lactoferrin and Virus-Diseases

It has been demonstrated that lactoferrin (LF) plays a role in host defence, but evidence on its potential antiviral property from clinical studies is fragmented. Our systematic review aimed at identifying the effects of orally administered LF against virus infections. The systematic search was conducted on PubMed, Scopus, Web of Science, BioRxiv.org and ClinicalTrials.gov from database inception to 7th January 2021. Eligible articles investigated any virus family and provided data on the effects of orally administered LF of any origin in the prevention and/or management of confirmed viral infections in people of any age. A narrative synthesis of the results was performed. Quality was assessed with the Cochrane Risk-Of-Bias and ROBINS-1 tools. A total of 27 records were included, nine of which were registered protocols. We found data on Flaviviridae (n = 10), Retroviridae (n = 3), Coronaviridae (n = 2), Reoviridae (n = 2) and Caliciviridae (n = 1). Most published trials were at high risk of bias. The findings were heterogeneous across and within viral families regarding virological, immunological and biological response, with no clear conclusion. Some weak but positive results were reported about decrease of symptom severity and duration, or reduction in viral loads. Despite high tolerability, the effects of LF as oral supplement are still inconsistent, both in preventing and managing viral infections. Small sample sizes, variety in recruitment and treatment protocols, and low study quality may have contributed to such heterogeneity. Better-designed studies are needed to further investigate its potential benefits against viral infections, including SARS-CoV-2.

Topics: Anti-Infective Agents; COVID-19; Humans; Lactoferrin; SARS-CoV-2; Virus Diseases

Cathepsin G (CatG) is involved in controlling numerous processes of the innate and adaptive immune system. These features include the proteolytic activity of CatG and play a pivotal role in alteration of chemokines as well as cytokines, clearance of exogenous and internalized pathogens, platelet activation, apoptosis, and antigen processing. This is in contrast to the capability of CatG acting in a proteolytic-independent manner due to the net charge of arginine residues in the CatG sequence which interferes with bacteria. CatG is a double-edged sword; CatG is also responsible in pathophysiological conditions, such as autoimmunity, chronic pulmonary diseases, HIV infection, tumor progression and metastasis, photo-aged human skin, Papillon-Lefèvre syndrome, and chronic inflammatory pain. Here, we summarize the latest findings for functional responsibilities of CatG in immunity, including bivalent regulation of major histocompatibility complex class I molecules, which underscore an additional novel role of CatG within the immune system.

Topics: Animals; Antigen Presentation; Autoimmunity; Cathepsin G; Gene Expression Regulation; Histocompatibility Antigens Class I; Humans; Killer Cells, Natural; Lactoferrin; Neoplasms; T-Lymphocytes, Regulatory; Virus Diseases

Newborns are at increased risk of infection due to genetic, epigenetic, and environmental factors. Herein we examine the roles of the neonatal innate immune system in host defense against bacterial and viral infections. Full-term newborns express a distinct innate immune system biased toward T(H)2-/T(H)17-polarizing and anti-inflammatory cytokine production with relative impairment in T(H)1-polarizing cytokine production that leaves them particularly vulnerable to infection with intracellular pathogens. In addition to these distinct features, preterm newborns also have fragile skin, impaired T(H)17-polarizing cytokine production, and deficient expression of complement and of antimicrobial proteins and peptides (APPs) that likely contribute to susceptibility to pyogenic bacteria. Ongoing research is identifying APPs, including bacterial/permeability-increasing protein and lactoferrin, as well as pattern recognition receptor agonists that may serve to enhance protective newborn and infant immune responses as stand-alone immune response modifiers or vaccine adjuvants.

Topics: Antimicrobial Cationic Peptides; Bacterial Infections; Blood Proteins; Cytokines; Humans; Immunity, Innate; Infant, Newborn; Inflammasomes; Lactoferrin; Lectins, C-Type; Receptors, Cytoplasmic and Nuclear; Sepsis; Signal Transduction; Toll-Like Receptors; Virus Diseases

