Lactoferrin inhibits or promotes Legionella pneumophila intracellular multiplication in nonactivated and interferon gamma-activated human monocytes depending upon its degree of iron saturation. Iron-lactoferrin and nonphysiologic iron chelates reverse monocyte activation against Legionella pneumophila.

Abstract

We have been exploring the role of iron in the pathogenesis of the intracellular bacterial pathogen Legionella pneumophila In previous studies, we have demonstrated that L. pneumophila intracellular multiplication in human monocytes is iron dependent and that IFN-y-activated monocytes inhibit L. pneumophila intracellular multiplication by limiting the availability of iron. In this study, we have investigated the effect on L. pneumophila intracellular multiplication of lactoferrin, an ironbinding protein which is internalized via specific receptors on monocytes, and of nonphysiologic iron chelates which enter monocytes by a receptor-independent route.Apolactoferrin completely inhibited L. pneumophila multiplication in nonactivated monocytes, and enhanced the capacity of IFN-y-activated monocytes to inhibit L. pneumophila intracellular multiplication. In contrast, iron-saturated lactoferrin had no effect on the already rapid rate of L. pneumophila multiplication in nonactivated monocytes. Moreover, it reversed the capacity of activated monocytes to inhibit L. pneumophila intracellular multiplication, demonstrating that L. pneumophila can utilize iron from the lactoferrin-lactoferrin receptor pathway. The capacity of iron-lactoferrin to reverse monocyte activation was dependent upon its percent iron saturation and not just its total iron content. Similarly, the nonphysiologic iron chelates ferric nitrilotriacetate and ferric ammonium citrate completely reversed and ferric pyrophosphate partially reversed the capacity of IFNy-activated monocytes to inhibit L. pneumophila intracellular multiplication, demonstrating that L. pneumophila can utilize iron derived from nonphysiologic iron chelates internalized by monocytes independently of the transferrin and lactoferrin endocytic pathways.This study suggests that at sites of inflammation, lactoferrin may inhibit or promote L. pneumophila intracellular multiplication in mononuclear phagocytes depending upon its degree of iron saturation. In addition, this study suggests a

Degranulating Neutrophils Promote Leukotriene B4 Production by Infected Macrophages To Kill Leishmania amazonensis Parasites

“…Neutrophils could act by providing potent antimicrobial molecules to the macrophage. This mechanism was initially proposed in a mouse study of experimental mycobacteriosis (47); later, this mechanism was also observed in infection by Legionella pneumophila (48). Neutrophil granule enzymes, such as NE, could activate the microbicidal functions of macrophages through interactions with surface receptors (49).…”

Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens.

“…Consistent with this hypothesis, FeNTA reverses the capacity of chloroquine and ammonium chloride to inhibit L. pneumophila multiplication, and its ability to do so is dependent upon its iron content, as NTA has no effect. We have previously demonstrated that FeNTA can enter the monocyte and supply iron to intracellular L. pneumophila (24).…”

“…In the absence of supplemental iron, chloroquine had no effect on L. pneumophila multiplication at concentrations of 30, 150, or 750 1AM (24,120, and 600 times the lowest effective concentration in tissue culture experiments). At a concentration of 3.75 mM (3,000 times the lowest effective concentration tested in tissue culture), chloroquine had a slight effect on L. pneumophila multiplication, and at a concentration of 18.75 mM (15,000 times the lowest effective concentration tested in tissue culture), chloroquine markedly inhibited L. pneumophila multiplication (Fig.…”

Recombinant BCG expressing Mycobacterium tuberculosis major extracellular proteins

“…One mechanism by which activated macrophages resist intracellular pathogens is by reducing their uptake, for example by downregulating complement receptor function [12], as in the case of Mycobacterium leprae, thereby denying pathogens their preferred intracellular niche. Another way is to inhibit the multiplication of pathogens that are ingested by denying them access to essential nutrients, such as iron in the case of Legionella pneumophila [13,14], or by assaulting them with toxic oxygen molecules in the case of Toxoplasma gondii [15]. Second, 4 cytotoxic lymphocytes lyse infected macrophages, again denying the pathogens a host cell in which to multiply.…”