title: Monoclonal antibodies to heat shock protein 60 alter the pathogenesis of Histoplasma capsulatum.
abstract: Heat shock proteins with molecular masses of approximately 60 kDa (Hsp60) are widely distributed in nature and are highly conserved immunogenic molecules that can function as molecular chaperones and enhance cellular survival under physiological stress conditions. The fungus Histoplasma capsulatum displays an Hsp60 on its cell surface that is a key target of the cellular immune response during histoplasmosis, and immunization with this protein is protective. However, the role of humoral responses to Hsp60 has not been fully elucidated. We generated immunoglobulin G (IgG) isotype monoclonal antibodies (MAbs) to H. capsulatum Hsp60. IgG1 and IgG2a MAbs significantly prolonged the survival of mice infected with H. capsulatum. An IgG2b MAb was not protective. The protective MAbs reduced intracellular fungal survival and increased phagolysosomal fusion of macrophages in vitro. Histological examination of infected mice showed that protective MAbs reduced the fungal burden and organ damage. Organs of infected animals treated with protective MAbs had significantly increased levels of interleukin-2 (IL-2), IL-12, and tumor necrosis factor alpha and decreased levels of IL-4 and IL-10. Hence, IgG1 and IgG2a MAbs to Hsp60 can modify H. capsulatum pathogenesis in part by altering the intracellular fate of the fungus and inducing the production of Th1-associated cytokines.
authors.affiliation: Department of Medicine (Division of Infectious Diseases) & Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Guimarães
authors.forename: Susana
authors.initials: S
authors.lastname: Frases
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Gomez
authors.forename: Rosely M
authors.initials: RM
authors.lastname: Zancopé-Oliveira
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Nosanchuk
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000908:Antibodies, Fungal / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000946:Antigens, Fungal / Q000276:immunology; D018834:Chaperonin 60 / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D018604:Epitope Mapping; D005260:Female; D006658:Histoplasma / Q000276:immunology / Q000472:pathogenicity*; D006660:Histoplasmosis / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008264:Macrophages; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010587:Phagocytosis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells
chemical_list: D000908:Antibodies, Fungal; D000911:Antibodies, Monoclonal; D000946:Antigens, Fungal; D018834:Chaperonin 60; D016207:Cytokines; D007074:Immunoglobulin G; D011994:Recombinant Proteins