Lactoferrin, a multifunctional iron binding glycoprotein, plays an important role in immune regulation and defence mechanisms against bacteria, fungi and viruses. Lactoferrin's iron withholding ability is related to inhibition of microbial growth as well as to modulation of motility, aggregation and biofilm formation of pathogenic bacteria. Independently of iron binding capability, lactoferrin interacts with microbial, viral and cell surfaces thus inhibiting microbial and viral adhesion and entry into host cells. Lactoferrin can be considered not only a primary defense factor against mucosal infections, but also a polyvalent regulator which interacts in viral infectious processes. Its antiviral activity, demonstrated against both enveloped and naked viruses, lies in the early phase of infection, thus preventing entry of virus in the host cell. This activity is exerted by binding to heparan sulphate glycosaminoglycan cell receptors, or viral particles or both. Despite the antiviral effect of lactoferrin, widely demonstrated in vitro studies, few clinical trials have been carried out and the related mechanism of action is still under debate. The nuclear localization of lactoferrin in different epithelial human cells suggests that lactoferrin exerts its antiviral effect not only in the early phase of surface interaction virus-cell, but also intracellularly. The capability of lactoferrin to exert a potent antiviral activity, through its binding to host cells and/or viral particles, and its nuclear localization strengthens the idea that lactoferrin is an important brick in the mucosal wall, effective against viral attacks and it could be usefully applied as novel strategy for treatment of viral infections.

Topics: Animals; Antiviral Agents; Binding Sites; Cats; Cattle; Female; Heparitin Sulfate; Humans; Immunity, Innate; Iron Chelating Agents; Lactoferrin; Mice; Models, Molecular; Protein Binding; Rats; Virus Diseases; Virus Internalization; Virus Replication; Viruses

The airway provides numerous defense mechanisms to prevent microbial colonization by the large numbers of bacteria and viruses present in ambient air. An important component of this defense is the antimicrobial peptides and proteins present in the airway surface fluid (ASF), the mucin-rich fluid covering the respiratory epithelium. These include larger proteins such as lysozyme and lactoferrin, as well as the cationic defensin and cathelicidin peptides. While some of these peptides, such as human beta-defensin (hBD)-1, are present constitutively, others, including hBD2 and -3 are inducible in response to bacterial recognition by Toll-like receptor-mediated pathways. These peptides can act as microbicides in the ASF, but also exhibit other activities, including potent chemotactic activity for cells of the innate and adaptive immune systems, suggesting they play a complex role in the host defense of the airway. Inhibition of antimicrobial peptide activity or gene expression can result in increased susceptibility to infections. This has been observed with cystic fibrosis (CF), where the CF phenotype leads to reduced antimicrobial capacity of peptides in the airway. Pathogenic virulence factors can inhibit defensin gene expression, as can environmental factors such as air pollution. Such an interference can result in infections by airway-specific pathogens including Bordetella bronchiseptica, Mycobacterium tuberculosis, and influenza virus. Research into the modulation of peptide gene expression in animal models, as well as the optimization of peptide-based therapeutics shows promise for the treatment and prevention of airway infectious diseases.

Topics: Animals; Antimicrobial Cationic Peptides; Cathelicidins; Cystic Fibrosis; Defensins; Disease Models, Animal; Humans; Lactoferrin; Muramidase; Proteinase Inhibitory Proteins, Secretory; Proteins; Respiratory System; Toll-Like Receptors; Tuberculosis, Pulmonary; Virus Diseases

The first function attributed to lactoferrin (Lf), an iron binding protein belonging to the non-immune natural defences, was antimicrobial activity that depended on its capacity to sequester iron. Iron-independent microbicidal activities, requiring direct interaction between this cationic protein and microbial surface components, were later demonstrated. Many other anti-microbial and anti-viral functions have since been ascribed to Lf. In mucosal secretions, iron and Lf modulate the motility and aggregation of pathogenic bacteria. Lf inhibits bacterial adhesion on abiotic surfaces through ionic binding to biomaterials, or specific binding to bacterial structures or both. Lf inhibition of bacterial adhesion to host cells requires Lf binding to bacteria and/or host cells. Lf hinders microbial internalization by binding to both glycosaminoglycans and bacterial proteins which can be degraded by Lf-mediated proteolysis. Moreover, Lf internalisation and localisation to the host cell nuclei could modulate bacterial entry into cells through gene regulation. Finally, the capability of Lf to exert antiviral activity, through its binding to host cells and/or viral particles, strengthens the idea that it is an important brick in the mucosal wall, effective against both microbial and viral attacks.

Topics: Animals; Anti-Infective Agents; Antiviral Agents; Bacterial Infections; Humans; Lactoferrin; Virus Diseases

Lactoferrin (LF) is an iron binding glycoprotein that is present in several mucosal secretions. Many biological functions have been ascribed to LF. One of the functions of LF is the transport of metals, but LF is also an important component of the non-specific immune system, since LF has antimicrobial properties against bacteria, fungi and several viruses. This review gives an overview of the present knowledge about the antiviral activities and, when possible, the antiviral modes of action of this protein. Lactoferrin displays antiviral activity against both DNA- and RNA-viruses, including rotavirus, respiratory syncytial virus, herpes viruses and HIV. The antiviral effect of LF lies in the early phase of infection. Lactoferrin prevents entry of virus in the host cell, either by blocking cellular receptors, or by direct binding to the virus particles.

