Modulatory immune responses in fungal infection associated with organ transplant - advancements, management, and challenges

Abstract

Organ transplantation stands as a pivotal achievement in modern medicine, offering hope to individuals with end-stage organ diseases. Advancements in immunology led to improved organ transplant survival through the development of immunosuppressants, but this heightened susceptibility to fungal infections with nonspecific symptoms in recipients. This review aims to establish an intricate balance between immune responses and fungal infections in organ transplant recipients. It explores the fundamental immune mechanisms, recent advances in immune response dynamics, and strategies for immune modulation, encompassing responses to fungal infections, immunomodulatory approaches, diagnostics, treatment challenges, and management. Early diagnosis of fungal infections in transplant patients is emphasized with the understanding that innate immune responses could potentially reduce immunosuppression and promise efficient and safe immuno-modulating treatments. Advances in fungal research and genetic influences on immune-fungal interactions are underscored, as well as the potential of single-cell technologies integrated with machine learning for biomarker discovery. This review provides a snapshot of the complex interplay between immune responses and fungal infections in organ transplantation and underscores key research directions.

Keywords: challenge; fungal infections; immune response; management - healthcare; organ transplantation.

Figure 1

Signaling cascades activated in innate cells upon recognizing fungal components. Fungal PAMPs lead to the signaling of TLRs via MyD88, which orchestrates the activation of NFKβ and MAPKs, resulting in antifungal action. CLRs (dectin-1, DC-SIGN, Mincle) via Syk activate the calcineurin-NFAT signaling cascade and ROS (reactive oxygen species) production. Furthermore, it leads to inflammasome activation, which promotes maturating of caspase 1. Caspase 1 induces the generation of active forms of cytokines IL-1β and IL-18, which are then released.

Figure 2

General mechanism of trained immunity. Stimulations of different cells, i.e., monocytes in blood or hematopoietic cells and myeloid progenitor cells (central), lead to the development of trained immunity. Upon induction of receptor signal by myeloid cells, signally pathway AKT/mTOR/HIFα leads to glycolysis. Pyruvate, a metabolic intermediate, enters the tricarboxylic acid cycle, resulting in several metabolites that modulate histone acetylation and methylation, resulting in the activation of genes governing inflammatory cytokines.

Figure 3

Immunotherapies to target and prevent fungal infection. In adoptive T cell transfer, initial antigen-specific T cells are stimulated with fungal extracts. Sorting of stimulated T cells via specific markers (e.g., CD154/CD137) is followed by further stimulation and clonal expansion of the fungus-specific T cell population. Chimeric antigen receptors are produced containing the domains identified by target antigens (e.g., dectin-1 recognizes fungal β-glucans), whereby upon attachment of these receptors to T cells, these fungus-specific antibodies are expanded. Administration of cytokines can provide the optimal repertoire of immune cells to counter fungal infection