Muniz VS, Silva JC, Braga YAV, Melo RCN, Ueki S, Takeda M, Hebisawa A, Asano K, Figueiredo RT, Neves JS. Eosinophils release extracellular DNA traps in response to Aspergillus fumigatus. J Allergy Clin Immunol. 2018 Feb;141(2):571-585.e7. 

DOI: 10.1016/j.jaci.2017.07.048

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Eosinophils mediate the immune response in different infectious conditions. The release of extracellular DNA traps (ETs) by leukocytes has been described as an innate immune response mechanism that is relevant in many disorders including fungal diseases. Different stimuli induce the release of human eosinophil ETs (EETs). Aspergillus fumigatus is an opportunistic fungus that may cause eosinophilic allergic bronchopulmonary aspergillosis (ABPA). It has been reported that eosinophils are important to the clearance of A fumigatus in infected mice lungs. However, the immunological mechanisms that underlie the molecular interactions between A fumigatus and eosinophils are poorly understood.

Banerjee I, Behl B, Mendonca M, Shrivastava G, Russo AJ, Menoret A, Ghosh A, Vella AT, Vanaja SK, Sarkar SN, Fitzgerald KA, Rathinam VAK. Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis. Immunity. 2018 Sep 18;49(3):413-426.e5.

DOI: 10.1016/j.immuni.2018.07.006

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Inflammasome complexes trigger the enzymatic activity of caspase-1, which activates interleukin-1β (IL-1β) and IL-18 (Martinon et al., 2002). Caspase-1 also targets gasdermin D, a pore-forming protein (Kayagaki et al., 2015, Shi et al., 2015). The pore-forming activity of gasdermin D resides in its N-terminal domain and is inhibited by its C-terminal domain. Caspase-1 cleaves gasdermin D at the linker region between these two domains, liberating the N-terminal domain, which migrates to the plasma membrane-forming pores with an inner diameter of 10–15 nm (Aglietti et al., 2016, Ding et al., 2016, Liu et al., 2016, Sborgi et al., 2016). An important consequence of gasdermin D activation is a lytic form of cell death called pyroptosis (He et al., 2015, Kayagaki et al., 2015, Shi et al., 2015). However, new evidence points out that gasdermin D executes additional functions independent of cell death; gasdermin D pores mediate the release of IL-1β and IL-18 without inducing cell death in response to certain ligands (Evavold et al., 2018). Additionally, after cytosolic LPS sensing by caspase-11, gasdermin D activates the NLRP3 inflammasome by inducing potassium (K+) efflux (Kayagaki et al., 2015, Rühl and Broz, 2015, Schmid-Burgk et al., 2015). Central to these distinct functions of gasdermin D is its membrane pore-forming activity. However, whether gasdermin D executes any additional immune functions is largely unknown.
A key surveillance mechanism in the cytosol, in addition to inflammasomes, is the cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) pathway. cGAS is a sensor for cytosolic DNA, and the binding of DNA by cGAS triggers its nucleotidyl transferase activity leading to the synthesis of cGAMP from ATP and GTP. cGAMP stimulates the transcription of type I interferon genes via the STING adaptor-TBK1 kinase-IRF3 transcription factor axis (Burdette et al., 2011, Wu et al., 2013). The type I interferon response elicited by cGAS plays important roles in host defense (Schneider et al., 2014). However, it is increasingly appreciated that the sustained production of type I interferons at high amounts is detrimental to the host, particularly during infections with intracellular bacteria such as Francisella novicida, Mycobacterium tuberculosis, and Listeria monocytogenes (Auerbuch et al., 2004, Henry et al., 2010, Mayer-Barber et al., 2014, McNab et al., 2015, Storek et al., 2015). Therefore, the magnitude and duration of cGAS-driven type I interferon responses should be kept in check. However, how the host restrains cGAS signaling during infections is poorly defined.
Here, we demonstrate that gasdermin D activated by the Aim2 inflammasome complex suppresses cytosolic DNA-induced production of type I interferons in macrophages. Consistent with this finding, mice lacking gasdermin D displayed enhanced IFN-β response to F. novicida infection. Pyroptosis and the extracellular release of IL-1 cytokines are dispensable for the inhibition of IFN-β by gasdermin D. Mechanistically, gasdermin D-induced membrane pores leaked intracellular potassium (K+) ions, and this K+ efflux in turn impaired type I interferon responses to cytosolic DNA and F. novicida. Gasdermin D-K+ efflux axis targeted cGAS to reduce cGAMP synthesis and thus IFN-β production. In summary, this study uncovers a previously unrecognized key role for gasdermin D in restraining cytosolic DNA-elicited interferon responses. Collectively, an emerging theme from the findings of this work and the recent studies (Evavold et al., 2018, Kayagaki et al., 2015) is that the fundamental pore-forming ability of gasdermin D and the consequent ionic fluxes confer gasdermin D additional biological functions independent of the terminal cell lytic event.