Topics: Animals; Antiviral Agents; Humans; Lactoferrin; Milk; Virus Diseases; Virus Replication

Topics: Humans; Lactoferrin; Lectins; Leptin; Milk, Human; Neuropeptides; Nutritional Physiological Phenomena; Virus Diseases; Viruses; Vitamin A

The in vivo evidence of the antimicrobial and antiviral activity of bovine milk and colostrum derived components are reviewed with special emphasis on lactoferrin and lactoperoxidase. Their mode of action and the rationale for their application in efficacy trials with rodents, farm animals, fish and humans, to give protection against infectious agents, are described. A distinction is made between efficacy obtained by oral and non-oral administration of these non-specific defence factors which can be commercially applied in large quantities due to major achievements in dairy technology. From the in vivo studies one can infer that lactoferrin and lactoperoxidase are very promising, naturally occurring antimicrobials for use in fish farming, husbandry, oral hygiene and functional foods. Other promising milk-derived compounds include lipids, from which anti-infective degradation products are generated during digestion, and antimicrobial peptides hidden in the casein molecules.

Topics: Animals; Bacterial Infections; Cattle; Cattle Diseases; Colostrum; Female; Fish Diseases; Humans; Infant, Newborn; Lactoferrin; Lactoperoxidase; Milk; Neutrophils; Oncorhynchus mykiss; Pregnancy; Swine; Swine Diseases; Virus Diseases

Topics: Animals; Humans; Lactoferrin; Virus Diseases

Topics: Animals; Antibodies, Viral; Bacterial Infections; Female; Hot Temperature; Humans; Immunoglobulin A, Secretory; Interferons; Intestines; Lactoferrin; Lactoperoxidase; Leukocytes; Lipids; Milk, Human; Transferrin; Virus Diseases

Lactoferrin is a nutrient classically found in mammalian milk. It binds iron and is transferred via a variety of receptors into and between cells, serum, bile, and cerebrospinal fluid. It has important immunological properties, and is both antibacterial and antiviral. In particular, there is evidence that it can bind to at least some of the receptors used by coronaviruses and thereby block their entry. Of importance are Heparan Sulfate Proteoglycans (HSPGs) and the host receptor angiotensin-converting enzyme 2 (ACE2), as based on other activities lactoferrin might prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from attaching to the host cells. Lactoferrin (and more specifically enteric-coated LF because of increased bioavailability) may consequently be of preventive and therapeutic value during the present COVID-19 pandemic.

Topics: Angiotensin-Converting Enzyme 2; Animals; Anti-Bacterial Agents; Bacterial Infections; Dietary Supplements; Heparan Sulfate Proteoglycans; Humans; Lactoferrin; Peptidyl-Dipeptidase A; Receptors, Cell Surface; Receptors, Coronavirus; Receptors, Virus; Virus Diseases

This study evaluates potential markers in blood and stools for their ability to distinguish bacterial from viral gastroenteritis. A total of 108 patients were prospectively recruited, of which 27 showed bacterial, 30 viral, and 51 no detectable pathogen, respectively. Cytokines, C-reactive protein (CRP), and white blood cells as well as the 2 fecal markers lactoferrin and calprotectin were determined. Statistics comprised Kruskal-Wallis test and U test in addition to an assessment of receiver operating characteristic. Interferon γ (IFNγ) levels were significantly increased in the viral group compared to the bacterial and nonspecific group. For the bacterial group, both fecal markers lactoferrin and calprotectin as well as CRP were significantly higher in comparison to the other 2 groups. To differentiate between bacterial and viral gastroenteritis, CRP, serum IFNγ, and the fecal proteins lactoferrin and calprotectin may be useful. A corresponding algorithm should be evaluated prospectively.

