Natural killer cells are pivotal for in vivo protection following systemic infection by Sporothrix schenckii

Abstract

Natural killer (NK) cells are one of the first cell types to enter inflammation sites and have been historically known as key effector cells against tumours and viruses; now, accumulating evidence shows that NK cells are also capable of direct in vitro activity and play a protective role against clinically important fungi in vivo. However, our understanding of NK cell development, maturation and activation in the setting of fungal infections is preliminary at best. Sporotrichosis is an emerging worldwide-distributed subcutaneous mycosis endemic in many countries, affecting humans and other animals and caused by various related thermodimorphic Sporothrix species, whose prototypical member is Sporothrix schenckii. We show that following systemic infection of BALB/c mice with S. schenckii sensu stricto, NK cells displayed a more mature phenotype as early as 5 days post-infection as judged by CD11b/CD27 expression. At 10 days post-infection, NK cells had increased expression of CD62 ligand (CD62L) and killer cell lectin-like receptor subfamily G member 1 (KLRG1), but not of CD25 or CD69. Depletion of NK cells with anti-asialo GM1 drastically impaired fungal clearance, leading to a more than eightfold increase in splenic fungal load accompanied by heightened systemic inflammation, as shown by augmented production of the pro-inflammatory cytokines tumour necrosis factor-α, interferon-γ and interleukin-6, but not interleukin-17A, in the spleen and serum. Our study is, to the best of our knowledge, the first to demonstrate that a fungal infection can drive NK cell maturation in vivo and that such cells are pivotal for in vivo protection against S. schenckii.

Investigation of Obesity-Alleviation Effect of Eurycoma longifolia on Mice Fed with a High-Fat Diet through Metabolomics Revealed Enhanced Decomposition and Inhibition of Accumulation of Lipids

“…The introduction of metabolomics technology could effectively facilitate an "information-rich" analytical process toward E. longifolia-based omics studies. BALB/c mice, a classic in vivo model for investigating the biological interaction and molecular mechanisms, 16 was chosen as the biological object. Metabolomics analysis was performed on a platform integrating LC-MS/MS with bioinformatics.…”

Microbial killing by NK cells

“…In vivo, perforin knockout mice displayed increased mortality and fungal burden in response to Histoplasma capsulatum infection, and NK cells exhibit natural and Ab‐dependent cell mediated cytotoxicity (ADCC) against Histoplasma . Optimal host defense to H. capsulatum, A. fumigatus , and Sporothrix schenckii in mouse models has been attributed to NK cells, and it has been reported that NK cells are active against Pneumocystis . NK cells make use of various components of cellular cytotoxicity in unique ways as described in the sections below, which may inform alternate routes of tumor killing as well as providing information about microbial host defense.…”

Sporothrix schenckii regulates macrophage inflammatory responses via the c‐JUN‐induced Dab2 transcription

“…35 However, when the splenic fungal load is increased and accompanied with heightened systemic inflammation, the proinflammatory cytokines Tnfα and Il-6 show an increase in production. 36 Activities of these cytokines may differ as a function of their presence within specific tissues; however, the question regarding the "decision" between responses that promote the survival and antifungal roles of macrophages versus responses that ultimately lead to cell death made remains elusive. Therefore, the roles played by inflammatory factors at different stages during fungal infections of organisms represents an important issue to be addressed in subsequent studies.…”

“…It has been reported that mast cells can be directly activated by inducing de novo synthesis of the inflammatory mediators, Tnf‐α and Il‐6 35 . However, when the splenic fungal load is increased and accompanied with heightened systemic inflammation, the proinflammatory cytokines Tnf‐α and Il‐6 show an increase in production 36 . Activities of these cytokines may differ as a function of their presence within specific tissues; however, the question regarding the “decision” between responses that promote the survival and antifungal roles of macrophages versus responses that ultimately lead to cell death made remains elusive.…”