Contribution ofCandida albicansCell Wall Components to Recognition by and Escape from Murine Macrophages

Abstract

The pathogenicity of the opportunistic human fungal pathogen Candida albicans depends on its ability to escape destruction by the host immune system. Using mutant strains that are defective in cell surface glycosylation, cell wall protein synthesis, and yeast-hypha morphogenesis, we have investigated three important aspects of C. albicans innate immune interactions: phagocytosis by primary macrophages and macrophage cell lines, hyphal formation within macrophage phagosomes, and the ability to escape from and kill macrophages. We show that cell wall glycosylation is critically important for the recognition and ingestion of C. albicans by macrophages. Phagocytosis was significantly reduced for mutants deficient in phosphomannan biosynthesis (mmn4⌬, pmr1⌬, and mnt3 mnt5⌬), whereas O-and N-linked mannan defects (mnt1⌬ mnt2⌬ and mns1⌬) were associated with increased ingestion, compared to the parent wild-type strains and genetically complemented controls. In contrast, macrophage uptake of mutants deficient in cell wall proteins such as adhesins (ece1⌬, hwp1⌬, and als3⌬) and yeast-locked mutants (clb2⌬, hgc1⌬, cph1⌬, efg1⌬, and efg1⌬ cph1⌬), was similar to that observed for wild-type C. albicans. Killing of macrophages was abrogated in hypha-deficient strains, significantly reduced in all glycosylation mutants, and comparable to wild type in cell wall protein mutants. The diminished ability of glycosylation mutants to kill macrophages was not a consequence of impaired hyphal formation within macrophage phagosomes. Therefore, cell wall composition and the ability to undergo yeast-hypha morphogenesis are critical determinants of the macrophage's ability to ingest and process C. albicans.

Recognition of yeast nucleic acids triggers a host‐protective type I interferon response

“…We hypothesized that this sharp decline in IFN-a/b mRNA levels was secondary to yeast-induced cDC toxicity, based on the previous observations on the ability of C. albicans to kill macrophages [16]. Indeed, under the conditions employed in the experiments detailed above, we observed a marked reduction in the percentage of viable cDCs after the first few hours of infection (Fig.…”

“…On the contrary, IFN-b and IFN-a4 mRNA elevations were readily measured in cDCs as early as 1 and 2 h respectively, after C. albicans stimulation, peaked at 3 h and rapidly declined thereafter (Fig. 1A and 1B).We hypothesized that this sharp decline in IFN-a/b mRNA levels was secondary to yeast-induced cDC toxicity, based on the previous observations on the ability of C. albicans to kill macrophages [16]. Indeed, under the conditions employed in the experiments detailed above, we observed a marked reduction in the percentage of viable cDCs after the first few hours of infection (Fig.…”

Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

“…Second, C-type lectin receptors (CLRs) recognize ␤-glucan and other types of glycosylated mannan (7,8). Cell wall glycosylation is critical for the recognition and uptake of C. albicans, as defects in phosphomannan biosynthesis decrease the phagocytosis of fungal cells by macrophages (9). Additionally, proteins covalently associated with mannose polymers on the outer cell wall layer constitute major antigens (9,10,11).…”

Innate immune cell response uponCandida albicansinfection

“…29 Other CLRs, MR and DC-SIGN recognize N-linked mannan and specifically mediate C. albicans binding and internalization via phagocytes. [30][31][32] Although MR lacks signaling motifs, it performs endocytosis, mediates internalization of their ligands and also contributes to antigen presentation. 33 Galectin-3, an S-type lectin receptor, recognizes b -(1-2) oligomannan and efficiently helps defend against disseminated C. albicans in a mouse model.…”