Immunity and tolerance to fungi in hematopoietic transplantation: principles and perspectives

Abstract

Resistance and tolerance are two complementary host defense mechanisms that increase fitness in response to low-virulence fungi. Resistance is meant to reduce pathogen burden during infection through innate and adaptive immune mechanisms, whereas tolerance mitigates the substantial cost of resistance to host fitness through a multitude of anti-inflammatory mechanisms, including immunological tolerance. In experimental fungal infections, both defense mechanisms are activated through the delicate equilibrium between Th1/Th17 cells, which provide antifungal resistance, and regulatory T cells limiting the consequences of the ensuing inflammatory pathology. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme in the tryptophan catabolism, plays a key role in induction of tolerance against fungi. Both hematopoietic and non-hematopoietic compartments contribute to the resistance/tolerance balance against Aspergillus fumigatus via the involvement of selected innate receptors converging on IDO. Several genetic polymorphisms in pattern recognition receptors influence resistance and tolerance to fungal infections in human hematopoietic transplantation. Thus, tolerance mechanisms may be exploited for novel diagnostics and therapeutics against fungal infections and diseases.

Keywords: IDO; fungal infections; resistance; single nucleotide polymorphism; tolerance.

Figure 1

The resistance and tolerance defense strategies in infections. Resistance reduces microbial burden during infection through innate and adaptive immune mechanisms, whereas tolerance mitigates the damage to host tissues caused by both the resistance mechanisms and pathogen’s virulence. Both the host and the pathogen can reduce fitness costs through tolerance mechanisms that reduce both the direct tissue damage by pathogens as well as immunopathology.

Figure 2

Single nucleotide polymorphisms of human immune genes associated with susceptibility to fungal infections and diseases. The SNPs specifically addressed in this review are among those most notoriously associated with impaired PAMP/DAMP/PRR signaling and consequent susceptibility to fungal disease in HSCT recipients. In particular, we discuss the relevance of TLR4 D299G (a non-synonymous mutation demonstrated to increase the risk for fungal colonization or disease, likely depending on the type of transplant and associated clinical variables), DECTIN1 Y238X (an early stop codon mutation affecting dectin-1 function and that has been revealed to modulate susceptibility to mucosal candidiasis, as well as Candida colonization and invasive aspergillosis) and RAGE −374T > A and S100B +427C > T (SNPs compromising their transcriptional regulation and demonstrated to underlie an hyperfunctional RAGE-mediated DAMP signaling and consequent susceptibility to aspergillosis). For further details on these and other SNPs and relevant references, see Romani (2011).