Melanin triggers antifungal defences

Melanins are enigmatic pigments that have many roles, and the melanin in pathogenic fungi can aid host infection. Identification of a mammalian protein that recognizes melanin now reveals an antifungal defence pathway.

Most organisms produce numerous varieties of the highly diverse dark pigments known as melanins, which are among the last remaining biological frontiers with the unknown. These polymer molecules can act in protective or harmful ways, in biological functions as diverse as providing protection against DNA-damaging ultraviolet radiation1 to bolstering fungal cell-wall strength2. Melanins bolster microbial virulence3, including that of many disease-causing fungi. The presence of melanin can trigger an immune response in the infected organism4, but how this occurs was unknown. In a paper in Nature, Stappers et al.5 report the identification of a protein that can recognize a type of melanin produced by the fungus Aspergillus fumigatus. Their finding illuminates the immune-system response to a fungal infection that can be lethal in people who have a suppressed immune system, such as those who have undergone transplantation surgery6.

Melanin pigments are stable free radicals, and, in animals and fungi, they are produced in membrane-bound organelles known as melanosomes, which shield the cell cytoplasm from the potentially damaging free-radical reaction needed for melanin production. They are insoluble and resistant to degradation by acids. These striking characteristics probably explain why their structures are difficult to analyse and are not fully understood. Host immune cells can trigger potentially damaging cell-signalling pathways in fungi. But such attacks can be neutralized by fungal melanin, which also reduces susceptibility to antifungal drugs3.

Human disease caused by fungi of the genus Aspergillus is called aspergillosis. If a lung infection takes hold in someone who has inhaled A. fumigatus spores, it can result in an infection that spreads elsewhere in the body. When A. fumigatus infects the lungs, host cells can trigger a cellular-degradation pathway called autophagy that aids fungal destruction. However, fungal melanin can inhibit autophagy7. Moreover, melanin is linked to inflammation.

The ability of melanin to target host defences, and the molecule’s role in fungal virulence, raises the question of whether mammalian cells can recognize melanin. Stappers and colleagues investigated this by studying members of the C-type lectin protein family, which has previously been identified8 as being involved in antifungal defence. Using an in vitro biochemical approach, the authors tested whether any C-type lectins from mice can bind fungal spores from A. fumigatus. One of the proteins they tested could do so, and they named it MelLec.

The authors tested strains of A. fumigatus containing mutations that block steps in the melanin-synthesis pathway, and found that MelLec recognizes 1,8-dihydroxynaphthalene melanin. MelLec did not recognize other tested forms of melanin that are associated with fungal disease.

The authors found that mouse MelLec is expressed in the endothelial cells that line the surface of vessels forming the circulatory system. This suggests that it responds to infection after A. fumigatus has breached the lung defences in air-filled sacs called alveoli and moved farther into the body to reach the circulatory system (Fig. 1). In humans, MelLec is expressed in endothelial cells and in a type of immune cell known as a myeloid cell9.

Figure 1 | A receptor that recognizes melanin and triggers antifungal defences. a, Infection by the fungus Aspergillus fumigatus can be lethal to certain people with weakened immune systems6, and many aspects of the body’s immune response to such infections are unknown. A. fumigatus spores contain melanin and can infect air-filled sacs in the lungs called alveoli. Using mice, Stappers et al.5 investigated a protein family linked to antifungal defences8 called C-lectins, and found evidence that one of these proteins, named MelLec by the authors, can bind a type of melanin pigment present in fungi. Melanin pigment can be sensed by MelLec in cells lining blood vessels, but how melanin reaches MelLec is unknown. b, As infection progresses, the germinating spores form cellular protrusions. Melanin recognition by MelLec triggers the synthesis of cytokine molecules that can attract immune cells called neutrophils. Neutrophils can then enter the alveolus and target the infection.

The authors genetically engineered mice that lacked MelLec. These mice seemed normal, but after treatment with molecules to induce immunosuppression and the injection of A. fumigatus spores into their bloodstream, they were more susceptible to infection than wild-type counterparts that had undergone the same treatment. Direct introduction of A. fumigatus into the lungs of mice lacking MelLec resulted in fewer immune cells called neutrophils entering the animals’ lungs than was the case for wild-type mice, suggesting that melanin recognition by MelLec aids neutrophil recruitment to sites of infection. The authors found that the reduced neutrophil recruitment in mice lacking MelLec was linked to lower expression of neutrophil-attracting molecules called cytokines.

Although A. fumigatus is ubiquitous in the environment, not everyone with impaired immunity develops aspergillosis, suggesting that some individuals might be particularly vulnerable to the infection. To investigate this, Stappers and colleagues studied people who were in an immunosuppressed state following transplantation. Those who had a mutant version of MelLec in which a specific glycine amino-acid residue was replaced by alanine were more susceptible to infection by A. fumigatus than those who had the normal version of the protein. In vitro analysis of human cells revealed that this mutation is associated with decreased cytokine production in response to fungal exposure compared with cytokine production in cells containing the normal version of MelLec.

The identification of a MelLec mutation linked to susceptibility to fungal infection suggests an immediate clinical application in identifying patients at high risk of developing Aspergillus infections and who might benefit the most from antifungal treatments. Moreover, individuals with a functioning immune system can develop a hypersensitive reaction to Aspergillus, a condition known as allergic pulmonary aspergillosis, and other MelLec mutations might be responsible for this predisposition.

As with all good scientific studies, the answer to the question of whether the body can sense melanin raises many additional questions. For example, how does melanin pigment on spores in the alveoli reach MelLec on cells located more internally? Perhaps when spores germinate and form cellular protrusions, these damage alveolar integrity and enable the spores to reach blood vessels. Another possibility is that spores are ingested and transported by macrophage cells of the immune system10.

Stapper and colleagues’ work might mark the beginning of an era in which additional melanin-binding molecules are discovered. l-Dopa melanin and other types of melanin are pro-inflammatory4, so it seems reasonable to speculate that they are recognized by as-yet-unknown host proteins. Furthermore, MelLec offers a target for drug development because drugs that enhance its activity might boost immune responses to Aspergillus infection.

Like the discovery of the Toll-like receptor proteins that sense microbial infection in the fruit fly Drosophila melanogaster, Stapper and colleagues’ identification of this first known melanin receptor arose from fungal-infection studies in model animals. At a time when researchers are increasingly urged to focus on studies with immediate clinical relevance, it is important to remember that transformative work often begins with model systems. Given that fungi are major pathogens targeting invertebrates, perhaps MelLec homologues exist in animal models such as D. melanogaster and the worm Caenorhabditis elegans, opening the door to the use of these organisms for additional investigation of this phenomenon. These and other studies building on the work of Stapper and colleagues might further our understanding of host-defence mechanisms.

Nature 555, 319-320 (2018)


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