Protective Antibodies and Endemic Dimorphic Fungi

Nosanchuk, Joshua D.

doi:10.2174/1566524054022530

Cited by 21 publications

(18 citation statements)

References 88 publications

(130 reference statements)

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“…Administration of immunoglobulin M (IgM) isotype MAbs that bind a histone 2B-like protein (H2B) on the surface of H. capsulatum var. capsulatum yeast cells reduces the fungal burden, decreases pulmonary inflammation, and prolongs survival in a murine model of infection (32,33). These protective MAbs have been associated with enhanced levels of IL-4, IL-6, and IFN-␥ in the lungs of infected mice.…”

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confidence: 99%

Monoclonal Antibodies to Heat Shock Protein 60 Alter the Pathogenesis ofHistoplasma capsulatum

et al. 2009

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Heat shock proteins with molecular masses of ∼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.

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Monoclonal Antibodies to Heat Shock Protein 60 Alter the Pathogenesis ofHistoplasma capsulatum

et al. 2009

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“…Protection mediated by MAbs was associated with enhanced levels of interleukin-4 (IL-4), IL-6, and gamma interferon (IFN-␥) in the lungs of infected mice. Although MAbs to H2B increased phagocytosis of yeast through a CR3-dependent process, the intracellular growth and survival of the opsonized yeast were reduced (31,32). IgG1 and IgG2a subclass MAbs to surface Hsp60 also bound H. capsulatum and activated the antifungal properties of macrophages in a dosedependent manner, as described in other pathogen-antibody models, including with antibody interactions with other fungi (11,27) and for antibodies to pathogen heat shock proteins (21,49).…”

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confidence: 74%

“…The therapeutic use of MAbs has emerged as a potential alternative or adjunctive approach to control systemic fungal infections, such as cryptococcosis, candidiasis and histoplasmosis (31,40). However, the concentration and subclass of MAbs used in vivo must be finely determined (40).…”

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confidence: 99%

“…However, ingestion of opsonized H. capsulatum can stimulate significant oxidant release (5,47), suggesting that induction of the respiratory oxidative burst may occur upon Fc-mediated phagocytosis. Although experimental findings suggest that the protective response against histoplasmosis is mainly cellular, we have demonstrated that monoclonal antibodies (MAbs) can modify the pathogenesis of histoplasmosis to benefit the host (11,12,31,32). However, the mechanisms involved in humoral protection against H. capsulatum yeast cells are not fully understood.…”

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confidence: 99%

“…However, the mechanisms involved in humoral protection against H. capsulatum yeast cells are not fully understood. Immunoglobulin M (IgM) MAbs against the histone 2B-like protein (H2B) and IgG1 and IgG2a against the Hsp60 protein reduced the H. capsulatum fungal burden, decreased pulmonary inflammation, and prolonged survival in a murine infection model (11,31,32). In contrast, an IgG2b MAb to Hsp60 was not protective (11).…”

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Agglutination ofHistoplasma capsulatumby IgG Monoclonal Antibodies against Hsp60 Impacts Macrophage Effector Functions

et al. 2011

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Histoplasma capsulatum can efficiently survive within macrophages, facilitating H. capsulatum translocation from the lung into the lymphatics and bloodstream. We have recently generated monoclonal antibodies (MAbs) to an H. capsulatum surface-expressed heat shock protein of 60 kDa (Hsp60) that modify disease in a murine histoplasmosis model. Interestingly, the MAbs induced different degrees of yeast cell agglutination in vitro. In the present study, we characterized the agglutination effects of the antibodies to Hsp60 on H. capsulatum yeast cells by light microscopy, flow cytometry, dynamic light scattering, measuring zeta potential, and using optical tweezers. We found that immunoglobulin Gs (IgGs) to Hsp60 cause H. capsulatum aggregation dependent on the (i) concentration of MAbs, (ii) MAb binding constant, and (iii) IgG subclass. Furthermore, infection of macrophages using agglutinates of various sizes after incubation with different Hsp60-binding MAbs induced association to macrophages through distinct cellular receptors and differentially affected macrophage antifungal functions. Hence, the capacity of IgG MAbs to agglutinate H. capsulatum significantly impacted pathogenic mechanisms of H. capsulatum during macrophage infection, and the effect was dependent on the antibody subclass and antigen epitope.

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Histoplasmosis

2011

Fundamental Medical Mycology

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Protective Antibodies and Endemic Dimorphic Fungi

Cited by 21 publications

References 88 publications

Monoclonal Antibodies to Heat Shock Protein 60 Alter the Pathogenesis ofHistoplasma capsulatum

Monoclonal Antibodies to Heat Shock Protein 60 Alter the Pathogenesis ofHistoplasma capsulatum

Agglutination ofHistoplasma capsulatumby IgG Monoclonal Antibodies against Hsp60 Impacts Macrophage Effector Functions

Histoplasmosis

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