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Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum
Joshua D. Nosanchuk, … , George S. Deepe Jr., Arturo Casadevall
Joshua D. Nosanchuk, … , George S. Deepe Jr., Arturo Casadevall
Published October 15, 2003
Citation Information: J Clin Invest. 2003;112(8):1164-1175. https://doi.org/10.1172/JCI19361.
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Article Infectious disease

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

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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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Figure 3

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For the in vivo studies, ten mice were used for each condition studied i...
For the in vivo studies, ten mice were used for each condition studied in each experiment. Differences in fungal burden were analyzed by Kruskal-Wallis test, and differences in survival were analyzed by log-rank test. The experiments were repeated at least twice, and similar results were obtained. (a) CFU determinations of Hc 14 days after infection of C57BL/6 mice with 5 × 106 yeast. Bars are means of CFUs from four plates for each condition, and the error bars denote SD. The P values were generated by Kruskal-Wallis test comparing the median CFUs for mAb-treated mice with those for mice that received mAb 5C11 (control): *P < 0.001, **P < 0.01, ***P = 0.02. The experiment was repeated with similar results. (b and c) Histology of lungs from C57BL/6 mice pretreated with protective and nonprotective mAb and infected with 5 × 106 yeast. (b) Representative image of lung from a mouse treated with protective mAb 9C7, showing peribronchiolar inflammation and intact alveoli. (c) The lungs of mice given control mAb had dense inflammatory infiltrates filling much of the alveoli. The original magnification was ×250, and the samples were stained with H&E. The inset in b shows Hc by Gomori’s methenamine-silver staining. (d) mAb to Hc prolongs survival of lethally infected mice. Mice were pretreated with 100 μg of mAb to Hc, nonspecific mAb (5C11), or PBS and infected with 1.25 × 107 yeast. Compared with that of mice that received mAb 5C11 (control), survival was significantly prolonged with mAb to Hc (9C7, P = 0.002; 3B9, P = 0.004; 5B8, P = 0.007). (e) Preincubation of mAb 9C7 with Hc before lethal infection significantly prolonged survival compared with controls (9C7, P < 0.001). (f) Significant prolongation of the survival of lethally infected mice compared with controls (P < 0.001) was achieved by administration of mAb 9C7 before infection and treatment with subinhibitory concentrations of amphotericin B.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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