Detrimental Influence of Alveolar Macrophages on Protective Humoral Immunity during Francisella tularensis SchuS4 Pulmonary Infection

Abstract

ABSTRACT Opsonizing antibody is a critical component of the host protective immune response against many respiratory pathogens. However, the role of antibodies in protection against pulmonary infection with highly virulent Francisella tularensis strain SchuS4 is unclear, and the mechanism that allows F. tularensis to evade antibody-mediated bacterial clearance is not fully understood. We have now found that depletion of alveolar macrophages reveals an otherwise cryptic protective effect of opsonizing antibody. While antibody opsonization alone failed to confer any survival benefit against SchuS4 lung infection, significant protection was observed when mice were depleted of alveolar macrophages prior to infection. Blood immune signature analyses and bacterial burden measurements indicated that the treatment regimen blocked establishment of productive, systemic infection. In addition, protection was found to be dependent upon neutrophils. The results show for the first time a protective effect of opsonizing antibodies against highly virulent F. tularensis SchuS4 pulmonary infection through depletion of alveolar macrophages, the primary bacterial reservoir, and prevention of systemic dissemination. These findings have important implications for the potential use of therapeutic antibodies against intracellular pathogens that may escape clearance by residing within mucosal macrophages.