Characterization of the antifungal functions of a WGA-Fc (IgG2a) fusion protein binding to cell wall chitin oligomers

Abstract

The majority of therapeutic strategies for mycosis require the protracted administration of antifungals, which can result in significant toxicities and have unacceptable failure rates. Hence, there is an urgent need for the development of improved therapeutic approaches, and monoclonal antibody-based drugs are potentially a powerful alternative to standard antifungals. To develop a broad antibody-like reagent against mycosis, wheat germ agglutinin (WGA) was linked to the effector Fc region of murine IgG2a. The resultant WGA-Fc displayed high affinity to purified chitin and bound efficiently to fungal cell walls, co-localizing with chitin, in patterns ranging from circular (Histoplasma capsulatum) to punctate (Cryptococcus neoformans) to labeling at the bud sites (Candida albicans and Saccharomyces cerevisiae). WGA-Fc directly inhibited fungal growth in standard cultures. WGA-Fc opsonization increased fungal phagocytosis, as well augmented the antifungal functions by macrophages. Prophylactic administration of WGA-Fc fully protected mice against H. capsulatum, correlating with a reduction in lung, spleen and liver fungal burdens. Administration of WGA-Fc also dramatically diminished pulmonary inflammation. Hence, the opsonic activity of WGA-Fc effectively modulates fungal cell recognition and promotes the elimination of fungal pathogens. Therefore, we propose WGA-Fc as a potential “pan-fungal” therapeutic that should be further developed for use against invasive mycoses.

Difficult but Not Impossible: in Search of an Anti-Candida Vaccine

“…The killer toxin discussed in this review, among others [39], is also an option for passive immunotherapy [40]. Lastly, the IgG2a WGA-Fc, which binds to chitin, is among a line of universal vaccine candidates [41].…”

Modulation of the fungal mycobiome is regulated by the chitin-binding receptor FIBCD1

“…2, H-J). Binding was found to be restricted to cells staining positive for wheat germ agglutinin (WGA), a chitin-binding lectin recognizing exposed chitin in growing fungi (Rodrigues et al, 2008;Liedke et al, 2017). Binding was Ca 2+ dependent and was abolished in the presence of GlcNAc, confirming specific binding through the conserved S1 binding site.…”

Monoclonal Antibodies as Tools to Combat Fungal Infections

“…In a more recent study, Liedke et al generated a chitin-specific, recombinant antibody-chimera consisting of the chitin-binding domain of the lectin wheat germ agglutinin (WGA) and the Fc portion of a murine IgG 2a . Only 10 µg of WGA-Fc were sufficient to elicit full protection in mice that received a normally lethal dose of H. capsulatum [81]. In vitro, WGA-Fc triggered increased phagocytosis and complement deposition and thereby promoted an efficient elimination of the pathogen.…”

“…Remarkably, WGA-Fc also bound to C. albicans and C. neoformans and sparked an enhanced killing of these pathogens by murine macrophages. Due to this cross-reactivity, WGA-Fc is a promising candidate for the development of a pan-fungal therapeutic [81].…”