Abstract
ABSTRACTCryptococcus neoformans is a major opportunistic fungal pathogen that causes fatal meningoencephalitis in immunocompromised individuals and is responsible for a large proportion of AIDS-related deaths. The fungal cell wall is an essential organelle which undergoes constant modification during various stages of growth and is critical for fungal pathogenesis. One critical component of the fungal cell wall is chitin, which in C. neoformans is predominantly deacetylated to chitosan. We previously reported that three chitin deacetylase (CDA) genes have to be deleted to generate a chitosan-deficient C. neoformans strain. This cda1Δ2Δ3Δ strain was avirulent in mice, as it was rapidly cleared from the lungs of infected mice. Here, we report that clearance of the cda1Δ2Δ3Δ strain was associated with sharply spiked concentrations of proinflammatory molecules that are known to be critical mediators of the orchestration of a protective Th1-type adaptive immune response. This was followed by the selective enrichment of the Th1-type T cell population in the cda1Δ2Δ3Δ strain-infected mouse lung. Importantly, this response resulted in the development of robust protective immunity to a subsequent lethal challenge with a virulent wild-type C. neoformans strain. Moreover, protective immunity was also induced in mice vaccinated with heat-killed cda1Δ2Δ3Δ cells and was effective in multiple mouse strains. The results presented here provide a strong framework to develop the cda1Δ2Δ3Δ strain as a potential vaccine candidate for C. neoformans infection.
Highlights
Cryptococcus neoformans is a major opportunistic fungal pathogen that causes fatal meningoencephalitis in immunocompromised individuals and is responsible for a large proportion of AIDS-related deaths
We found that deletion of three C. neoformans chitin deacetylase genes, CDA1, CDA2, and CDA3, was sufficient to render the yeast cells devoid of chitosan
We further demonstrate that pulmonary vaccination with the chitosandeficient strain was able to stimulate a robust protective immunity to a subsequent lethal challenge with a virulent wild-type C. neoformans strain in multiple mouse strains
Summary
Cryptococcus neoformans is a major opportunistic fungal pathogen that causes fatal meningoencephalitis in immunocompromised individuals and is responsible for a large proportion of AIDS-related deaths. We report that clearance of the cda1⌬2⌬3⌬ strain was associated with sharply spiked concentrations of proinflammatory molecules that are known to be critical mediators of the orchestration of a protective Th1-type adaptive immune response This was followed by the selective enrichment of the Th1-type T cell population in the cda1⌬2⌬3⌬ strain-infected mouse lung. Vaccination of mice with IFN-␥-expressing C. neoformans (strain H99␥) resulted in significant increases in the levels of Th1-type proinflammatory cytokines and chemokines in the lung, with concomitant decreases in the levels of cytokines that are mediators of Th2-type anti-inflammatory activities This polarized Th1 immunogenic response was associated with clearance of the H99␥ cells used for vaccination and, in turn, induced protective immunity against a lethal pulmonary infection with wild-type C. neoformans [19]. Protective immunity developed during infection with an sgl1⌬ strain is shown to be triggered by the C. neoformansderived sterylglucosides [22]
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