O-Linked Glycans of Candida albicans Interact with Specific GPCRs in the Coronary Endothelium and Inhibit the Cardiac Response to Agonists

Abstract

Candida albicans is an opportunistic fungal pathogen that may cause invasive infections in immunocompromised patients, disseminating through the bloodstream to other organs. In the heart, the initial step prior to invasion is the adhesion of the fungus to endothelial cells. Being the fungal cell wall’s outermost structure and the first to come in contact with host cells, it greatly modulates the interplay that later will derive in the colonization of the host tissue. In this work, we studied the functional contribution of N-linked and O-linked mannans of the cell wall of C. albicans to the interaction with the coronary endothelium. An isolated rat heart model was used to assess cardiac parameters related to vascular and inotropic effects in response to phenylephrine (Phe), acetylcholine (aCh) and angiotensin II (Ang II) when treatments consisting of: (1) live and heat-killed (HK) C. albicans wild-type yeasts; (2) live C. albicans pmr1Δ yeasts (displaying shorter N-linked and O-linked mannans); (3) live C. albicans without N-linked and O-linked mannans; and (4) isolated N-linked and O-linked mannans were administered to the heart. Our results showed that C. albicans WT alters heart coronary perfusion pressure (vascular effect) and left ventricular pressure (inotropic effect) parameters in response to Phe and Ang II but not aCh, and these effects can be reversed by mannose. Similar results were observed when isolated cell walls, live C. albicans without N-linked mannans or isolated O-linked mannans were perfused into the heart. In contrast, C. albicans HK, C. albicans pmr1Δ, C. albicans without O-linked mannans or isolated N-linked mannans were not able to alter the CPP and LVP in response to the same agonists. Taken together, our data suggest that C. albicans interaction occurs with specific receptors on coronary endothelium and that O-linked mannan contributes to a greater extent to this interaction. Further studies are necessary to elucidate why specific receptors preferentially interact with this fungal cell wall structure.