Review Article | Published:

Immunity to fungal infections

Nature Reviews Immunology volume 11, pages 275288 (2011) | Download Citation


Fungal diseases represent an important paradigm in immunology, as they can result from either a lack of recognition by the immune system or overactivation of the inflammatory response. Research in this field is entering an exciting period of transition from studying the molecular and cellular bases of fungal virulence to determining the cellular and molecular mechanisms that maintain immune homeostasis with fungi. The fine line between these two research areas is central to our understanding of tissue homeostasis and its possible breakdown in fungal infections and diseases. Recent insights into immune responses to fungi suggest that functionally distinct mechanisms have evolved to achieve optimal host−fungus interactions in mammals.

Key points

  • Fungi can interact with humans in multiple ways, establishing symbiotic, commensal, latent or pathogenic relationships. Although the burdens of fungal diseases may rival those of many of the best-known bacterial diseases, humans have evolved with ubiquitous or commensal fungi in host–fungus relationships that for the most part are positive or neutral.

  • The co-evolution of humans and fungi suggests that complex mechanisms exist to allow the host immune system to respond to fungi and, likewise, that fungi have developed sophisticated mechanisms to antagonize immune responses. Indeed, fungal diseases represent an important paradigm in immunology, as they can result either from lack of recognition or from overactivation of the inflammatory response.

  • We are entering an exciting period of transition from studying the molecular and cellular bases of the virulence of fungal pathogens to determining the mechanisms of immune adaptations that maintain homeostasis with fungi.

  • As the immune system cannot ignore fungi, a fine balance between pro- and anti-inflammatory signals is required for a stable host–fungus relationship, the disruption of which leads to pathological consequences. Thus, the challenge for future studies is to gain a better understanding of the control of inflammation, the molecular bases of regulation and rupture, and the way in which innocuous but opportunistic fungal pathogens maintain 'friendly' relationships, or evade or subvert host inflammation.

  • The use of multidisciplinary approaches, including functional genomics, proteomics and bioinformatics, will have important biomedical implications. These may include the identification of new susceptibility genes, the identification of more accurate biomarkers that predict inflammatory fungal disorders, and the development of multi-pronged therapeutic approaches that target specific inflammatory or metabolic end points in fungal infections and diseases.

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I thank the large number of researchers who have contributed to this field and whose work was not cited or was cited through the review articles of others because of space limitations. This work is supported by the EU Specific Targeted Research Projects SYBARIS (FP7-Health-2009-single-stage, contract number 242220) and ALLFUN (FP7-Health-2010-single-stage, contract number 260338) and by the Fondazione per la Ricerca sulla Fibrosi Cistica (project number FFC21/2010). I also thank C. Massi Benedetti of the University of Perugia for editorial assistance and my numerous collaborators for their dedicated work in my laboratory.

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  1. Department of Experimental Medicine and Biochemical Sciences, Microbiology Section, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.

    • Luigina Romani


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The author declares no competing financial interests.



A unicellular form of a fungus, consisting of oval or spherical cells, usually about 3 to 5 μm in diameter, that reproduce asexually by a process termed blastoconidia formation (budding) or by fission.


An asexual or sexual reproductive element of a fungus.

Toll-like receptors

(TLRs). A family of membrane-spanning proteins that recognize pathogen-associated molecular patterns (which are shared by various microorganisms), as well as damaged host cell components. TLRs signal to the host that a microbial pathogen is present or that tissue damage has occurred. They are characterized by an ectodomain that has varying numbers of leucine-rich repeat motifs and a cytoplasmic Toll/IL-1 receptor (TIR) domain that recruits adaptors, such as the myeloid differentiation primary response protein 88 (MYD88) and TIR domain-containing adaptor protein inducing IFNβ (TRIF; also known as TICAM1).

C-type lectin receptors

(CLRs). A large family of proteins that have one or more carbohydrate-recognition domains. CLRs exist as transmembrane and soluble proteins, and include the mannose receptor, dectin 1, dectin 2 and DC-SIGN, as well as soluble molecules, such as the complement-activating mannose-binding lectins, which are involved in antifungal immunity.


A large multiprotein complex that contains certain NOD-like receptors, RIGI-like receptors and IFI200 proteins, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC; also known as PYCARD) and pro-caspase 1. Assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 to generate the active cytokines.

Allergic bronchopulmonary aspergillosis

(ABPA). A condition that is characterized by an exaggerated airway inflammation (hypersensitivity response) to Aspergillus spp. (most commonly Aspergillus fumigatus). It occurs most often in patients with asthma or cystic fibrosis.

Protease-activated receptors

(PARs). A family of four G protein-coupled receptors. Proteolytic cleavage within the extracellular amino terminus exposes a tethered ligand domain, which activates the receptors to initiate multiple signalling cascades. Many proteases that activate PARs are produced during tissue damage, and PARs make important contributions to tissue responses to injury, including haemostasis, repair, cell survival, inflammation and pain.

NOD-like receptors

(NLRs). A family of cytosolic proteins that recognize pathogen-associated molecular patterns and endogenous ligands. The recognition of ligands induces a signalling cascade leading to activation of nuclear factor-κB, or the inflammasome, to produce pro-inflammatory cytokines. NLRs are also involved in signalling for cell death.


In moulds, spores germinate to produce branching filaments called hyphae, which are 2–10 μm in diameter and which may form a mass of intertwining strands called a mycelium.


A family of small, moderately hydrophobic proteins that are characterized by the conserved spacing of eight cysteine residues. Hydrophobins are present on the surface of many fungal conidia, and are responsible for the rodlet configuration of the outer conidial layer.

Delayed-type hypersensitivity response

A cellular immune response to antigen that develops over a period of 24–72 hours. The response is characterized by the infiltration of T cells and monocytes and depends on the production of T helper 1-type cytokines.


A chronic granulomatous disease involving the lungs, skin, mucous membranes, lymph nodes and internal organs that is caused by Paracoccidioides brasiliensis. Symptoms include skin ulcers, adenitis and pain owing to abdominal organ involvement.


An intestinal microorganism that contributes to host nutrition and fitness through a mutualistic, beneficial interaction.


A microbial symbiont that can cause diseases as a consequence of the perturbation of intestinal homeostasis.


Alteration of the symbiont microbial community.

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