The ability to undergo the yeast-to-hypha transition is believed to be a key virulence factor of Candida albicans. Hyphae facilitate active penetration of host cells, host cell damage, and escape from immune cells. In addition, C. albicans mutants locked in the yeast morphology have been shown to be avirulent or attenuated in systemic infections further emphasizing the importance of hyphae for virulence. C. albicans mutants lacking the EED1 gene or its expression are able to initiate germ tube formation, but fail to elongate these into hypha and eventually switch back to yeast cell growth. Despite being attenuated in damaging epithelial cells and macrophages in vitro and in virulence in an intraperitoneal infection model in vivo, surprisingly, the eed1∆/∆ mutant was as virulent as the wild type in systemic candidiasis. The retained virulence of mutants lacking EED1 or its expression was accompanied by rapid yeast replication within internal organs, especially in the kidney, the main target organ of systemic candidiasis. Whereas the renal pro-inflammatory cytokine response was delayed early after infection, increased cytokine production was observed at later time points, likely as the result of the increased immune cell infiltration, suggesting a contribution of immunopathology to pathogenesis. This work shows that rapid proliferation is likely the consequence of enhanced metabolic adaptation and increased fitness, as the eed1Δ/Δ mutant shows better growth in kidney homogenates and on certain physiologically relevant carbon sources in vitro. High kidney yeast burden resulted in kidney damage and systemic inflammation comparable to wild type infections. Therefore, rapid proliferation by metabolic adaptation and increased fitness, resulting in high organ yeast burden, can compensate for the loss of filament formation in C. albicans
