19 severity and mortality in a cohort of hospitalized Italian patients, Am. J. Hematol
Paesano, Pacifici, Benedetti, Berlutti, Frioni et al., Safety and efficacy of lactoferrin versus ferrous sulphate in curing iron deficiency and iron deficiency anaemia in hereditary thrombophilia pregnant women: An interventional study, BioMetals,
doi:10.1007/s10534-014-9723-xRosa, Cutone, Lepanto, Paesano, Valenti, Lactoferrin: A Natural Glycoprotein Involved in Iron and Inflammatory Homeostasis, Int. J. Mol. Sci,
doi:10.3390/ijms18091985Rosa, Lepanto, Cutone, Siciliano, Paesano et al., Influence of oral administration mode on the efficacy of commercial bovine lactoferrin against iron and inflammatory homeostasis disorders, BioMetals,
doi:10.1007/s10534-020-00236-2Salaris, Scarpa, Elli, Bertolini, Guglielmetti et al., Protective effects of lactoferrin against SARS-CoV-2 infection in vitro, Nutrients,
doi:10.3390/nu13020328Scheller, Chalaris, Schmidt-Arras, Rose-John, The pro-and anti-inflammatory properties of the cytokine interleukin-6, Biochim. Biophys. Acta (BBA)-Bioenerg,
doi:10.1016/j.bbamcr.2011.01.034Valenti, Rosa, Capobianco, Lepanto, Schiavi et al., Role of lactobacilli and lactoferrin in the mucosal cervicovaginal defense, Front. Immunol,
doi:10.3389/fimmu.2018.00376Walls, Park, Tortorici, Wall, Mcguire et al., Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein, Cell,
doi:10.1016/j.cell.2020.02.058Wang, Chan, Kloer, Comparative studies on the chemical and immunochemical properties of human milk, human pancreatic juice and bovine milk lactoferrin, Comp. Biochem. Physiol. Part B Comp. Biochem,
doi:10.1016/0305-0491(84)90100-7Xu, Shi, Wang, Zhang, Huang et al., Pathological findings of COVID-19 associated with acute respiratory distress syndrome, Lancet Respir. Med,
doi:10.1016/S2213-2600(20)30076-XXu, Zhong, Deng, Peng, Dan et al., High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa, Int. J. Oral Sci,
doi:10.1038/s41368-020-0074-xZhang, Chen, Swaroop, Xu, Wang et al., Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro, Cell Discov,
doi:10.1038/s41421-020-00222-5Zou, Chen, Zou, Han, Hao et al., Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection, Front. Med,
doi:10.1007/s11684-020-0754-0Zuo, Warnock, Harbaugh, Yalavarthi, Gockman et al., Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients, Sci. Rep,
doi:10.1038/s41598-020-80010-zZwirzitz, Reiter, Skrabana, Ohradanova-Repic, Majdic et al., Lactoferrin is a natural inhibitor of plasminogen activation, J. Biol. Chem,
doi:10.1074/jbc.RA118.003145DOI record:
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