Host-Pathogen Interactions in Fungal Pathogenesis

Fungal pathogens exploit a series of finely tuned interactions to invade and persist within their hosts. Initial adhesion to epithelial or endothelial surfaces is mediated by fungal adhesins and the formation of biofilms, which confer protection against immune clearance and pharmacological treatment. Morphological transitions—most notably yeast-to-hypha switching in Candida species—facilitate tissue penetration and escape from phagocytic cells. Host recognition relies on pattern recognition receptors such as dectin-1 and Toll-like receptors, which detect conserved fungal cell-wall components including β-glucan and mannans. Upon engagement, these receptors trigger signalling cascades that mobilise neutrophils, macrophages and complement factors to contain infection. Fungi counter these defences through masking of immunogenic epitopes, secretion of immunomodulatory proteins and alteration of the phagosomal environment, sometimes inducing endoplasmic reticulum stress in immune cells and driving maladaptive inflammation. The balance between protective immunity and immunopathology is further shaped by cytokine milieu, with molecules such as interleukin-1 receptor antagonist and interferon-gamma dictating the efficacy of neutrophil and macrophage responses. Advances in transcriptomics and in vivo imaging have begun to unravel how specific host pathways modulate fungal dissemination, emphasising the need for therapies that restore immune homeostasis while targeting key fungal virulence determinants.

Research from Nature Portfolio

Recent studies have revealed that disruption of tyrosine kinase 2 signalling enhances cutaneous defence against Candida albicans. Mice lacking TYK2 exhibit reduced fungal spread and more rapid wound closure, underpinned by the formation of necrotic neutrophil barriers around invading yeast. Transcriptomic profiling demonstrated that TYK2 controls interferon-inducible gene networks in neutrophils, while TYK2-dependent interferon-gamma promotes fungal dissemination from skin to kidneys. These findings uncover a paradoxical role for TYK2 in impairing cutaneous antifungal immunity and suggest that selective modulation of this pathway could bolster barrier defences against fungal invasion.

Research from all publishers

Investigations into macrophage-secreted interleukin-1 receptor antagonist (IL-1Ra) have shown that two distinct waves of IL-1Ra release during systemic Candida albicans infection impede neutrophil recruitment and function. Neutralisation of IL-1Ra restores neutrophil competence and resolves otherwise lethal candidiasis, identifying IL-1Ra as both a biomarker and therapeutic target. Separately, studies of inflammatory endoplasmic reticulum stress responses in myeloid cells have revealed that hyperactivation of the IRE1α pathway drives fatal kidney immunopathology in disseminated candidiasis. Inhibition of IRE1α attenuates proinflammatory cytokine production and prolongs survival, highlighting ER stress signalling as a potential adjunct to antifungal therapy. On the pathogen side, sequence variation within the secreted aspartyl protease Sap2 has been shown to enhance complement evasion by degrading C3b and promote switching of macrophages to an M2-like, immunosuppressive phenotype, thereby facilitating fungal persistence and dissemination.

Host-Pathogen Interactions in Fungal Pathogenesis publication trend

The graph below shows the total number of articles in host-pathogen interactions in fungal pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Neutrophil: A phagocytic white blood cell that provides rapid response to fungal invasion.

Interleukin-1 receptor antagonist (IL-1Ra): A cytokine that blocks IL-1 signalling, modulating inflammatory responses.

Tyrosine kinase 2 (TYK2): A signalling enzyme involved in cytokine receptor pathways affecting immune cell activation.

Dectin-1: A C-type lectin receptor that recognises β-glucan on fungal cell walls to trigger innate immunity.

Endoplasmic reticulum (ER) stress: A condition of protein‐folding imbalance that activates adaptive signalling in host cells.

M2-like macrophages: A macrophage phenotype associated with anti‐inflammatory and tissue‐repair functions.

Complement C3b: An activated complement fragment that opsonises pathogens for phagocytic clearance.

References

1. Targeted removal of macrophage-secreted interleukin-1 receptor antagonist protects against lethal Candida albicans sepsis. Immunity (2023).
2. Lack of TYK2 signaling enhances host resistance to Candida albicans skin infection. Nature Communications (2024).
3. Sequence Variation of Candida albicans Sap2 Enhances Fungal Pathogenicity via Complement Evasion and Macrophage M2‐Like Phenotype Induction. Advanced Science (2023).
4. Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis. Journal of Clinical Investigation (2023).