Alveolar Macrophage Apoptosis Contributes to Pneumococcal Clearance in a Resolving Model of Pulmonary Infection

Abstract

The role of alveolar macrophages (AM) in host defense against pulmonary infection has been difficult to establish using in vivo models. This may reflect a reliance on models of fulminant infection. To establish a unique model of resolving infection, with which to address the function of AM, C57BL/6 mice received low-dose intratracheal administration of pneumococci. Administration of low doses of pneumococci produced a resolving model of pulmonary infection characterized by clearance of bacteria without features of pneumonia. AM depletion in this model significantly increased bacterial outgrowth in the lung. Interestingly, a significant increase in the number of apoptotic AM was noted with the low-dose infection as compared with mock infection. Caspase inhibition in this model decreased AM apoptosis and increased the number of bacteremic mice, indicating a novel role for caspase activation in pulmonary innate defense against pneumococci. These results suggest that AM play a key role in clearance of bacteria from the lung during subclinical infection and that induction of AM apoptosis contributes to the microbiologic host defense against pneumococci.

Alveolar macrophages in pulmonary host defence – the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing

“…We have demonstrated that macrophage apoptosis is a feature of in-vitro challenge of macrophages to S. pneumoniae and also occurs in vivo [30,36]. It is observed with both human and murine macrophages.…”

“…Using defined inocula of S. pneumoniae, depletion of alveolar macrophages with liposomes containing clodronate or mice with genetic modifications that alter intracellular killing of bacteria (as discussed below), we have demonstrated that mice with decreased numbers of alveolar macrophages, or with alveolar macrophages of reduced microbicidal capacity, are more susceptible to development of pneumonia and that the threshold inoculum required to generate pneumonia is reduced significantly [30,[32][33][34]. The capacity of macrophages to clear bacteria is finite, and even in wildtype mice the inoculum can be increased to a 'tippingpoint' beyond which alveolar macrophages no longer control the bacteria in the airway [30,31]. At these higher inocula alveolar macrophage depletion does not alter bacterial clearance because the macrophage capacity for bacterial clearance is already saturated.…”

“…In murine models of pulmonary infection alveolar macrophages clear bacteria up to a defined threshold without overt features of pneumonia, but when alveolar macrophages fail to control these subclinical infections recruitment of inflammatory cells, predominantly neutrophils, is required to control infection [30,31]. Using defined inocula of S. pneumoniae, depletion of alveolar macrophages with liposomes containing clodronate or mice with genetic modifications that alter intracellular killing of bacteria (as discussed below), we have demonstrated that mice with decreased numbers of alveolar macrophages, or with alveolar macrophages of reduced microbicidal capacity, are more susceptible to development of pneumonia and that the threshold inoculum required to generate pneumonia is reduced significantly [30,[32][33][34]. The capacity of macrophages to clear bacteria is finite, and even in wildtype mice the inoculum can be increased to a 'tippingpoint' beyond which alveolar macrophages no longer control the bacteria in the airway [30,31].…”

Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

“…The commonest cause of community-acquired pneumonia in this population is infection with Streptococcus pneumoniae, the pneumococcus (2). The successful resolution of bacterial pneumonia is dependent on a coordinated immune response with neutrophil recruitment when resident defenses are overwhelmed (3). After clearance of bacteria, a resolution phase, mediated by apoptosis of recruited cells and clearance by phagocytosis, prevents tissue injury by activated neutrophils (4).…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Protection against the extracellular bacteria requires efficient recruitment of neutrophils and macrophages to the site of infection (199,200). Recent research established a role for type I IFNs in interfering with this innate defense mechanism.…”