Streptococcus pneumoniae-Induced Caspase 6-Dependent Apoptosis in Lung Epithelium

Abstract

Streptococcus pneumoniae is the major pathogen of community-acquired pneumonia and one of the most common causes of death due to infectious diseases in industrialized countries. Lung epithelium lines the airways and constitutes the first line of innate defense against respiratory pathogens. Little is known about the molecular interaction of pneumococci with lung epithelial cells. Apoptosis of lung epithelium is involved in some bacterial lung infections. In this study different pneumococcal strains specifically induced either apoptotic or necrotic death of human alveolar and bronchial epithelial cells. Pneumococcus-induced apoptosis did not depend on the virulence factors pneumolysin and H 2 O 2 . Apoptotic cells showed increased activity of caspases 6, 8, and 9 but not increased activity of caspase 3. Moreover, programmed cell death could be strongly reduced by a caspase 6 inhibitor and a pan-caspase inhibitor. Inhibitors of calpain and chymotrypsin-and trypsin-like proteases also reduced pneumococcus-induced apoptosis. Furthermore, pneumococcus-infected human alveolar epithelial cells showed Bid cleavage and reduced levels of Bcl2 and Bax. Overexpression of Bcl2 in these cells reduced apoptosis significantly. Thus, pneumococci induced apoptosis of human alveolar and bronchial epithelial cells. Programmed cell death was executed by caspase 6 and noncaspase proteases, but not by caspase 3, and could be blocked by overexpression of Bcl2.

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

“…Here, we observed that S. pneumoniae could cause greater permeability of the cell membrane of host cells (observed as PI uptake), indicative of necrosis. H 2 O 2 may contribute to necrosis, as well as exposure to the pneumococcal cell wall, which has previously been reported to be a necrosis-inducing factor (24,26). With regard to apoptosis, we show that H 2 O 2 secreted by S. pneumoniae leads to DNA damage in a contact-independent fashion and that the levels of H 2 O 2 are sufficiently high to induce significant apoptosis (Annexin V and TUNEL-positive cells).…”

“…Another possible source of DNA damage is pneumolysin, a pneumococcal toxin that has been shown to cause apoptosis in alveolar cells when present at high concentrations in cell media in vitro (24). Although pneumolysin is cytoplasmic without any secretory signal (39), others have detected pneumolysin in bacterial supernatant (40,41).…”

“…Although induction of cell death is key to pathogenicity, the underlying mechanisms by which S. pneumoniae induces apoptosis (23)(24)(25) and necrosis (26) in host cells is not yet well understood. Although it is known that certain pneumococcal proteins elicit a potentially cytotoxic inflammatory response (4,27), here we asked whether S. pneumoniae or its secreted factors could directly generate DNA damage responses that could contribute to cell death.…”

“…pneumoniae-Induced DNA Damage Levels Correlate with Levels of Apoptosis and Necrosis. Host cell death is a key feature of S. pneumoniae pathogenicity (3,(23)(24)(25)(26). To reveal the relative cytotoxicity of the three serotypes of S. pneumoniae, we exposed mammalian alveolar epithelial cells to S. pneumoniae.…”

Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q

“…47 CASP6 is a candidate because it induces apoptosis in response to infection by Streptococous pneumoniae. 48 We sequenced all exons of CASP6, DAPP1, NFkB1, and SCYE1 on genomic DNA, and the cDNA of BANK1 and NFkB1 in at least one CVID patient from the NL1 family. However, no mutations were found in these genes/transcripts.…”