Objectives:
Angioinvasion and tissue injury are hallmarks of infections mediated by Mucor circinelloides (mucormycosis) and Candida albicans (systemic candidiasis). Several studies have shown that pro-angiogenic Fibroblast Growth Factor-2 (FGF-2) is essential for tissue repair. Recently, studies have shown that FGF-2 treatment increased survival rates of murine models of aspergillosis. However, the role of FGF-2 and its regulated angiogenesis is understudied in systemic candidiasis and mucormycosis infections. C. albicans is a dimorphic fungus that exhibits yeast and hyphae morphologies. Our lab was able to generate an M. circinelloides mutant that exhibits yeast morphology in most conditions. We have previously shown that immune cells such as macrophages and lymphoblastoid cell lines overexpress FGF-2 when challenged with either C. albicans or M. circinelloides hyphae, but not yeast. The main objective of the current study is to determine if the FGF-2 response from a non-immune cell line, Human Umbilical Vein Endothelial Cells (HUVECs) is specific to hyphae form of fungal pathogens. Our second goal is to identify the fungal factors that affect host FGF-2 expression.
Methods:
HUVEC cells were challenged with either C. albicans or M. circinelloides yeast or hyphae strains for 24 hours. PBS was used as a mock control. The supernatants were collected to perform FGF-2 ELISA. To determine if live hyphae are essential for FGF-2 expression, we compared FGF-2 expression in HUVECs by challenging them with either live, heat-killed or PFA treated C. albicans or M. circinelloides hyphae. To determine if secreted or released factors from fungi are linked with host FGF-2 overexpression, we have grown the fungal pathogens overnight in tissue culture medium, and then we used the spent medium to infect HUVECs.
Results:
Our results show that HUVECs challenged with C. albicans or M. circinelloides hyphae show a significant increase in FGF-2 expression when compared to their yeast counterparts. Unlike M. circinelloides, only viable C. albicans hyphae is linked with increase in FGF-2 response. We also found that C. albicans strains deficient in candidalysin cannot increase host FGF-2 expression. Our data also show that secreted factors from M. circinelloides hyphae, but not yeast causes an increase in host FGF-2 expression. We also found that cell damage is significantly reduced in monocultures pre-treated with FGF-2 nAb followed by challenge with M. circinelloides
Conclusion:
Host FGF-2 response is specific to hyphae form of fungal pathogens. Our results suggest that secretion of candidalysin by C. albicans hyphae into host cells is essential to provoke an FGF-2 response. Hyphae specific factors from M. circinelloides can increase host FGF-2 response. Our future studies will focus on determining the role of FGF-2 in murine models of mucormycosis and candidiasis.

The Pro-angiogenic Growth Factor, FGF-2, as a Host-Response Against Invasive Fungal Pathogens