Enhanced virulence of Histoplasma capsulatum through transfer and surface incorporation of glycans from Cryptococcus neoformans during co-infection.

Radames J B Cordero,Susie Coutinho Liedke,Glauber R De S Araújo,Luis R Martinez,Marcio L Rodrigues,Susana Frases,Joshua D Nosanchuk,Leonardo Nimrichter,Jose Mauro Peralta,Allan J Guimaraes,Arturo Casadevall

doi:10.1038/srep21765

Abstract

Cryptococcus neoformans (Cn) and Histoplasma capsulatum (Hc) co-exist in the environment and occasionally co-infect individuals, which can lead to severe disease/lethal outcomes. We investigated specific interactions between Cn-Hc to determine the impact of synchronous infection in virulence and disease. Co-infected mice had significantly higher mortality than infection with either species or acapsular Cn-Hc. Coating of Hc with cryptococcal glycans (Cn-gly) resulted in higher pulmonary fungal burden in co-infected animals relative to control. Co-cultivation or addition of Cn-gly resulted in enhanced pellicle formation with a hybrid polysaccharide matrix with higher reactivity to GXM mAbs. Transfer and incorporation of Cn polysaccharide onto Hc surface was time and temperature dependent. Cn-gly transfer altered the zeta potential of Hc and was associated with increased resistance to phagocytosis and killing by macrophages. Mice infected with Hc and subsequently injected with purified Cn-gly died significantly more rapidly than Hc alone infected, establishing the precedent that virulence factors from one fungus can enhance the virulence of unrelated species. These findings suggest a new mechanism of microbial interaction involving the transfer of virulence traits that translates into enhanced lethality during mixed fungal infections and highlights the importance of studying heterogeneous microbial populations in the setting of infection.

Highlights

Have been infected by the fungus[4,5]
We explored the possibility that Cryptococcus neoformans (Cn) and Histoplasma capsulatum (Hc) co-infection could worsen disease prognosis in mice
Co-infection with Hc and Cn H99 resulted in higher mortality rates, with 100% death after 12 days, relative to mice infected with Hc and acapsular Cn cap[59] (p = 0.0038) or monospecies inoculum of either Hc (**p = 0.0007), Cn H99 (**p = 0.007) or Cn cap[59] (**p = 0.0014; Fig. 1a)

Summary

Introduction

Have been infected by the fungus[4,5]. the majority of individuals acquiring Hc do not develop clinically significant infections, there are still ~3,500 hospitalizations due to histoplasmosis in the USA annually, with a crude mortality rate of ~8%5. Additional roles of the cryptococcal capsule in virulence have been demonstrated using congenic strain pairs that differ only by mutations or replacement of specific capsular synthesis/assembly genes, such as the well characterized CAP genes family (CAP10, CAP59, CAP60, CAP64), CAS genes (CAS1, CAS3, CAS31) and many others[23,30] These mutations result in acapsular or hypocapsular phenotypes[23] that were severely attenuated in murine models of infection[30]. The Hc surface is less well understood relative to that of Cn, and only a few gly have been partially characterized, Hc can incorporate exogenously added cryptococcal exoPS in vitro[25] It is unclear whether PS transfer occurs in the environment or during mammalian co-infection. The observations presented in this work raise the possibility that fungi can interchange virulence factors and that this process can modulate the immune response and lead to enhanced damage to mammalian hosts

Methods

Results

Conclusion