Pathogen-specific antibodies: codependent no longer

Abstract

Antibody-mediated defense against pathogens typically requires complex interactions between antibodies and other constituents of the humoral and cellular immune systems. However, recent evidence indicates that some antibodies alone can inhibit pathogen function in the absence of complement, phagocytes, or NK cells. In this issue of the JCI, McClelland et al. have begun to elucidate the molecular bases by which antibodies alone can impact pathogen growth and metabolism. They show that mAbs specific for the polysaccharide capsule of the human pathogenic fungus Cryptococcus neoformans elicit diverse effects on fungal gene expression, lipid biosynthesis, susceptibility to amphotericin B, cellular metabolism, and protein phosphorylation. These data suggest that pathogens have the capacity to generate broad metabolic responses as a result of surface binding by pathogen-specific antibodies, effects that may hold therapeutic promise.

Figure 1. A pathogen’s view of humoral immune defense.

(A) Pathogen-specific antibody typically mediates its effects through the ability of its Fc constant region to act as a bridge to other host defense mechanisms (e.g., complement, phagocytes, and NK cells). Recognition of Fc by these immune components induces the fatal injuries to the pathogen, on which antibody defense is dependent. Cytotoxic processes include complement-dependent assembly of transmembrane pores (membrane attack complexes [MAC]), engulfment by phagocytes (macrophage or neutrophil), and release of antimicrobial agents by NK cells. CR1, complement receptor 1. (B) Possible direct effects of specific antibody on pathogen activity. The work of McClelland et al. (2) suggests multiple pathways by which antibodies may act on their target microbes in the absence of other immune factors. The diagram shows a cross-section of the human fungal pathogen C. neoformans, including the polysaccharide capsule that surrounds the fungal cell wall. In this study, mAb binding to both the outer (IgM) and inner (IgG) regions of the C. neoformans capsule triggered different genetic pathways and diverse, concomitant changes in fungal physiology and metabolism. Arrows denote hypothetical signaling pathways, currently undefined, which inform C. neoformans of the presence of the capsule-bound mAb and thus alter gene expression patterns. McClelland et al. report myriad responses to mAb binding, including upregulation of fatty acid–synthesis genes, activation of lipid biosynthesis, reduced cellular metabolism, reduced expression of protein synthesis genes, diminished protein phosphorylation, and increased sensitivity to the antifungal drug amphotericin B. Further elucidation of the biochemical and cell-biological consequences of antibody binding may lead to rational design of microbicidal antibodies.