Abstract
Cryptococcus neoformans is an encapsulated yeast that causes disease mainly in immunosuppressed hosts. It is considered a facultative intracellular pathogen because of its capacity to survive and replicate inside phagocytes, especially macrophages. This ability is heavily dependent on various virulence factors, particularly the glucuronoxylomannan (GXM) component of the polysaccharide capsule. Inflammasome activation in phagocytes is usually protective against fungal infections, including cryptococcosis. Nevertheless, recognition of C. neoformans by inflammasome receptors requires specific changes in morphology or the opsonization of the yeast, impairing proper inflammasome function. In this context, we analyzed the impact of molecules secreted by C. neoformans B3501 strain and its acapsular mutant Δcap67 in inflammasome activation in an in vitro model. Our results showed that conditioned media derived from B3501 was capable of inhibiting inflammasome-dependent events (i.e., IL-1β secretion and LDH release via pyroptosis) more strongly than conditioned media from Δcap67, regardless of GXM presence. We also demonstrated that macrophages treated with conditioned media were less responsive against infection with the virulent strain H99, exhibiting lower rates of phagocytosis, increased fungal burdens, and enhanced vomocytosis. Moreover, we showed that the aromatic metabolite DL-Indole-3-lactic acid (ILA) and DL-p-Hydroxyphenyllactic acid (HPLA) were present in B3501's conditioned media and that ILA alone or with HPLA is involved in the regulation of inflammasome activation by C. neoformans. These results were confirmed by in vivo experiments, where exposure to conditioned media led to higher fungal burdens in Acanthamoeba castellanii culture as well as in higher fungal loads in the lungs of infected mice. Overall, the results presented show that conditioned media from a wild-type strain can inhibit a vital recognition pathway and subsequent fungicidal functions of macrophages, contributing to fungal survival in vitro and in vivo and suggesting that secretion of aromatic metabolites, such as ILA, during cryptococcal infections fundamentally impacts pathogenesis.
Highlights
Cryptococcus neoformans is a fungal pathogen that primarily affects immunocompromised patients with acquired immunodeficiency syndrome (AIDS) [1]
Since many of the virulence factors presented by C. neoformans are secreted [10, 15], we evaluated whether components released by the fungus (CM) were able to inhibit inflammasome canonical activation
The reduction in IL-1β observed with CMCAP and MM is likely explained by the presence of glycine (Figure 2(a))
Summary
Cryptococcus neoformans is a fungal pathogen that primarily affects immunocompromised patients with acquired immunodeficiency syndrome (AIDS) [1]. The ability of C. neoformans to remain viable and survive inside the host is dependent on its many virulence factors, which allow the fungus to modulate and evade the immune response [10, 11]. Glucuronoxylomannan (GXM) is the most prevalent of these capsular polysaccharides, facilitating C. neoformans resistance against phagocytosis and suppressing various immune responses [19,20,21,22,23,24,25,26] These virulence factors enable this fungus to effectively survive and thrive as a facultative intracellular pathogen, within macrophages [27,28,29,30,31,32,33]. Phagocytic cells that are unable to kill intracellular yeast cells can return fungal cells to the extracellular environment, either through nonlytic exocytosis called vomocytosis [35,36,37,38] or a rapid, highly inflammatory and inflammasome-dependent cell death referred to as pyroptosis [39,40,41]
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