Listeria monocytogenesInfection in Caspase-11-Deficient Mice

Abstract

Caspase-11 (Cas11) is a cysteine protease involved in programmed cell death and cytokine maturation. Through activation of Cas1 (interleukin-1beta [IL-1beta]-converting enzyme), Cas11 is directly involved in the maturation of IL-1beta and IL-18. Apoptosis is mediated through Cas3. Given the role of apoptosis and cytokine signaling during the innate immune response in intracellular infection, we examined Cas11-deficient (Cas11(-/-)) mice during infection with Listeria monocytogenes. Cas11(-/-) and wild-type C57BL/6 mice were equally susceptible to intravenous infection with L. monocytogenes, resulting in similar bacterial burdens in tissue and similar survival rates. By contrast, enhanced susceptibility was observed in control mice on a mixed genetic 129/C57BL/DBA2 background. Cas11(-/-) and wild-type mice infected with Listeria had similar hepatic microabscess formation in terms of histologic appearance, size, and number. Apoptosis of L. monocytogenes-infected hepatocytes in vivo and in vitro in primary culture was not altered by the absence of Cas11. Serum IL-18 and IL-1beta levels were similar in Cas11(-/-) mice and controls. Endotoxin (lipopolysaccharide [LPS])-challenged Cas11(-/-) mice were deficient in the production of gamma interferon. IL-1beta responses in Cas11(-/-) were normal with intravenous administration of LPS but decreased with intraperitoneal administration. Our findings suggest that Cas11 deficiency does not impair the immune response to infection with L. monocytogenes. Apoptosis and maturation of IL-18 and IL-1beta were normal despite Cas11 deficiency. LPS-induced proinflammatory pathways are altered by the absence of Cas11. While Cas11-mediated Cas1 and Cas3 activation is crucial for cytokine maturation and apoptosis during inflammation, alternative pathways allow normal inflammatory and apoptotic responses during infection with L. monocytogenes.

The inflammatory caspases: guardians against infections and sepsis

“…60 Nonetheless, it seems that the requirement of caspase-11 for caspase-1 activation is not absolute and is restricted to certain stimuli, as caspase-1 could be normally activated in the absence of caspase-11 in response to Listeria infection (Table 1). 61 This is consistent with observations in human macrophages, where caspase-5, a caspase-11-related protein, is only recruited to the NALP1 inflammasome and not other caspase-1 activating complexes. In contrast to caspase-11, caspase-12 inhibits the activity of caspase-1.…”

Chlamydia pneumoniaeAugments the Oxidized Low-Density Lipoprotein-Induced Death of Mouse Macrophages by a Caspase-Independent Pathway

“…Furthermore, other types of obligate intracellular gram-negative bacteria, such as Legionella longbeachae, have been shown to induce apoptosis in macrophages (34).…”

Reduced Apoptosis and Ameliorated Listeriosis in TRAIL-Null Mice

“…The underlying mechanisms of apoptosis following Lm infection and its contribution to the host defense are not clear. It has been speculated that apoptosis of infected hepatocytes serves to limit the spreading of the bacterium (9). However, apoptosis of immune cells would diminish host defense and facilitate the spread of intracellular pathogens.…”