Titan Cells Confer Protection from Phagocytosis in Cryptococcus neoformans Infections

Okagaki, Laura H.; Nielsen, Kirsten

doi:10.1128/ec.00121-12

Cited by 151 publications

(175 citation statements)

References 25 publications

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“…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.…”

Section: Discussionmentioning

confidence: 86%

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

et al. 2013

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e Cryptococcus neoformans var. grubii is the most frequent cause of AIDS-associated cryptococcosis worldwide, while Cryptococcus gattii usually infects immunocompetent people. To understand the mechanisms which cause differential susceptibility to these cryptococcal species in HIV infection, we established and characterized a model of cryptococcosis in CD4C/HIV MutA transgenic (Tg) mice expressing gene products of HIV-1 and developing an AIDS-like disease. Tg mice infected intranasally with C. neoformans var. grubii strain H99 or C23 consistently displayed reduced survival compared to non-Tg mice at three graded inocula, while shortened survival of Tg mice infected with C. gattii strain R265 or R272 was restricted to a single high inoculum. HIV-1 transgene expression selectively augmented systemic dissemination to the liver and spleen for strains H99 and C23 but not strains R265 and R272. Histopathologic examination of lungs of Tg mice revealed large numbers of widely scattered H99 cells, with a minimal inflammatory cell response, while in the non-Tg mice H99 was almost completely embedded within extensive mixed inflammatory cell infiltrates. In contrast to H99, R265 was dispersed throughout the lung parenchyma and failed to induce a strong inflammatory response in both Tg and non-Tg mice. HIV-1 transgene expression reduced pulmonary production of CCL2 and CCL5 after infection with H99 or R265, and production of these two chemokines was lower after infection with R265. These results indicate that an altered immune response in these Tg mice markedly enhances C. neoformans but not C. gattii infection. This model therefore provides a powerful new tool to further investigate the immunopathogenesis of cryptococcosis.

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Section: Discussionmentioning

confidence: 86%

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

et al. 2013

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“…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.…”

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confidence: 85%

Titan Cell Production Enhances the Virulence of Cryptococcus neoformans

et al. 2012

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To characterize the effect of titan cell formation on the host-pathogen interaction, we utilized a previously described C. neoformans mutant, the gpr4⌬ gpr5⌬ mutant, which has minimal titan cell production in vivo. The gpr4⌬ gpr5⌬ mutant strain had attenuated virulence, a lower CFU, and reduced dissemination compared to the wild-type strain. Titan cell production by the wild-type strain also resulted in increased eosinophil accumulation and decreased phagocytosis in the lungs compared to those with the gpr4⌬ gpr5⌬ mutant strain. Phagocytosed cryptococcal cells exhibited less viability than nonphagocytosed cells, which potentially explains the reduced cell survival and overall attenuation of virulence in the absence of titan cells. These data show that titan cell formation is a novel virulence factor in C. neoformans that promotes establishment of the initial pulmonary infection and plays a key role in disease progression.

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“…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].…”

Section: ó Association Of Microbiologists Of India 2012mentioning

confidence: 99%

“…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].…”

Section: ó Association Of Microbiologists Of India 2012mentioning

confidence: 99%