Topics: Adult; Aged; Aged, 80 and over; Bacterial Infections; Biomarkers; Blood Chemical Analysis; C-Reactive Protein; Cytokines; Diagnosis, Differential; Feces; Female; Gastroenteritis; Humans; Lactoferrin; Leukocyte L1 Antigen Complex; Male; Middle Aged; Virus Diseases

Serum granulocyte-colony stimulating factor (G-CSF) was measured with an ELISA method in patients with acute bacterial and viral infections, or with an atypical pneumonia. Before initiation of antibiotic treatment, G-CSF was found to be significantly increased (799 +/- 1501 ng/l) in sera from 34 patients with an acute bacterial infection compared with the 27 patients with a viral infection (58 +/- 34 ng/l; P < 0.001) and with the eight patients with an atypical pneumonia (60 +/- 33) ng/l; P < 0.001). No significant difference in G-CSF levels was seen between gram-positive and gram-negative bacterial infections. In septic shock, increased G-CSF levels were seen both in patients with leucocytosis and leucopenia. In uncomplicated bacterial infections, both G-CSF and IL-6 were increased on day 0, and decreased rapidly after initiation of antibacterial therapy and before the patients became afebrile. In bacterial infections on day 0, G-CSF levels correlated with mononuclear cells (rs = -0.62, P < 0.001), IL-6 (rs = 0.40, P < 0.05) and S-MPO (rs = -0.5, P < 0.01). In viral infections, G-CSF was correlated with mononuclear cells (rs = 0.41, P < 0.05), white blood cell counts (rs = 0.56, P < 0.01), neutrophils (rs = 0.41, P < 0.05) and CRP (rs = 0.47, P < 0.05). We conclude that G-CSF is rapidly raised in the blood in acute bacterial infections but not in acute viral infections or in infections with Mycoplasma pneumonia. Our results also support the theory that G-CSF is involved in the mechanisms of mobilization of neutrophils into the peripheral circulation.

Topics: Acute Disease; Bacterial Infections; C-Reactive Protein; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-6; Kinetics; Lactoferrin; Leukocyte Count; Peroxidase; Pneumonia, Mycoplasma; Virus Diseases

Typical alterations of the white blood cell count are often missed during the acute course of infectious diseases. Activiation and degranulation of granulocytes are followed by elevation of E alpha 1 PI and lactoferrin plasma concentrations under these conditions. The aim of our study was the evaluation of the diagnostic significance of these granulocyte parameters in relation with the absolute granulocyte count in infected pediatric patients. A total number of 106 patients at the age of 1 day to 16 years were studied. 25 children suffered from viral, 26 from localized and 23 from systemic bacterial infections, 32 children exhibiting no signs of infection served as controls. Results of the study are given as medians and ranges. Total granulocyte count was elevated above controls (4.8; 2.2-12.7/nl) only in patients with localized bacterial infections (13.3; 5.5-36.5/nl). E alpha 1 PI and lactoferrin plasma concentrations correlated well (r = 0.72) and were found to be significantly elevated in patients with localized bacterial infections (856; 363-4820 micrograms/l and 748; 206-2078 micrograms/l) and septicemia respectively (661; 256-2078 micrograms/l and 871; 160-9550 micrograms/l). A clearcut differentiation of septic and locally infected patients was given by the ratio of E alpha 1 PI and total granulocyte counts. Significantly elevated E alpha 1 PI concentrations of patients exhibiting viral infections (295; 86-690 micrograms/l) may suggest effective granulocyte activation under this condition. Finally we conclude that E alpha 1 PI and lactoferin plasma concentration related to total granulocyte counts in infected patients may serve as a helpful indicator of granulocyte activation during the acute course of the disease.

Topics: Adolescent; Bacterial Infections; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Lactoferrin; Leukocyte Count; Male; Sepsis; Serine Proteinase Inhibitors; Serpins; Viremia; Virus Diseases

In an attempt to elucidate the previously observed decrease in plasma lactoferrin-neutrophil ratio in subjects with acute viral infections, a study of the neutrophil lactoferrin content in such infections was undertaken. With the use of an immunoperoxidase stain for lactoferrin, neutrophils in viral illness were shown to have reduced lactoferrin content (mean score 97.9 +/- SD [38.0] per 100 neutrophils) as compared with normal subjects (mean score 196.4 +/- SD [3.6] per 100 neutrophils) (t = 7.69; P less than 0.0005). This suggests an acquired defect of neutrophil lactoferrin synthesis in viral infection. This finding is of importance when seen against the well-recognized increased risk of bacterial superinfection in subjects who have recently had a viral infection.

