Candidiasis represents the most common fungal infection in hospitalized patients and Candida albicans remains the main etiologic agent of candidiasis, as this otherwise normal commensal of humans is capable of causing life-threatening infections in an expanding spectrum of immunocompromissed patients. Neonates, and in particular very low birth weight (VLBW) infants, are highly susceptible to candidiasis, mostly due to their immature immune system;and this risk increases with decreasing birth weight and gestational age. In fact, candidiasis represents now the second most common infection in VLBW neonates. Of note, these infections carry unacceptably high mortality rates (about 45% despite antifungal treatment), double than those associated with infections due to gram positive and gram negative bacteria. Neonatal candidiasis also adds incremental co-morbidity (i.e. neurodevelopmental impairment), length of hospital stay and economic costs. Clearly, these high mortality rates indicate that current antifungal therapy is still ineffective, ue mainly to the limited arsenal of antifungal drugs and the emergence of resistance to most classes of antifungals. These difficulties encountered in the treatment of candidiasis, including i neonates, have led to an increased interest in the search for innovative therapies. Antibody therapy constitutes a very attractive alternative to classical treatment using """"""""small molecule"""""""" or """"""""chemical"""""""" drugs. In the field of Medical Mycology, seminal papers by the Casadevall group led to a reappraisal of the role of antibodies and a revived interest in the development of antibody-based therapies for the treatment of fungal infections. Despite the fact that the role of antibody response in host defense against candidiasis remains controversial, recently it has been conclusively demonstrated that passive administration of monoclonal antibodies (Mabs) contributes to protection during disseminated candidiasis in relevant animal models. Our main hypothesis is that the development of Mabs will increase the treatment options against candidiasis, with special emphasis on neonatal candidiasis. By virtue of their biological activities, including preliminary data indicating their protective effect in an animal model of infection, we have identified three very promising Mabs (3H3, 1H4 and C7) which serve as the basis of this proposal. Thus, experiments in this small grant will further advance these Mabs as candidates for the development of new biologics for the antibody-therapy of neonatal candidiasis;for which we will i) determine their efficacy in passive transfer of protection (serum therapy) experiments using a novel murine model of invasive candidiasis in neonates, and ii) determine the in vitro and in vivo efficacy of combinations between these Mabs and clinically used antifungal drugs.
Because of their immature immune system preterm neonates are at increased risk of infection. Candidiasis is the most frequent fungal infection in neonates, and these infections are very difficult to treat. This proposal aims to develop novel antibody-based therapies that can be used in combination with current antifungal agents, which may lead to a substantial reduction in morbidity, mortality and extended hospital stay, while simultaneously reducing healthcare costs.
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