Abstract
Streptococcus pneumoniae is responsible for significant mortality and morbidity worldwide and causes invasive pneumococcal diseases including pneumococcal meningitis. Pyroptosis is caspase-1-dependent inflammatory cell death and is known to be induced by various microbial infections. In the present study, we investigated the molecular mechanisms that regulate pyroptosis induced by S. pneumoniae in microglia. Our results revealed that S. pneumoniae induced pyroptosis through caspase-1 activation and IL-1β production. We also found that the activation of caspase-1 and the maturation of IL-1β and IL-18 in the S. pneumoniae-triggered pyroptotic cell death process were mediated by NLRP3 inflammasome. In addition, pneumococcal infection increased the expression of autophagy-related genes and induced autophagosome formation. We also showed that the inhibition of autophagy promoted pneumococcus-induced pyroptosis. Furthermore, ROS was generated by pneumococcal infection and inhibited caspase-1 activation within 4 h of infection. However, in the late phase of infection, IL-1β secretion and caspase-1-dependent cell death were induced by ROS. These results suggest that autophagy induction transiently delay pyroptosis induced by S. pneumoniae in microglia. Our study also revealed that the activation of caspase-1 and the production of IL-1β were induced by pneumolysin and that pneumolysin triggered pyroptosis in microglial cells. Similar to the in vitro results, S. pneumoniae induced caspase-1 activation and caspase-1-dependent cytokine maturation in the mouse meningitis model. Thus, the present data demonstrate that S. pneumoniae induces pyroptosis in murine microglia and that NLRP3 inflammasome is critical for caspase-1 activation during the process. Furthermore, the induction of autophagy could transiently protect microglia from pyroptosis.
Highlights
S. pneumoniae is a Gram-positive, extracellular bacterium that is responsible for high mortality and morbidity worldwide
We identified the molecular mechanisms that regulate cell death induced by S. pneumoniae in microglia
We found that pyroptosis is triggered by S. pneumoniae in BV-2 microglial cells and that potassium efflux was required for this process
Summary
S. pneumoniae is a Gram-positive, extracellular bacterium that is responsible for high mortality and morbidity worldwide. The most common manifestations of pneumococcal disease include otitis media, pneumonia and meningitis. Meningitis has the worst prognosis of any pneumococcal disease, with a mortality rate of 15~30 % [1]. The poor prognosis of meningitis is related to the weakness of the host defense mechanisms within the brain, which are notably ineffective in eliminating major meningitis pathogenesis [2]. It has become evident that the host inflammatory reaction to the pathogen, rather than the pathogen itself, is largely responsible for the damage that results from bacterial meningitis [3]. The exact mechanisms of immune activation in pneumococcal meningitis remain unclear, recent studies have suggested that the presence of S. pneumoniae is recognized by resident immunocompetent cells by means of surface and intracellular pattern recognition receptors such as TLRs and NLRs [4]
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