Regulation of Innate Immune Response toCandida albicansInfections by α_Mβ₂-Pra1p Interaction

Abstract

Candida albicans is a common opportunistic fungal pathogen and is the leading cause of invasive fungal diseases in immunocompromised individuals. The induction of cell-mediated immunity to C. albicans is one of the main tasks of cells of the innate immune system, and in vitro evidence suggests that integrin ␣ M ␤ 2 (CR3, Mac-1, and CD11b/CD18) is the principal leukocyte receptor involved in recognition of the fungus. Using ␣ M ␤ 2 -KO mice and mutated strains of C. albicans in two models of murine candidiasis, we demonstrate that neutrophils derived from mice deficient in ␣ M ␤ 2 have a reduced ability to kill C. albicans and that the deficient mice themselves exhibit increased susceptibility to fungal infection. Disruption of the PRA1 gene of C. albicans, the primary ligand for ␣ M ␤ 2 , protects the fungus against leukocyte killing in vitro and in vivo, impedes the innate immune response to the infection, and increases fungal virulence and organ invasion in vivo. Thus, recognition of pH-regulated antigen 1 protein (Pra1p) by ␣ M ␤ 2 plays a pivotal role in determining fungal virulence and host response and protection against C. albicans infection.

Distinct Effects of Integrins αXβ2and αMβ2on Leukocyte Subpopulations during Inflammation and Antimicrobial Responses

“…Activated PMN were recovered by lavage from the inflamed peritoneal cavity 6 to 8 h after thioglycolate stimulation, while iM/monocytes were obtained at 72 h (21,25,26). In wild-type (WT) mice at 6 to 7 h, PMN constituted 90% to 95% of all cells in the lavage fluid, identified as Ly6G ϩϩ cells by flow cytometry (Fig.…”

“…Candida albicans and Escherichia coli were selected as opportunistic fungal and bacterial pathogens, respectively. The ability of the ␤ 2 integrins to directly recognize these opportunistic pathogens, C. albicans via ␤-glucans or Pra1 mannoprotein (14,20,21) and E. coli via LPS (22)(23)(24), was an additional consideration in choosing these models of infection.…”

IL-33 Priming Regulates Multiple Steps of the Neutrophil-Mediated Anti-Candida albicans Response by Modulating TLR and Dectin-1 Signals

“…5F, 5G). It will be necessary to determine how the upregulation of CR3 expression preferentially increased the phagocytosis of opsonized versus non-opsonized C. albicans, considering that CR3 is important for both opsonic and non-opsonic phagocytosis (19,20,33,34,47). One possibility is that opsonized C. albicans has a higher affinity for CR3 because two different binding sites are available: one for iC3b and the other for b-glucans (16,48).…”

“…CR3 expression is rapidly upregulated by a range of stimulators, including GM-CSF, fMLF, PMA, TNF-a, and IL-10 (27)(28)(29)(30)(31), and this upregulation of CR3 expression is important for neutrophil migration through venules during inflammation (32). Mice lacking C3 or CR3 are susceptible to infection with C. albicans, and neutrophils derived from such mice show reduced ability to kill C. albicans (33,34). The CR3 of neutrophils recognizes non-opsonized and opsonized C. albicans, and signaling via CR3 results in the killing of these pathogens by a respiratory burst response in a spleen tyrosine kinase (Syk)-dependent manner (35)(36)(37).…”

Secreted aspartic protease 2 of Candida albicans inactivates factor H and the macrophage factor H-receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18)

“…The CR3 and the related CR4 (CD11c/CD18) receptors are major opsonic receptors, which bind the C3b cleavage product iC3b. CR3 can also bind directly to fungal surface moieties, such as beta-glucan and pH-regulated antigen 1, which interactions are important in the antifungal innate cellular response (van Bruggen et al, 2009;Soloviev et al, 2007Soloviev et al, , 2011Losse et al, 2011).…”