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

Tyler G Normile,Maurizio Del Poeta,Antonella Rella

doi:10.3389/fcimb.2021.739027

Tyler G Normile, Maurizio Del Poeta + Show 1 more

Open Access

https://doi.org/10.3389/fcimb.2021.739027

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Abstract

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.

Highlights

Given the rise in lymphopenia due to HIV/AIDS, solid organ transplant, chemotherapy (Li et al, 2019; Fierer, 2019; Pathakumari et al, 2020), and immunosuppressive therapies to control chronic diseases (Grebenciucova et al, 2016; Ward et al, 2016; Bryan et al, 2020), opportunistic invasive fungal infections have emerged as a global health concern, killing ~1.5 million people per year
Our previous work uncovered that deletion of the sterylglucosidase gene causes an accumulation of SGs in C. neoformans Dsgl1 cells (Rella et al, 2015)
We have shown that C. neoformans Dsgl1 elicits a robust, pro-inflammatory host response in the lungs that stimulates the clearance of the mutant leading to subsequent protection from a lethal WT challenge

Summary

Introduction

Given the rise in lymphopenia due to HIV/AIDS, solid organ transplant, chemotherapy (Li et al, 2019; Fierer, 2019; Pathakumari et al, 2020), and immunosuppressive therapies to control chronic diseases (Grebenciucova et al, 2016; Ward et al, 2016; Bryan et al, 2020), opportunistic invasive fungal infections have emerged as a global health concern, killing ~1.5 million people per year Among these opportunistic fungal infections, cryptococcosis is caused by Cryptococcus neoformans and Cryptococcus gattii (Chang and Chen, 2015; Diaz, 2020; Montoya et al, 2021), resulting in ~220,000 new cases and ~180,000 deaths annually (Rajasingham et al, 2017; Mayer and Kronstad, 2020). Despite extensive vaccine development research, no fungal vaccines are currently available for clinical use

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