Cryptococcus neoformans responds to presence of Mycobacterium by diversifying its morphologies and remodelling its capsular material

Abstract

Introduction. Cryptococcus neoformans and Mycobacterium tuberculosis (MTb) are opportunistic pathogens that share overlapping geographical distributions and physiological niches within the human body. Both are recognized by the World Health Organization as high-priority pathogens. Gap Statement. Although clinical reports of co-infections with cryptococcosis and tuberculosis are increasing, experimental studies exploring their interactions remain scarce. Aim. We aimed to observationally evaluate whether C. neoformans isolates would alter morphology when co-cultured with Mycobacteria spp. and observe how these changes might alter the host immune response to C. neoformans cells. Methodology. We cultured C. neoformans reference strain and clinical isolates in physiologically relevant growth media, in the presence or absence of Mycobacterium spp. Then, we generated alveolar-like macrophages and created a stimulation environment similar to a tuberculosis environment to perform phagocytic killing assays of C. neoformans cells. Results. Here, we demonstrate that C. neoformans can grow in the presence of either heat-killed MTb antigen or the live vaccine strain, Mycobacterium bovis BCG. In response to the presence of mycobacteria, C. neoformans increased in number and exhibited enhanced virulence-associated traits, including titan cell formation, capsule enlargement and increased survival from phagocytosis. Conclusion. This work provides proof of principle for a dynamic, inter-pathogen interaction that may contribute to the exacerbation of disease outcomes in settings of a co-infection.