Dissecting the contribution of IgG subclasses in restricting airway infection with Legionella pneumophila

Abs are able to mediate local protection from pulmonary infection with Legionella pneumophila, the causative agent of a severe form of pneumonia known as Legionnaires' disease. L. pneumophila is able to infect alveolar macrophages in the lung and replicates intracellularly in a vacuolar compartment with endoplasmic reticulum-like characteristics. However, Abs opsonize the bacteria and confer an FcR-mediated signal to phagocytic host cells that vetoes the bacterial evasion strategies, thereby efficiently targeting the bacteria to intracellular lysosomal degradation. In this study we analyzed the prevalence of pathogen-specific IgG subclasses present in immunized mice and found that the presence of IgG2c and IgG3 correlated with reduced bacterial titers after intranasal infection. We then isolated different IgG subclasses and compared their differential prophylactic potential in restricting airway L. pneumophila replication. We found that all IgG subclasses were effective in restricting pulmonary airway infection in mice when administered at high and equivalent doses. However, at limiting Ab concentrations we found a superior role of IgG2c in restricting L. pneumophila replication in a prophylactic setting. Furthermore, we assessed the therapeutic efficacy of administering an mAb during an established infection and found that bacterial titers could be reduced very efficiently with such a treatment. Thus, we propose the therapeutic use of Abs for the treatment of intracellular bacterial infections in situations where antibiotics might be ineffective.