Overlooked <i>Candida glabrata</i> petites are echinocandin tolerant, induce host inflammatory responses, and display poor <i>in vivo</i> fitness

Abstract

<i>Candida glabrata</i> is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called "petite." This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and <i>in vivo</i> mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite <i>C. glabrata</i> cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our <i>ex vivo</i> observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of <i>C. glabrata</i> isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite <i>C. glabrata</i> isolates.