Complement Receptor 3 Deficiency Influences Lesion Progression duringLeishmania majorInfection in BALB/c Mice

Abstract

Leishmania major is an obligately intracellular protozoan parasite that causes cutaneous leishmaniasis. Like numerous intracellular pathogens, Leishmania exploits cell surface receptors as a means of entry into host cells. Complement receptor 3 (CR3; also called CD11b/CD18), a ␤ 2 integrin on phagocytic cells, is one such receptor. Ligation of CR3 has been shown to inhibit the production of interleukin-12, the cytokine that is pivotal in establishing the cell-mediated response necessary to combat intracellular infection. Here we investigate the role that CR3 plays in the establishment and progression of cutaneous leishmaniaisis in vivo. Dermal lesions of wild-type BALB/c mice are characteristically progressive and lead to extensive tissue necrosis coupled with elevated parasite burdens; CD11b-deficient BALB/c mice, however, demonstrate an intermediate phenotype characterized by chronic lesions and a reduced incidence of tissue damage. Infection followed by a reinfection challenge indicates that both susceptible (BALB/c) and resistant (C57BL/6) mice, regardless of CD11b status, develop resistance to L. major. In addition, CD11b does not bias the T helper cytokine response to L. major infection. Our results further indicate that CD11b is not necessary for disease resolution in resistant mice; rather, this protein appears to play a minor role in susceptibility.Leishmania species are a group of intracellular protozoan parasites that infect cells of the monocyte/macrophage lineage. These parasites cause a range of clinical manifestations, from localized, self-limiting cutaneous lesions to systemic fatal infections. Approximately 350 million people are at risk of infection worldwide (3), and an estimated 2 million new infections occur annually (16).Leishmania entry into host cells is receptor mediated. Leishmania parasites have been shown to engage Fc receptors (FcR) (62), mannose receptor (8), Toll-like receptors 2, 3 (24), and 4 (37), and complement receptor 3 (CR3; also called Mac-1 or ␣ M ␤ 2 ) (46); however, the interactions of Leishmania parasites with CR3 have been the best characterized. CR3 is a versatile leukocyte-associated receptor with a number of endogenous and pathogen-associated ligands; as a result, this protein has multiple functions, playing roles in immunity, adhesion, and cell migration (21). Such versatility is a reflection of the structure of CR3 as a heterodimer of CD11b and CD18. Most ligands interact with the CD11b chain lectin and I domains, which recognize mainly pathogen-associated molecules (21) and endogenous ligands (33), respectively. The ligand binding promiscuity of CR3 includes extracellular matrix proteins (63), ICAM-1 (40), and bacterial lipopolysaccharide (LPS) (42). The best-defined function of CR3 is its role as the receptor for C3bi, a complement component protein (35). Interestingly, the predominant Leishmania surface molecule lipophosphoglycan is readily opsonized by complement (17) and binds to CR3 directly (58). Although CR3 is present on the very cells that are meant to c...

Interaction of Macrophage Antigen 1 and CD40 Ligand Leads to IL-12 Production and Resistance in CD40-Deficient Mice Infected with Leishmania major

“…Interestingly, the interaction of Leishmania to Mac-1 results in silent entry of the parasite into the phagocytes, thereby avoiding the activation and release of reactive oxygen intermediates and subsequent lysis of the parasites (43,44). Also, a report showed that Mac-1-deficient C57BL/6 mice display similar lesions and parasite burden as WT mice postinfection with L. major (45). Although this observation is inconsistent with our findings, it is conceivable that Mac-1 is a functionally redundant pathway that becomes important only in the absence of CD40-CD40L interaction.…”

The Src kinases Hck, Fgr, and Lyn activate Abl2/Arg to facilitate IgG-mediated phagocytosis andLeishmaniainfection

“…We and others have demonstrated that IgG-opsonized amastigote uptake occurs primarily through an FcRγ-mediated process, whereas C3bi-opsonized promastigote uptake occurs primarily through a CR3-mediated process (Carter et al, 2009;Kima et al, 2000;Mosser and Edelson, 1985;Russell and Wright, 1988;Ueno and Wilson, 2012). SFKs are known to facilitate immunoglobulinmediated phagocytosis.…”

Timing is everything: dendritic cell subsets in murine Leishmania infection

“…Functionally, the C11b hi subset of dDCs could potentially be involved in susceptibility, as mice lacking CD11b (complement receptor 3) fared marginally better than their wild type BALB/c counterparts. This is likely due to the fact that in the CD11b knock-out mice, the CD11b hi subset of cells are still present but do not express the integrin [54]. However, this study focused on CD11b expression on macrophages and neutrophils, while CD11b expression on the Langerin À subset of dDCs could also contribute to this effect.…”