Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum
Joshua D. Nosanchuk, Judith N. Steenbergen, Li Shi, George S. Deepe Jr., Arturo Casadevall
Joshua D. Nosanchuk, Judith N. Steenbergen, Li Shi, George S. Deepe Jr., Arturo Casadevall
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Article Infectious disease

Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum

Abstract

A protective role for antibodies has not previously been described for host defense against the pathogenic fungus Histoplasma capsulatum (Hc). Mouse mAb’s were generated from mice immunized with Hc yeast that binds the cell surface of Hc. Administration of mAb’s before Hc infection reduced fungal burden, decreased pulmonary inflammation, and prolonged survival in a murine infection model. Protection mediated by mAb’s was associated with enhanced levels of IL-4, IL-6, and IFN-γ in the lungs of infected mice. The mAb’s increased phagocytosis of yeast by J774.16 cells through a CR3-dependent process. Ingestion of mAb-opsonized Hc by J774.16 macrophage-like cells was associated with yeast cell growth inhibition and killing. The mAb’s bound to a 17-kDa antigen expressed on the surface of Hc. The antigen was identified as a histone H2B–like protein. This study establishes that mAb’s to a cell surface protein of Hc alter the intracellular fate of the fungus and mediate protection in a murine model of lethal histoplasmosis, and it suggests a new candidate antigen for vaccine development.

Authors

Joshua D. Nosanchuk, Judith N. Steenbergen, Li Shi, George S. Deepe Jr., Arturo Casadevall

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Western blot analysis of mAb binding to Hc surface protein. (a) Immunobl...
Western blot analysis of mAb binding to Hc surface protein. (a) Immunoblots of cell wall proteins demonstrating binding of mAb’s 3B9, 5B8, and 9C7 to proteins at 17 and 34 kDa. (b) Binding of mAb 9C7 to Hc surface proteins before and after serial treatment with 1 mM DTT, 1% Triton, 10 mM CHAPS, and 100 mM sodium carbonate, pH 10. (c) Binding of mAb 9C7 to Hc proteins after serial treatment and reactivity of the Hc-binding mAb’s to recombinant protein (second through fourth lanes). (d) Gene sequence and deduced amino acid sequence of the protein recognized by the mAb to Hc. (e) The protein sequence is compared with that of histone H2B sequences reported in other fungi. These sequence data are available from GenBank/EMBL/DDBJ under accession no. AY316539.