Topics: Adult; Herpesvirus 4, Human; Humans; Lactoferrin; Lactoglobulins; Neutrophils; Reference Values; Tumor Virus Infections; Virus Diseases

The effect of parenteral hydrocortisone on plasma lactoferrin concentration, neutrophil count and lactoferrin:neutrophil ratio was assessed in 10 volunteer subjects. Administration of a single dose of corticosteroid was followed by a significant rise in the circulating neutrophil count, a significant but proportionately smaller rise in the plasma lactoferrin concentration and a significant fall in the lactoferrin:neutrophil ratio. Acute viral infections were found to be associated with a disproportionately low plasma lactoferrin concentration relative to the circulating neutrophil count. The relatively low lactoferrin concentrations in both these situations could be of significance in regard to the propensity to bacterial infection and superinfection which these 2 groups of subjects display. Compared to patients with viral infection, those suffering from Plasmodium falciparum malaria showed a significantly elevated lactoferrin:neutrophil ratio, although this ratio was not significantly different when malarial patients were compared to normal individuals. These findings suggest that the pathogenesis of relative neutropenia in viral and protozoal illnesses is fundamentally different. Finally, it was found that the temperature at which specimen collection takes place does not appear to be a significant variable determining the plasma lactoferrin concentration.

Topics: Acute Disease; Enzyme-Linked Immunosorbent Assay; Humans; Hydrocortisone; Lactoferrin; Lactoglobulins; Leukocyte Count; Malaria; Male; Neutrophils; Plasmodium falciparum; Specimen Handling; Temperature; Time Factors; Virus Diseases

The effects of season and variations in the prevalence of infectious disease on the concentrations and daily production of breast-milk immunoproteins were studied in 152 rural Gambian mothers and their children up to 26 months post-partum. IgA, IgG, IgM, C3, C4, lactoferrin, lysozyme and secretory component concentrations and breast-milk volumes were measured longitudinally over a six month period which encompassed dry and rainy seasons. No increase in the production of any immunoprotein was observed at the time of maximum prevalence of serious infectious diseases, especially diarrhoea, in the children. Enhanced secretion of certain immunoproteins was noted in mothers of children aged 9-18 months at the beginning of the rainy season. There was some evidence that this may have been associated with skin sepsis, particularly impetigo, in the children. The production of most immunoproteins fell during the rainy season. This was not the result of declining maternal food intakes as similar decreases were seen for women receiving a dietary supplement.

Topics: Bacterial Infections; Complement C3; Complement C4; Developing Countries; Female; Gambia; Humans; Immunoglobulins; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Lactation; Lactoferrin; Milk, Human; Muramidase; Mycoses; Pregnancy; Rural Population; Seasons; Secretory Component; Virus Diseases

The CSF levels of lactoferrin, lysozyme, and beta 2-microglobulin (beta 2 mu) were measured in patients with evident, probable, or possible inflammatory CNS reactions and compared to those found in neurologically apparently healthy patients. Patients with viral CNS infections had significantly raised beta 2 mu and lysozyme levels but normal lactoferrin levels, indicating a local activation of lymphocytes and monocytes but not of granulocytes. Patients with bacterial CNS infections had significantly raised levels of all three cell markers, but the increase of lysozyme and lactoferrin was relatively more pronounced than that of beta 2 mu, indicating that the inflammatory response to bacterial agents is dominated by monocytes and granulocytes. Patients with primary or secondary malignant brain tumors were characterized by a moderate increase of beta 2 mu and a considerable increase in both lysozyme and lactoferrin, i.e., the same protein pattern as observed in bacterial CNS infection. The lysozyme levels were moderately increased in half the patients with benign cerebral tumors while the levels of beta 2 mu and lactoferrin were normal, indicating that benign and malignant brain tumors induce different local inflammatory CNS reactions. Half the patients with pituitary gland adenoma had elevated beta 2 mu and lysozyme levels but normal lactoferrin levels, suggesting that immunological mechanisms are associated with the adenoma development. Patients with MS had moderately but significantly raised CSF levels of beta 2 mu and lysozyme and a third of them also had raised levels of lactoferrin, a protein pattern suggesting a low-active inflammatory process in CNS involving mononuclears and granulocytes. A similar protein pattern was found in Guillain-Barré syndrome. In cerebrosarcoidosis we noted considerably increased lysozyme and beta 2 mu but normal lactoferrin levels, consistent with the idea that the sarcoid granuloma mass is dominated by monocytic inflammatory cells. The data obtained indicate a clinical value of lactoferrin, lysozyme, and beta 2 mu as differential indices of inflammatory cell reactions taking place in various CNS processes.

Topics: Adult; Albumins; Bacterial Infections; beta 2-Microglobulin; Beta-Globulins; Central Nervous System Diseases; Cerebrospinal Fluid Proteins; Female; Humans; Inflammation; Lactoferrin; Lactoglobulins; Male; Muramidase; Virus Diseases