Mold, Mycotoxins and a Dysregulated Immune System: A Combination of Concern?

Abstract

Fungi represent one of the most diverse and abundant eukaryotes on earth. The interplay between mold exposure and the host immune system is still not fully elucidated. Literature research focusing on up-to-date publications is providing a heterogenous picture of evidence and opinions regarding the role of mold and mycotoxins in the development of immune diseases. While the induction of allergic immune responses by molds is generally acknowledged, other direct health effects like the toxic mold syndrome are controversially discussed. However, recent observations indicate a particular importance of mold/mycotoxin exposure in individuals with pre-existing dysregulation of the immune system, due to exacerbation of underlying pathophysiology including allergic and non-allergic chronic inflammatory diseases, autoimmune disorders, and even human immunodeficiency virus (HIV) disease progression. In this review, we focus on the impact of mycotoxins regarding their impact on disease progression in pre-existing immune dysregulation. This is complemented by experimental in vivo and in vitro findings to present cellular and molecular modes of action. Furthermore, we discuss hypothetical mechanisms of action, where evidence is missing since much remains to be discovered.

Keywords: dysfunctional immune system; immune response; immune system disorders; molds; mycotoxins.

Figure 1

Overview of mechanisms underlying the exacerbating effects of mycotoxin exposure under a dysregulated immune system. (a) Mycotoxins in the pathogenesis of MS: exposure to GTX alters the blood brain barrier [98]. Mycotoxins affect neural tissue by damaging astrocytes, oligodendrocytes, and microglia. Loss of oligodendrocytes leads to further demyelination while targeted astrocytes release proinflammatory cytokines contributing to the neuroinflammatory environment. Another direct effect of mycotoxins is the induction of proinflammatory gene expression in the CNS. Indirect pathways via proinflammatory cytokines like IL-1$$\beta$$ are hypothesized to interact with microglia through an augmented kynurenine/tryptophan ratio, which promotes the secretion of neurotoxic metabolites. (b) Mycotoxins in asthmatic conditions: exposure to mycotoxins worsens the respiratory epithelium barrier impairment. Dendritic cells take up mycotoxins leading to a decreased production of IL-12 and an increased ROS production as well as overactivation of the inflammasome. IL-12 reduction further emphasizes the Th1/Th2 imbalance contributing to the increased airway inflammation in asthmatic mouse model (c) Potential modes of action between mycotoxin exposure and HIV replication: exposure to mycotoxins modulates immune response via induction of ROS. ROS inhibits oxidative defense machinery via Nrf2 retention and induces proinflammatory response via NF-κB induction. Both, mycotoxin related oxidative stress and proinflammatory signals could potentially contribute to an increased HIV burden and disease progression. Figure 1a adapted from “Allergic airway sensitization”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates; Figure 1b adapted from “Pathogenesis of Multiple Sclerosis”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.