Cell wall mannan of Candida krusei mediates dendritic cell apoptosis and orchestrates Th17 polarization via TLR-2/MyD88-dependent pathway

Thu Ngoc Yen Nguyen,Rangsini Mahanonda,Noppadol Sa-Ard-Iam,Oranart Matangkasombut,Panachai Wongsrisupphakul,Panuwat Padungros,Patcharee Ritprajak,Min-Kyung Choo

doi:10.1038/s41598-018-35101-3

Abstract

Dendritic cells (DCs) abundantly express diverse receptors to recognize mannans in the outer surface of Candida cell wall, and these interactions dictate the host immune responses that determine disease outcomes. C. krusei prevalence in candidiasis worldwide has increased since this pathogen has developed multidrug resistance. However, little is known how the immune system responds to C. krusei. Particularly, the molecular mechanisms of the interplay between C. krusei mannan and DCs remain to be elucidated. We investigated how C. krusei mannan affected DC responses in comparison to C. albicans, C. tropicalis and C. glabrata mannan. Our results showed that only C. krusei mannan induced massive cytokine responses in DCs, and led to apoptosis. Although C. krusei mannan-activated DCs underwent apoptosis, they were still capable of initiating Th17 response. C. krusei mannan-mediated DC apoptosis was obligated to the TLR2 and MyD88 pathway. These pathways also controlled Th1/Th17 switching possibly by virtue of the production of the polarizing cytokines IL-12 and IL-6 by the C. krusei mannan activated-DCs. Our study suggests that TLR2 and MyD88 pathway in DCs are dominant for C. krusei mannan recognition, which differs from the previous reports showing a crucial role of C-type lectin receptors in Candida mannan sensing.

Highlights

Candida species are the most common cause of opportunistic fungal infections in immunocompromised individuals, leading to illnesses ranging from non-life-threatening mucocutaneous lesions to systemically invasive infections
BMDCs stimulated with C. albicans and C. tropicalis mannans did not undergo maturation compared to the negative control, whereas those stimulated with C. krusei and C. glabrata mannans were potently activated
We investigated the molecular mechanisms underlying the induction of Dendritic cells (DCs) and T-cell immunity in response to C. krusei cell wall mannan

Summary

Introduction

Candida species are the most common cause of opportunistic fungal infections in immunocompromised individuals, leading to illnesses ranging from non-life-threatening mucocutaneous lesions to systemically invasive infections. The prevalence of C. krusei has increased since it became a multidrug-resistant pathogen because of its intrinsic fluconazole resistance and decreased susceptibility to flucytosine, amphotericin B and echinocandins[2,5,10,11,12,13]. The interactions of Candida mannans with several CLRs expressed on DCs induce Syk activation, which mediates innate resistance to systemic fungal infection and orchestrates the Th17 response[19,29,30]. Some mannose residues mediates signal transduction via the TLR/MyD88–dependent pathway, and participates in host defense against C. albicans infection[31,32,33]

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