© 2007 Nature Publishing Group

DOI:10.1038/nrmicro1625

URLsAspergillus fumigatushttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=9521

Histoplasma capsu-latumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12630

An elegant study from Bill Goldman’s laboratory has examined the innate immune response to Histoplasma capsulatum from both the host and fungal perspective.

H. capsulatum is a dimorphic fungal pathogen. Unlike oppor-tunistic fungal pathogens such as Aspergillus fumigatus, the dimorphic fungi are primary pathogens and so are generally capable of evading the host immune response. In this latest work, Chad Rappleye and colleagues examined the molecular mechanisms responsible for H. capsulatum immune evasion.

They began by investigating whether there was a role for α(1,3)-glucan. This polysaccharide is a component of the cell wall of many fungal pathogens and has been linked to primary fungal virulence for almost 30 years, yet the basis for this has remained unclear. In addition to α(1,3)-glucan, the H. capsulatum cell wall contains two other polysac-charide components, chitin and β-glucans. Using immunofluoresence microscopy, Rappleye et al. found

that the H. capsulatum cell wall has a layered structure, with the α(1,3)-glucan comprising the outermost layer, confirming earlier biochemical analyses.

They went on to investigate the effect of the outer α(1,3)-glucan layer on innate immune recogni-tion, first using α(1,3)-glucan-defi-cient yeast. The pattern-recognition receptor dectin 1 recognises fungal β-glucan. Live H. capsulatum yeast deficient in α(1,3)-glucan were able to bind to fibroblasts express-ing dectin 1 but yeast expressing α(1,3)-glucan were unable to do so. Taking this observation further, the effect of α(1,3)-glucan on the release of the pro-inflammatory cytokine tumour necrosis factor α (TNF-α) was examined, and it was found that α(1,3)-glucan-deficient yeast stimulated the production of fivefold more TNF-α than yeast expressing α(1,3)-glucan did. Finally, on the host side, the role of dectin 1 was analysed. A dectin-1-depleted macrophage cell line was established using RNA interference,

and it was found that the lack of the β-glucan receptor dectin 1 suppressed the pro-inflammatory response to H. capsulatum yeast. The authors therefore conclude that α(1,3)-glucan promotes H. capsu-latum virulence by blocking innate immune recognition of β-glucan by dectin 1.

These results indictating that the immunostimulatory β-glucan layer is masked in H. capsulatum and that there are no other exposed immu-nostimulatory molecules suggest that the response to H. capsulatum might be simpler than recent papers have indicated for Candida albicans, which lacks α(1,3)-glucan. Clearly, the host innate immune response to fungal pathogens is a complex process that is just beginning to be unwrapped.

Sheilagh Molloy

ORIGINAL RESEARCH PAPER Rappleye, C. A., Eissenberg, L. G. & Goldman, W. E. Histoplasma capsulatum α(1,3)-glucan blocks innate immune recognition by the β-glucan receptor. Proc. Natl Acad. Sci. USA 23, 1366–1370 (2007)FURTHER READING Taylor, P. R. et al. Dectin 1 is required for β-glucan recognition and control of fungal infection. Nature Immunol. 8, 31–38 (2007) | Saijo, S. et al. Dectin 1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nature Immunol. 8, 39–46 (2007) | Netea, M. G. et al. Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J. Clin. Invest. 116, 1642–1650 (2006)

I N N AT E I M M U N I T Y

Fungal hide and seek

Wild-type Histoplasma capsulatum yeasts stained with antibodies specific for α-(1,3)-glucan (left), β-(1,3)-glucan (centre) and both (right). Image kindly provided by Bill Goldman.

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | MICROBIOLOGY VOLUME 5 | MARCH 2007