Fig 1.
Schematic of type 2 immune responses to inhaled fungi.
Environmental fungi that enter the lungs are initially detected by airway epithelial cells. In response to fungi inputs, the airway epithelium produces a trio of innate type 2 cytokines (IL-33, TSLP, IL-25) that act on tissue resident lymphocytes such as ILC2s and TH2s to stimulate their expression of IL-4, IL-5, and IL-13. These lymphocyte-derived cytokines act on a variety of cell types to drive the physiological and pathophysiological outputs of allergic inflammation. Epithelial-derived cytokines such as TSLP also likely act in concert with fungal molecules on dendritic cells to initiate adaptive type 2 responses. Locally activated IRF4+ cDCs migrate to the draining lymph nodes where they active naïve CD4+ T cells to become IL-4-producing TFH cells that drive antibody IgE isotype switching. Created with Bio-render.
Fig 2.
Example mechanisms of fungal sensing by epithelial cells.
IL-33 release can be triggered by a variety of fungal inputs including proteases and chitin. While the exact mechanisms of input detection remain uncertain, type II pneumocytes have been identified as a dominant source of this cytokine. In response to fungal-derived damage, type II pneumocytes will activate necroptosis or ripoptosome signaling that results in secretion of the alarmin IL-33 (Left Panel). Another mechanism of damage sensing by epithelial cells involves direct recruitment of antigen-presenting cells in response to tissue disruption. In this model, the A. fumigatus-derived protease Alp1 cleaves tight junction proteins in pulmonary Club cells, resulting in TRPV4-dependent release of CCL2 in order to recruit monocyte-derived dendritic cells (Mo-DC) that are required for adaptive type 2 responses. Finally, while tuft cells are known to be activated by stimuli that are agonists for gustducin-coupled GPCRs, there are no known fungal derived molecules that directly trigger tuft cell activation. This is in contrast to models for tuft cell activation in response to intestinal protists, which is dependent on microbe succinate secretion. Created with Bio-render.
Fig 3.
Theoretical rationale underlying type 2 immune responses to fungi.
Fungi are very common drivers of allergic inflammation in mammals, which could be a result of misdirected anti-parasite responses or an evolutionarily selected response. While many studies show that type 2 immune responses are detrimental to the clearance of invasive fungal pathogens, the species that drive such infections have only recently become major sources of human infection due to the rise of HIV and increasing use of immunosuppressive drugs. One hypothesis is that type 2 responses were selected to occur in response to environmental fungi that act as inhaled irritants, but that cannot replicate at human body temperature. In this case, type 1 inflammation might pose the risk of excessive tissue damage; on the other hand, type 1 responses would be beneficial in the case of fungal that are capable of causing invasive disease. Type 2 cytokine-dependent upregulation of C-type lectin receptors such as Dectin-1 and mannose receptor in macrophages, and recruitment of innate type 2 immune cells such as eosinophils, may allow for “silent clearance” of inhaled fungi while limiting immunopathology. Created with Bio-render.