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Immunosuppression, interleukin-10 synthesis and apoptosis are induced in rats inoculated with Cryptococcus neoformans
Laura S Chiapello1, José L Baronetti, María P Aoki
1Institution, Micología, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Argentina.
Abstract:
Glucuronoxylomannan (GXM) is the major Cryptococcus neoformans capsular polysaccharide and represents the main virulence factor of this fungus. In in vitro studies we have demonstrated previously that this acidic and high-molecular-weight polysaccharide suppresses lymphoproliferation, modulates cytokine production and promotes apoptosis in spleen mononuclear (Spm) cells from rats. In this study we demonstrate that these phenomena also occur in vivo after the intracardiac inoculation of GXM into normal Wistar rats. The results of this study show suppression of the proliferative response Spm cells to concanavalin A (Con A) or heat-killed C. neoformans (HKCn) in the first 2 weeks after polysaccharide administration. In addition, increased levels of interleukin (IL)-10 were produced by Con A-stimulated Spm cells, coinciding with immunohistochemical GXM detection in the white pulp of spleen. In particular, high production of IL-10 with diminution of IL-2, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha synthesis were detected 14 days after GXM administration. In situ cell death detection by TdT-mediated biotin-dUTP nick-end labelling (TUNEL) reaction in sections of spleen, lung and liver demonstrates apoptosis in tissues with deposits of GXM. These data demonstrate the in vivo ability of GXM to modify cytokine synthesis by Spm cells and to promote host cell apoptosis.
Insights
Glucuronoxylomannan (GXM), a Cryptococcus neoformans polysaccharide, suppresses immune cell proliferation and promotes apoptosis in rats. This study confirms these immune-modulating effects occur in vivo, impacting cytokine production and host cell death.
Area of Science:
- Immunology
- Mycology
- Pathogenesis
Background:
- Glucuronoxylomannan (GXM) is the primary capsular polysaccharide of Cryptococcus neoformans and a key virulence factor.
- Previous in vitro studies showed GXM suppresses lymphoproliferation, modulates cytokine production, and induces apoptosis in rat spleen mononuclear (Spm) cells.
Purpose of the Study:
- To investigate the in vivo effects of GXM on immune responses in normal Wistar rats.
- To determine if GXM's previously observed in vitro immunomodulatory effects manifest in a living organism.
Main Methods:
- Intracardiac inoculation of GXM into Wistar rats.
- Assessing Spm cell proliferative responses to concanavalin A (Con A) and heat-killed C. neoformans (HKCn).
- Measuring cytokine levels (IL-10, IL-2, IFN-gamma, TNF-alpha) and detecting GXM and apoptosis in spleen, lung, and liver tissues using immunohistochemistry and TUNEL assays.
Main Results:
- GXM administration suppressed Spm cell proliferation in response to Con A and HKCn within two weeks.
- Elevated interleukin-10 (IL-10) production by Con A-stimulated Spm cells was observed, alongside decreased IL-2, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) synthesis at 14 days.
- GXM deposits were detected in spleen, lung, and liver tissues, correlating with in situ evidence of host cell apoptosis via TUNEL staining.
Conclusions:
- GXM exhibits significant immunomodulatory effects in vivo, suppressing adaptive immune responses.
- GXM actively promotes host cell apoptosis in multiple organs where it is deposited.
- These findings highlight GXM's role as a potent virulence factor capable of subverting host immunity during Cryptococcus neoformans infections.
