lactoferrin and Malaria

Host antimicrobial mechanisms reduce iron availability to pathogens. Iron proteins influencing the innate immune response include hepcidin, lactoferrin, siderocalin, haptoglobin, hemopexin, Nramp1, ferroportin and the transferrin receptor. Numerous global health threats are influenced by iron status and provide examples of our growing understanding of the connections between infection and iron metabolism.

Topics: Animals; Antimicrobial Cationic Peptides; Carrier Proteins; Cation Transport Proteins; Hepcidins; HIV; HIV Infections; Humans; Immunity, Innate; Iron; Lactoferrin; Lipocalin-2; Malaria; Mycobacterium tuberculosis; Plasmodium; Tuberculosis

The continuing unresolved debate over the interaction of iron and infection indicates a need for quantitative review of clinical morbidity outcomes. Iron deficiency is associated with reversible abnormalities of immune function, but it is difficult to demonstrate the severity and relevance of these in observational studies. Iron treatment has been associated with acute exacerbations of infection, in particular, malaria. Oral iron has been associated with increased rates of clinical malaria (5 of 9 studies) and increased morbidity from other infectious disease (4 of 8 studies). In most instances, therapeutic doses of oral iron were used. No studies in malarial regions showed benefits. Knowledge of local prevalence of causes of anemia including iron deficiency, seasonal malarial endemicity, protective hemoglobinopathies and age-specific immunity is essential in planning interventions. A balance must be struck in dose of oral iron and the timing of intervention with respect to age and malaria transmission. Antimalarial intervention is important. No studies of oral iron supplementation clearly show deleterious effects in nonmalarious areas. Milk fortification reduced morbidity due to respiratory disease in two very early studies in nonmalarious regions, but this was not confirmed in three later fortification studies, and better morbidity rates could be achieved by breast-feeding alone. One study in a nonmalarious area of Indonesia showed reduced infectious outcome after oral iron supplementation of anemic schoolchildren. No systematic studies report oral iron supplementation and infectious morbidity in breast-fed infants in nonmalarious regions.

Topics: Administration, Oral; Animals; Antibody Formation; Bacterial Infections; Breast Feeding; Confidence Intervals; Confounding Factors, Epidemiologic; Controlled Clinical Trials as Topic; Disease Susceptibility; Endemic Diseases; Female; Humans; Immunity, Cellular; Immunocompromised Host; Incidence; Infant; Infections; Iron; Iron Deficiencies; Lactoferrin; Malaria; Milk; Models, Animal; Odds Ratio; Parasitic Diseases; Pneumonia; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Time Factors; Transferrin

Although the effectiveness of BCG vaccination in preventing adult pulmonary tuberculosis (TB) has been highly variable, epidemiologic studies have suggested that BCG provides other general health benefits to vaccinees including reducing the impact of asthma, leprosy, and possibly malaria. To further evaluate whether BCG immunization protects against malarial parasitemia and to define molecular correlates of this non-specific immunity, mice were vaccinated with BCG and then challenged 2 months later with asexual blood stage Plasmodium yoelii 17XNL (PyNL) parasites. Following challenge with PyNL, significant decreases in parasitemia were observed in BCG vaccinated mice relative to naïve controls. To identify immune molecules that may be associated with the BCG-induced protection, gene expression was evaluated by RT-PCR in i) naïve controls, ii) BCG-vaccinated mice, iii) PyNL infected mice and iv) BCG vaccinated/PyNL infected mice at 0, 1, 5, and 9 days after the P. yoelii infection. The expression results showed that i) BCG immunization induces the expression of at least 18 genes including the anti-microbial molecules lactoferrin, eosinophil peroxidase, eosinophil major basic protein and the cathelicidin-related antimicrobial peptide (CRAMP); ii) an active PyNL infection suppresses the expression of important immune response molecules; and iii) the extent of PyNL-induced suppression of specific genes is reduced in BCG-vaccinated/PyNL infected mice. To validate the gene expression data, we demonstrated that pre-treatment of malaria parasites with lactoferrin or the cathelicidin LL-37 peptide decreases the level of PyNL parasitemias in mice. Overall, our study suggests that BCG vaccination induces the expression of non-specific immune molecules including antimicrobial peptides which may provide an overall benefit to vaccinees by limiting infections of unrelated pathogens such as Plasmodium parasites.

Topics: Animals; Antimicrobial Cationic Peptides; BCG Vaccine; Cathelicidins; Eosinophil Major Basic Protein; Eosinophil Peroxidase; Female; Gene Expression; Immunity, Innate; Lactoferrin; Malaria; Mice; Mice, Inbred C57BL; Plasmodium yoelii; Vaccination

Remnants of lipoproteins, intestinal chylomicrons, and very low density lipoprotein (VLDL), are rapidly cleared from plasma and enter hepatocytes. It has been suggested that remnant lipoproteins are initially captured in the space of Disse by heparan sulfate proteoglycans (HSPGs), and that their subsequent internalization into hepatocytes is mediated by members of the LDL-receptor gene family. Similarly to lipoprotein remnants, malaria sporozoites are removed from the blood circulation by the liver within minutes after injection by Anopheles mosquitoes. The sporozoite's surface is covered by the circumsporozoite protein (CS), and its region II-plus has been implicated in the binding of the parasites to glycosaminoglycan chains of hepatocyte HSPGs. Lactoferrin, a protein with antibacterial properties found in breast milk and neutrophil granules, is also rapidly cleared from the circulation by hepatocytes, and can inhibit the hepatic uptake of lipoprotein remnants. Here we provide evidence that sporozoites, lactoferrin, and remnant lipoproteins are cleared from the blood by similar mechanisms. CS, lactoferrin, and remnant lipoproteins compete in vitro and in vivo for binding sites on liver cells. The relevance of this binding event for sporozoite infectivity is highlighted by our demonstration that apoliprotein E-enriched beta-VLDI and lactoferrin inhibit sporozoite invasion of HepG2 cells. In addition, malaria sporozoites are less infective in LDL-receptor knockout (LDLR -/-) mice maintained on a high fat diet, as compared with littermates maintained on a normal diet. We conclude that the clearance of lipoprotein remnants and sporozoites from the blood is mediated by the same set of highly sulfated HSPGs on the hepatocyte plasma membrane.

Topics: Animals; Anopheles; Apolipoproteins E; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Lactoferrin; Lipoproteins; Lipoproteins, VLDL; Liver; Malaria; Mice; Plasmodium; Proteoglycans

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