The role of pneumolysin in pneumococcal pneumonia and meningitis

Abstract

Diseases caused by Streptococcus pneumoniae include pneumonia, septicaemia and meningitis. All these are associated with high morbidity and mortality. The pneumococcus can colonize the nasopharynx, and this can be a prelude to bronchopneumonia and invasion of the vasculature space. Proliferation in the blood can result in a breach of the blood-brain barrier and entry into the cerebrospinal fluid (CSF) where the bacteria cause inflammation of the meningeal membranes resulting in meningitis. The infected host may develop septicaemia and/or meningitis secondary to bronchopneumonia. Also septicaemia is a common precursor of meningitis. The mechanisms surrounding the sequence of infection are unknown, but will be dependent on the properties of both the host and bacterium. Treatment of these diseases with antibiotics leads to clearance of the bacteria from the infected tissues, but the bacteriolytic nature of antibiotics leads to an acute release of bacterial toxins and thus after antibiotic therapy the patients can be left with organ-specific deficits. One of the main toxins released from pneumococci is the membrane pore forming toxin pneumolysin. Here we review the extensive studies on the role of pneumolysin in the pathogenesis of pneumococcal diseases.

Fig. 1

Schematic representation of events during the early (right side) and late stage (left side) responses, based on our mouse (MF1) intransal infection model. In the early stages of infection pneumococci infect bronchiolar airspaces, and subsequently invade the lung epithelial cells. This leads to inflammation of these cells and release of chemokines, such as Il-8 (or mouse equivalent MIP-2). Upon pneumococcal infiltration, alveolar macrophages also release IL-8/MIP-2 and TNF-α. The release of IL-8/MIP-2 and TNF-α attracts neutrophils to the infected area. Neutrophils phagocytose pneumococci through complement C3 deposition and its associated receptors (opsonophagocytosis). Cytokines, such as TNF-α, are also released by infiltrating neutrophils, which in turn leads to a further increase in neutrophil infiltration into the infected areas. In the later stages of lung infection the pneumococci are lysed by activation of Lyt-A or by neutrophils, both events cause a release of pneumolysin into the surrounding tissue. This will have a wide range of cytotoxic and inhibitory effects on host tissue and immune cells, including complement activation, inhibition of neutrophil respiratory burst and release of the antibacterial, vasodilatory, nitric oxide from macrophages. In addition, the release of pneumolysin is thought to increases the probability of pneumococcal survival and growth in vivo.