Membrane Damage during Listeria monocytogenes Infection Triggers a Caspase-7 Dependent Cytoprotective Response

Abstract

The cysteine protease caspase-7 has an established role in the execution of apoptotic cell death, but recent findings also suggest involvement of caspase-7 during the host response to microbial infection. Caspase-7 can be cleaved by the inflammatory caspase, caspase-1, and has been implicated in processing and activation of microbial virulence factors. Thus, caspase-7 function during microbial infection may be complex, and its role in infection and immunity has yet to be fully elucidated. Here we demonstrate that caspase-7 is cleaved during cytosolic infection with the intracellular bacterial pathogen, Listeria monocytogenes . Cleavage of caspase-7 during L. monocytogenes infection did not require caspase-1 or key adaptors of the primary pathways of innate immune signaling in this infection, ASC, RIP2 and MyD88. Caspase-7 protected infected macrophages against plasma membrane damage attributable to the bacterial pore-forming toxin Listeriolysin O (LLO). LLO-mediated membrane damage could itself trigger caspase-7 cleavage, independently of infection or overt cell death. We also detected caspase-7 cleavage upon treatment with other bacterial pore-forming toxins, but not in response to detergents. Taken together, our results support a model where cleavage of caspase-7 is a consequence of toxin-mediated membrane damage, a common occurrence during infection. We propose that host activation of caspase-7 in response to pore formation represents an adaptive mechanism by which host cells can protect membrane integrity during infection.

Expression and protective role of two novel NACHT-containing proteins in pathogen infection

“…Furthermore, the gene expression profiles were differentially regulated by NALPL1 and NALPL2, which was identified by PCR array. In mammals, host activation of caspase-7 can protect membrane integrity during infection with the intracellular bacterial pathogen, Listeria monocytogenes (Cassidy et al, 2012). The induced expression of caspase-7 by NALPL2 in the present study may be attributable to inhibit bacterial invasion through protecting infected cells against plasma membrane damage.…”

Transcriptomic and Proteomic Analyses Reveal Key Innate Immune Signatures in the Host Response to the Gastrointestinal Pathogen Campylobacter concisus

“…In the context of C. concisus infection, it is unclear if caspase-7 is involved in apoptosis or the inflammatory response to microbial infection, given that APAF1 (0.39-fold) and several pathways associated with apoptosis were downregulated upon infection and the gene encoding PARP1, a protein that plays a caspase-7-mediated regulatory role in proinflammatory gene expression (47), was also downregulated (0.26-fold) upon infection. Interestingly, caspase-7 activation in response to toxin-mediated membrane damage has been proposed to be an adaptive mechanism by which host cells can maintain membrane integrity during infection (48). Given that C. concisus UNSWCD damages the host cell membrane (18,19) and produces an RTX toxin (repeats in the structural toxin) known to induce membrane pore formation (20), it is possible that the production of this toxin induces caspase-7 upon infection.…”

Multifaceted Activity of Listeriolysin O, the Cholesterol-Dependent Cytolysin of Listeria monocytogenes

“…Also, a more recent study suggested that LLO perforates the plasma membrane of bone marrow-derived macrophages at late stages of infection. Interestingly, the plasma membrane of caspase 7 −/− macrophages was more damaged, revealing a role for this cysteine protease in maintaining the integrity of infected cells [130]. Therefore, LLO secreted into the cytosol may undergo moderate perforation of host cell membranes affecting the biology of infected cells.…”