Steryl Glycosides in Fungal Pathogenesis: An Understudied Immunomodulatory Adjuvant

Normile, Tyler G.; McEvoy, Kyle; Poeta, Maurizio Del

doi:10.3390/jof6010025

Cited by 16 publications

(8 citation statements)

References 97 publications

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“…Our lab has previously engineered a mutant strain of C. neoformans (Δ sgl1 ) that accumulates large amounts of sterylglucosides (SGs) and provided the first evidence on the key role of sterylglucosidase 1 (Sgl1) on fungal virulence ( 45 ). SGs have been previously shown to possess immunological functions [reviewed in ( 46 )]. The use of the plant SG, β-sitosterol, increased T cell proliferation and Th1 polarization ( 47 , 48 ), significantly prolonged survival of mice infected with Candida albicans ( 49 , 50 ), and promoted the recovery of patients with pulmonary tuberculosis in combination with regular anti-tuberculosis treatment ( 48 ).…”

Section: Introductionmentioning

confidence: 99%

Three Models of Vaccination Strategies Against Cryptococcosis in Immunocompromised Hosts Using Heat-Killed Cryptococcus neoformans Δsgl1

Normile

Poeta

2022

Front. Immunol.

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Vaccines are one of the greatest medical accomplishments to date, yet no fungal vaccines are currently available in humans mainly because opportunistic mycoses generally occur during immunodeficiencies necessary for vaccine protection. In previous studies, a live, attenuated Cryptococcus neoformans Δsgl1 mutant accumulating sterylglucosides was found to be avirulent and protected mice from a subsequent lethal infection even in absence of CD4+ T cells, a condition most associated with cryptococcosis (e.g., HIV). Here, we tested three strategies of vaccination against cryptococcosis. First, in our preventative model, protection was achieved even after a 3-fold increase of the vaccination window. Second, because live C. neoformans Δsgl1-vaccinated mice challenged more than once with WT strain had a significant decrease in lung fungal burden, we tested C. neoformans Δsgl1 as an immunotherapeutic. We found that therapeutic administrations of HK C. neoformans Δsgl1 post WT challenge significantly improves the lung fungal burden. Similarly, therapeutic administration of HK C. neoformans Δsgl1 post WT challenge resulted in 100% or 70% survival depending on the time of vaccine administration, suggesting that HK Δsgl1 is a robust immunotherapeutic option. Third, we investigated a novel model of vaccination in preventing reactivation from lung granuloma using C. neoformans Δgcs1. Remarkably, we show that administration of HK Δsgl1 prevents mice from reactivating Δgcs1 upon inducing immunosuppression with corticosteroids or by depleting CD4+ T cells. Our results suggest that HK Δsgl1 represents a clinically relevant, efficacious vaccine that confers robust host protection in three models of vaccination against cryptococcosis even during CD4-deficiency.

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Section: Introductionmentioning

confidence: 99%

Three Models of Vaccination Strategies Against Cryptococcosis in Immunocompromised Hosts Using Heat-Killed Cryptococcus neoformans Δsgl1

Normile

Poeta

2022

Front. Immunol.

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“…SGs are known immunomodulatory glycolipids that have been used in a wide variety of therapeutic applications [reviewed in ( Grille et al., 2010 ; Normile et al., 2020b )]. They have been shown to be promising immunoadjuvants for protection against pulmonary tuberculosis in human clinical trials ( Donald et al., 1994 ), enhancement of human T cell differentiation in vivo ( Bouic et al., 1996 ), and protection against mouse models of invasive candidiasis ( Lee and Han, 2006 ; Lee et al., 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

Normile

Rella

Poeta

2021

Front. Cell. Infect. Microbiol.

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Cryptococcus neoformans is a fungal pathogen causing life-threatening meningoencephalitis in susceptible individuals. Fungal vaccine development has been hampered by the fact that cryptococcosis occurs during immunodeficiency. We previously reported that a C. neoformans mutant (Δsgl1) accumulating sterylglucosides (SGs) is avirulent and provides complete protection to WT challenge, even under CD4+ T cell depletion, an immunodeficient condition commonly associated with cryptococcosis. We found high levels of SGs in the lungs post-immunization with Δsgl1 that decreased upon fungal clearance. Th1 cytokines increased whereas Th2 cytokines concurrently decreased, coinciding with a large recruitment of leukocytes to the lungs. Depletion of B or CD8+ T cells did not affect either Δsgl1 clearance or protection from WT challenge. Although CD4+ T cell depletion affected clearance, mice were still protected indicating that clearance of the mutant was not necessary for host protection. Protection was lost only when both CD4+ and CD8+ T cells were depleted, highlighting a previously unexplored role of fungal-derived SGs as an immunoadjuvant for host protection against cryptococcosis.

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“…Sterylglycosidase-deleted EVs may be a potent tool for vaccination strategies against fungal infection. Recent studies on the vaccination strategies against fungus infection using fungal SGs as an adjuvant are reviewed [ 113 ].…”

Section: Biological Functions Of Steryl Glycosides In Mammalsmentioning

confidence: 99%

Structure, metabolism and biological functions of steryl glycosides in mammals

Shimamura

2020

Biochemical Journal

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Steryl glycosides (SGs) are sterols glycosylated at their 3β-hydroxy group. They are widely distributed in plants, algae, and fungi, but are relatively rare in bacteria and animals. Glycosylation of sterols, resulting in important components of the cell membrane SGs, alters their biophysical properties and confers resistance against stress by freezing or heat shock to cells. Besides, many biological functions in animals have been suggested from the observations of SG administration. Recently, cholesteryl glucosides synthesized via the transglycosidation by glucocerebrosidases (GBAs) were found in the central nervous system of animals. Identification of patients with congenital mutations in GBA genes or availability of respective animal models will enable investigation of the function of such endogenously synthesized cholesteryl glycosides by genetic approaches. In addition, mechanisms of the host immune responses against pathogenic bacterial SGs have partially been resolved. This review is focused on the biological functions of SGs in mammals taking into consideration their therapeutic applications in the future.

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Steryl Glycosides in Fungal Pathogenesis: An Understudied Immunomodulatory Adjuvant

Cited by 16 publications

References 97 publications

Three Models of Vaccination Strategies Against Cryptococcosis in Immunocompromised Hosts Using Heat-Killed Cryptococcus neoformans Δsgl1

Three Models of Vaccination Strategies Against Cryptococcosis in Immunocompromised Hosts Using Heat-Killed Cryptococcus neoformans Δsgl1

Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

Structure, metabolism and biological functions of steryl glycosides in mammals

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