Gonçalves DS, Ferreira MDS, Liedke SC, Gomes KX, de Oliveira GA, Leão PEL, Cesar GV, Seabra SH, Cortines JR, Casadevall A, Nimrichter L, Domont GB, Junqueira MR, Peralta JM, Guimaraes AJ. Extracellular vesicles and vesicle-free secretome of the protozoa Acanthamoeba castellanii under homeostasis and nutritional stress and their damaging potential to host cells. Virulence. 2018 Dec 31;9(1):818-836.

DOI: 10.1080/21505594.2018.1451184

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Acanthamoeba castellanii (Ac) are ubiquitously distributed in nature, and by contaminating medical devices such as heart valves and contact lenses, they cause a broad range of clinical presentations to humans. Although several molecules have been described to play a role in Ac pathogenesis, including parasite host-tissue invasion and escaping of host-defense, little information is available on their mechanisms of secretion. Herein, we describe the molecular components secreted by Ac, under different protein availability conditions to simulate host niches. Ac extracellular vesicles (EVs) were morphologically and biochemically characterized. Dynamic light scattering analysis of Ac EVs identified polydisperse populations, which correlated to electron microscopy measurements. High-performance thin liquid chromatography of Ac EVs identified phospholipids, steryl-esters, sterol and free-fatty acid, the last two also characterized by GC-MS. Secretome composition (EVs and EVs-free supernatants) was also determined and proteins biological functions classified. In peptone-yeast-glucose (PYG) medium, a total of 179 proteins were identified (21 common proteins, 89 exclusive of EVs and 69 in EVs-free supernatant). In glucose alone, 205 proteins were identified (134 in EVs, 14 common and 57 proteins in EVs-free supernatant). From those, stress response, oxidative and protein and amino acid metabolism proteins prevailed. Qualitative differences were observed on carbohydrate metabolism enzymes from Krebs cycle and pentose phosphate shunt. Serine proteases and metalloproteinases predominated. Analysis of the cytotoxicity of Ac EVs (upon uptake) and EVs-free supernatant to epithelial and glioblastoma cells revealed a dose-dependent effect. Therefore, the Ac secretome differs depending on nutrient conditions, and is also likely to vary during infection.

Vasconcellos LR, Siqueira MS, Moraes R, Carneiro LA, Bozza MT, Travassos LH. Heme Oxygenase-1 and Autophagy Linked for Cytoprotection. Curr Pharm Des. 2018;24(20):2311-2316. 

DOI: 10.2174/1381612824666180727100909

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Heme-oxygenase (HO) catalyzes the main enzymatic step of heme degradation and generates anti-inflammatory end products with protective roles in physiological and pathological situations. The importance of HO in pathological conditions is evidenced by its pharmacological inhibition or genetic blockage in different models of stress such as infection, inflammation and oxidative stress. Under these situations, another well-known protective process triggered is autophagy. Autophagy is a homeostatic process that eliminates defective cytosolic components and organelles, allowing cells and tissues to recover through recycling of functional blocks for anabolic reactions. Recently, studies have demonstrated a link between HO activity and autophagy activation.