Dissection of the anti-Candida albicans mannan immune response using synthetic oligomannosides reveals unique properties of β-1,2 mannotriose protective epitopes

Candida albicans mannan consists of a large repertoire of oligomannosides with different types of mannose linkages and chain lengths, which act as individual epitopes with more or less overlapping antibody specificities. Although anti-C. albicans mannan antibody levels are monitored for diagnostic purposes nothing is known about the qualitative distribution of these antibodies in terms of epitope specificity. We addressed this question using a bank of previously synthesized biotin sulfone tagged oligomannosides (BSTOs) of alpha and beta anomery complemented with a synthetic beta -mannotriose described as a protective epitope. The reactivity of these BSTOs was analyzed with IgM isotype monoclonal antibodies (MAbs) of known specificity, polyclonal sera from patients colonized or infected with C. albicans, and mannose binding lectin (MBL). Surface plasmon resonance (SPR) and multiple analyte profiling (MAP) were used. Both methods confirmed the usual reactivity of MAbs against either alpha or beta linkages, excepted for MAb B6.1 (protective epitope) reacting with beta -Man whereas the corresponding BSTO reacted with anti-alpha -Man. These results were confirmed in western blots with native C. albicans antigens. Using patients' sera in MAP, a significant correlation was observed between the detection of anti-mannan antibodies recognizing beta- and alpha -Man epitopes and detection of antibodies against beta -linked mannotriose suggesting that this epitope also reacts with human polyclonal antibodies of both specificities. By contrast, the reactivity of human sera with other alpha- and beta -linked BSTOs clearly differed according to their colonized or infected status. In these cases, the establishment of an alpha/beta ratio was extremely discriminant. Finally SPR with MBL, an important lectin of innate immunity to C. albicans, classically known to interact with alpha -mannose, also interacted in an unexpected way with the protective epitope. These cumulative data suggest that structure/activity investigations of the finely tuned C. albicans anti-mannose immune response are worthwhile to increase our basic knowledge and for translation in medicine.

Automated summary

The distribution of anti-C. albicans mannan antibodies in terms of epitope specificity varies significantly, with different specificities of antibodies reacting differently to alpha- and beta-linked BSTOs. The alpha/beta ratio plays a crucial role in diagnosing colonization or infection status. Additionally, the unexpected interaction of MBL with the protective epitope suggests the importance of further investigations on the finely tuned C. albicans anti-mannose immune response for medical translation.