Evasion of Innate Immune Responses by the Highly Virulent Cryptococcus gattii by Altering Capsule Glucuronoxylomannan Structure

Abstract

Cryptococcus neoformans causes life-threatening diseases mainly in immunosuppressed hosts such as AIDS patients; C. gattii causes disseminated infections even in healthy hosts. To identify the possible molecular mechanisms underlying this difference in virulence, we investigated the survival and histopathology of lung tissue in wild-type and CD4-depleted mice infected with C. neoformans H99 and C. gattii JP02 (the highly virulent strain isolated in Japan); we then compared dendritic cell (DC) cytokine release responses to different cell fractions from these two strains. JP02-infected mice exhibited shorter survival and fewer inflammatory cells in the lung than H99-infected control mice. Depletion of CD4-related cellular immunity reduced survival of H99-infected mice but had no effect on the survival or inflammatory cell infiltration in JP02-infected mice, suggesting that JP02 evades immune detection. To identify the molecule(s) conferring this difference, we measured cytokine production from murine DCs co-cultured with H99 and JP02 in vitro. The levels of inflammatory cytokines from DCs treated with intact JP02 cells, the extracted capsule, secreted extracellular polysaccharides, and purified glucuronoxylomannan (GXM) were markedly lower than those induced by intact H99 cells and corresponding H99 fractions. Structural analysis of GXM indicated that JP02 altered one of two O-acetyl groups detected in the H99 GXM. Deacetylated GXM lost the ability to induce inflammatory cytokine release from DCs, implicating these O-acetyl groups in immune recognition. We conclude that the highly virulent C. gattii processes a structural alteration in GXM that allows this pathogen to evade the immune response and therefore elimination.

Role of microglia in fungal infections of the central nervous system

“…63,64 In the periphery, the capsular polysaccharide can interfere with phagocytosis, antigen presentation, leukocyte migration and proliferation, and specific antibody responses, and can enhance HIV replication. 65,66 Alternatively, the black pigment melanin may play a role in anti-phagocytic activity of C. neoformans. 67 In avirulent nonmelanogenic C. neoformans infected mice produced numerous key cytokines as described above without fatality, the virulent melanogenic fungi produces little or no cytokine secretion in mice with massive tissue damage and a number of fatalities.…”

Conservation of Intracellular Pathogenic Strategy among Distantly Related Cryptococcal Species

“…The cryptococcal capsule, one of the major virulence factors of Cryptococcus, is mainly composed of glucuronoxylomannan (GXM), which has several immunomodulatory properties (9,19). However, it has been reported that the GXM capsule structure of C. gattii strains differs from that of C. neoformans strains and may be responsible for the different degrees of host activation (20) associated with the two species complexes. Urease is another major virulence factor shared by both species complexes and one that is proposed to have several roles, though these remain under debate (21).…”

Redistribution of a glucuronoxylomannan epitope towards the capsule surface coincides with Titanisation in the human fungal pathogenCryptococcus neoformans

“…Intriguingly, a recent transcriptomics study identified CAS31 as being absent from the genome of strain CBS 10101, a serotype C isolate that we subsequently found was not recognised by Crp127. Whilst we cannot rule out the possibility that other factors contribute to the inability of Crp127 to recognise serotype C strains, it is tempting to speculate that the loss of CAS31 function in this lineage may explain its lack of reactivity with Crp127 (32, 34).…”

“…Whilst there is no consensus surrounding the effect of GXM O -acetylation on virulence (17, 32), its influence on antibody binding suggests that changes in GXM O -acetylation could be a strategy deployed by cryptococci to avoid recognition by immune effectors. Additionally, despite the immunomodulatory roles for GXM O -acetylation that have been identified (30, 33), receptors that bind O -acetylated GXM remain elusive (34). Due to the enigmatic nature of this modification within the primary virulence factor of cryptococci, further investigation of GXM O -acetylation will help unravel the complexities of cryptococcal capsule structure with the ultimate aim of understanding the strategies deployed by this fatal fungal pathogen to evade host immunity.…”