Innate and Adaptive Immunity to Mucorales

Abstract

Mucormycosis is an invasive fungal infection characterised by rapid filamentous growth, which leads to angioinvasion, thrombosis, and tissue necrosis. The high mortality rates (50–100%) associated with mucormycosis are reflective of not only the aggressive nature of the infection and the poor therapeutics currently employed, but also the failure of the human immune system to successfully clear the infection. Immune effector interaction with Mucorales is influenced by the developmental stage of the mucormycete spore. In a healthy immune environment, resting spores are resistant to phagocytic killing. Contrarily, swollen spores and hyphae are susceptible to damage and degradation by macrophages and neutrophils. Under the effects of immune suppression, the recruitment and efficacy of macrophage and neutrophil activity against mucormycetes is considerably reduced. Following penetration of the endothelial lining, Mucorales encounter platelets. Platelets adhere to both mucormycete spores and hyphae, and exhibit germination suppression and hyphal damage capacity in vitro. Dendritic cells are activated in response to Mucorales hyphae only, and induce adaptive immunity. It is crucial to further knowledge regarding our immune system’s failure to eradicate resting spores under intact immunity and inhibit fungal growth under immunocompromised conditions, in order to understand mucormycosis pathogenicity and enhance therapeutic strategies for mucormycosis.

Comparative Analysis of Inflammatory Cytokine Release and Alveolar Epithelial Barrier Invasion in a Transwell® Bilayer Model of Mucormycosis

“…By contrast, destructive invasive growth and rapid induction of cell damage are hallmarks of mucormycosis (Ibrahim et al, 2005; Filler and Sheppard, 2006). Though the pathogens’ ability to produce an array of cytotoxic metabolites and lytic enzymes is well established (Binder et al, 2014; Ghuman and Voelz, 2017), our data did not reveal a prominent contribution of soluble mediators to epithelial cytolysis, suggesting that rapid mycelial growth of Mucorales, combined with an early and strong pro-inflammatory response by mononuclear cells, result in more pronounced epithelial cell damage and trans -epithelial movement of macromolecules.…”

Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets

“…Interestingly, all tested Mucorales species were unable to secrete GAG, and their culture SN did not induce activation of platelets or complement activation on the platelet surface. This is surprising, since angioinvasion and thrombosis are typical hallmarks of invasive mucormycosis, as reviewed elsewhere ( 45 ). Our results, however, indicate that the mechanism of Mucorales-induced thrombosis does not involve a pro-thrombotic activity of a secreted compound.…”

Understanding Mucormycoses in the Age of “omics”

“…Generally, mucormycoses will spread widely and cause extensive tissue damage by the time infection is diagnosed (Puebla, 2012;Katragkou et al, 2014). Mucorales establish infection in immunocompromised individuals with predisposing risk factors including uncontrolled diabetes resulting in hyperglycemia and ketoacidosis (DKA), chemotherapy, hematological disease, organ transplantation, elevated blood iron, deferoxamine or corticosteroid therapy, among others (Ghuman and Voelz, 2017). Mucorales can also cause lethal infections in a broader and more heterogeneous population than other opportunistic molds including injection drug users, patients receiving prolonged antifungal treatment lacking activity against Mucorales (i.e., Voriconazole), and those exposed to recent hospital construction (Michael et al, 2006;Rammaert et al, 2012;Lewis et al, 2012;Bernal-Martinez et al, 2013).…”