Leukocyte Integrin α_Xβ₂ Is the Principal Receptor for Candida Albicans on Macrophages and Is Essential for Antifungal Host Defense.

Abstract 1493

The induction of cell-mediated immunity to pathogens is the prime task of cells of the innate immune system. Integrin α_Mβ₂ (Mac-1, CR3, CD11b/CD18) is expressed on polymorphonuclear neutrophils (PMNs), monocytes, macrophages (MFC) and NK cells and has been implicated in diverse responses of these cells to infection, including phagocytosis, cell-mediated killing, chemotaxis and cellular activation. In PMNs integrin α_Mβ₂ serves as the principal receptor involved in recognition of the common opportunistic fungal pathogen Candida albicans, and this integrin recognizes the fungal mannoprotein pH-regulated Antigen 1 (Pra1). Professional antigen-presenting cells of myeloid lineage MFC and dendritic cells express integrin α_Xβ₂ (p150,95, CD11c/CD18) which is highly homologous to Integrin α_Mβ₂, but the role of α_Xβ₂ in the immune response to bacterial and fungal infections remains unclear. Employing α_M - and α_X-KO mice and mutated strains of C. albicans in a model of murine systemic candidiasis, we first demonstrate that mice deficient in α_Xβ₂ exhibit significantly increased susceptibility to the invasive fungal infection. C. albicans induced lethality in α_Xβ₂-KO mice more rapidly (2- to 3-fold faster) than the same inoculum in wild-type mice. MFC derived from mice deficient in α_×β₂ have a reduced ability to kill or phagocyte C. albicans. When the fungus was injected into mice, 6 hrs after peritoneal of thioglycollate, neutrophil recruitment to C. albicans showed a 20%-30% clearance of the fungus in the α_Mβ₂-KO murine intraperitoneal lavages and a 50–60% rise in the α_Xβ₂-KO lavages, which is consistent with our prior data showing α_Mβ₂-dependency for PMNs-mediated antifungal defense activity. In contrast, when the fungus was injected into the peritoneal cavity 16 hrs after thioglycollate, when most recruited leukocytes are MFC, the C. albicans injected into α_Xβ₂-KO mice showed a 23%-25% clearance of the fungus from the lavages while fungal clearance in α_Mβ₂-KO lavages increased by only 30–40%. Thus, MFC antifungal activity is α_Xβ₂-dependent. These results were further confirmed by in vitro fungicide assays employing isolated murine peritoneal PMNs and MFC. Fungal survival was greatest with PMN derived from α_Mβ₂-KO mice and MFC derived from the α_Xβ₂-KO mice-derived MFC. Disruption of the PRA1 gene of C. albicans, which is the primary ligand for α_Mβ₂, had no effect on MFC fungicide activity, which suggests that α_Xβ₂ recognizes a C. albicans ligand different from Pra1. Taken together, these results suggest that α_Xβ₂ is a principal receptor for C. albicans on macrophages and plays critical role in host antifungal defense in a Pra1-independent mechanism.