lactoferrin and Orthomyxoviridae-Infections

Ingestion of bovine lactoferrin (bLF) has been reported to show anti-infective, anti-cancer, and anti-inflammatory effects. In particular, it has become evident that oral bLF had a beneficial effect on infections of both digestive and nondigestive tract tissue in various animal models. Furthermore, the effects of bLF have been indicated in clinical studies on patients with Helicobacter pylori infection, chronic hepatitis C, tinea pedis, and other diseases. Immunomodulation in the intestine and systemic sites has been suggested to mediate the protective effects of oral bLF against infection. Recently, we demonstrated the beneficial effects of oral bLF in influenza virus infected mice. BLF administration reduced the lung consolidation score and the number of infiltrating leukocytes in bronchoalveolar lavage fluid. We also investigated the effect of oral bLF on the transcription of genes related to immunity in the small intestine of mice using the quantitative RT-PCR method. We found that intake of bLF increased the expression of IL-12p40, IFN-beta, and NOD2. Thus, oral bLF activates the transcription of important immune-related genes in the small intestine, and such transcriptional activation may promote systemic host immunity.

Topics: Animals; Cattle; Gene Expression Regulation; Humans; Intestine, Small; Lactoferrin; Orthomyxoviridae; Orthomyxoviridae Infections

Health policy precludes neonatal vaccination against influenza. Hence, morbidity and mortality are high under 6 months of age. Lactoferrin may activate diminished numbers of dysfunctional dendritic cells and reverse neonatal vaccine failures. Aluminum hydroxide/ALUM recruits neutrophils that secrete lactoferrin at deposition sites of antigen. We theorized lactoferrin + influenza antigen initiates an equivalent antibody response compared to ALUM. Three-day-old mice received subcutaneously 30 μg of H1N1 hemagglutinin + 200 μg of bovine lactoferrin versus hemagglutinin + ALUM. Controls received hemagglutinin, lactoferrin, or ALUM. After 21 days, sera measured anti-H1N1 (ELISA) and neutralizing antibody (plaque assays). ELISA detected equal antibody production with lactoferrin + hemagglutinin compared to hemagglutinin + ALUM; both sera also neutralized H1N1 virus at a 1:20 dilution (p < 0.01). Controls had no anti-H1N1 antibody. Neonates given lactoferrin had no anaphylaxis when challenged four weeks later. Lactoferrin is a safe and effective adjuvant for inducing antibody against influenza in neonates.

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Animals, Newborn; Cattle; Dogs; Hemagglutinin Glycoproteins, Influenza Virus; Influenza A Virus, H1N1 Subtype; Lactoferrin; Madin Darby Canine Kidney Cells; Mice, Inbred BALB C; Orthomyxoviridae Infections; Vaccination

Influenza is a highly contagious, acute respiratory illness, which represents one of the main plagues worldwide. Even though some antiviral drugs are available, the alarming increase of virus strains resistant to them highlights the need to find new antiviral compounds. As we have recently demonstrated that bovine lactoferrin (bLf) prevents influenza virus-induced apoptosis, in the present wor,k we have attempted to investigate in depth the mechanism of the anti-influenza virus effect of this protein. To this aim, experiments have been carried out whereby different forms of bLf were added to the cells during different phases of viral infection. Results obtained showed that bLf was able to prevent influenza virus cytopathic effects when incubated with the cells after the adsorption step, independently from ion saturation or carbohydrate content. Moreover, the influence of iron saturations or sialic acid/carbohydrates removal on bLf activity on the early phases of infection has been observed. Our results provide further insights on the antiviral activity of bLf and suggest novel strategies for treatment of influenza virus infection.

Topics: Animals; Antiviral Agents; Apoproteins; Apoptosis; Cattle; Cell Line; Cell Shape; Dogs; Dose-Response Relationship, Drug; Glycosylation; Host-Pathogen Interactions; Influenza A Virus, H3N2 Subtype; Inhibitory Concentration 50; Iron; Lactoferrin; Manganese; Orthomyxoviridae Infections; Protein Binding; Virus Attachment; Zinc

Milk contains a wide variety of host protective factors against infectious microbes. Among these protective factors, lactoferrin (LF) and lactoperoxidase (LPO) have been reported to exhibit antiviral activities as well as immuno-modulatory effects. In the present study, the effects of orally administered LF and LPO were assessed in a mouse influenza virus infection model. BALB/c mice were intranasally infected with 6.6x10(2) p.f.u. of influenza virus A/PR/8/34(H1N1). Bovine LF or LPO was administered once daily at a dose of 62.5 mg per mouse by gavage, starting 1 day before infection. Mice given LF or LPO showed a significantly lower lung consolidation score on day 6 after infection compared with the control mice that were given water instead. Concurrently, the number of infiltrated leukocytes recovered from bronchoalveolar lavage fluid (BALF) on day 6 was significantly lower in mice given LF or LPO. However, the virus yield in the BALF was not affected by these treatments. The serum level of IL-6, a pro-inflammatory cytokine, positively correlated with the lung consolidation score in each group and was significantly lower on day 6 in the mice given LPO. These results suggest the potential of oral administration of LF or LPO to attenuate pneumonia in influenza-virus-infected mice through the suppression of infiltration of inflammatory cells in the lung.

Topics: Administration, Oral; Animals; Antiviral Agents; Disease Models, Animal; Lactoferrin; Lactoperoxidase; Mice; Orthomyxoviridae; Orthomyxoviridae Infections