Titan Cells Confer Protection from Phagocytosis in Cryptococcus neoformans Infections

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>The human fungal pathogen<jats:named-content content-type="genus-species">Cryptococcus neoformans</jats:named-content>produces an enlarged “titan” cell morphology when exposed to the host pulmonary environment. Titan cells exhibit traits that promote survival in the host. Previous studies showed that titan cells are not phagocytosed and that increased titan cell production in the lungs results in reduced phagocytosis of cryptococcal cells by host immune cells. Here, the effect of titan cell production on host-pathogen interactions during early stages of pulmonary cryptococcosis was explored. The relationship between titan cell production and phagocytosis was found to be nonlinear; moderate increases in titan cell production resulted in profound decreases in phagocytosis, with significant differences occurring within the first 24 h of the infection. Not only were titan cells themselves protected from phagocytosis, but titan cell formation also conferred protection from phagocytosis to normal-size cryptococcal cells. Large particles introduced into the lungs were not phagocytosed, suggesting the large size of titan cells protects against phagocytosis. The presence of large particles was unable to protect smaller particles from phagocytosis, revealing that titan cell size alone is not sufficient to provide the observed cross-protection of normal-size cryptococcal cells. These data suggest that titan cells play a critical role in establishment of the pulmonary infection by promoting the survival of the entire population of cryptococcal cells.</jats:p>

Altered Immune Response Differentially Enhances Susceptibility to Cryptococcus neoformans and Cryptococcus gattii Infection in Mice Expressing the HIV-1 Transgene

“…This seemingly paradoxical finding could possibly be explained by the antiphagocytic properties of the cryptococcal capsule (55) and the reduced phagocytosis of cryptococcal giant (titan) cells (33,(56)(57)(58), which would allow C. neoformans to proliferate at a rate comparable to that of C. gattii despite the enhanced inflammatory cell response. However, in a recent report (41), C. gattii R265 produced higher lung burdens than those of C. neoformans H99 after infection of C57BL/6 and BALB/c mice, suggesting that the protective pulmonary immune responses to Cryptococcus of these two mouse strains may differ qualitatively or quantitatively from those of non-Tg C3H mice.…”

Titan Cell Production Enhances the Virulence of Cryptococcus neoformans

“…Third, titan cells are resistant to oxidative and nitrosative stresses similar to those employed by phagocytes to kill pathogens (33,46). Finally, titan cells are too large to be phagocytosed by host immune cells in the lungs, and the production of titan cells reduces phagocytosis of normal-size cryptococcal cells (32). Taken together, these data show that titan cells have characteristics that may promote survival in vivo.…”

Titan Cells: Barriers to Phagocytosis

“…Typically, Cryptococcal spores are inhaled into the lung, where they lodge in alveoli and establish pulmonary infections. Engulfment of normal cryptococcal cells by alveolar macrophages leads to formation of Titan cells via cell enlargement (up to 10 times) which includes cell cycle arrest or increase in DNA content (tetraploidy or octaploidy) [1,2]. Titan cell formation is induced by cAMP/PKA pathway, which helps in maintaining their virulence through thick anti-phagocytic polysaccharide capsule and melanin pigment [1].…”

“…Engulfment of normal cryptococcal cells by alveolar macrophages leads to formation of Titan cells via cell enlargement (up to 10 times) which includes cell cycle arrest or increase in DNA content (tetraploidy or octaploidy) [1,2]. Titan cell formation is induced by cAMP/PKA pathway, which helps in maintaining their virulence through thick anti-phagocytic polysaccharide capsule and melanin pigment [1]. Ste3a pheromone receptor and Gpr5 protein through cAMP/PKA pathway controls the Titan cell formation mediated by activation of Rim101 transcription factor [2].…”

“…It has been proven, that they are also capable of decreasing the overall rate of phagocytosis [1]. Recently, it has been shown that the large particles such as asbestos, inert beads etc cannot be phagocytised; this phenomenon is known as frustrated phagocytosis [1].…”