Role of proapoptotic BH3‐only proteins in Listeria monocytogenes infection

Abstract

The ability of pathogens to influence host cell survival is a crucial virulence factor. Listeria monocytogenes (Lm) infection is known to be associated with severe apoptosis of hepatocytes and spleen cells. This impairs host defense mechanisms and thereby facilitates the spread of intracellular pathogens. The general mechanisms of apoptosis elicited by Lm infection are understood, however, the roles of BH3-only proteins during primary Lm infection have not been examined. To explore the roles of BH3-only proteins in Lminduced apoptosis, we studied Listeria infections in mice deficient in Bim, Bid, Noxa or double deficient in BimBid or BimNoxa. We found that BimNoxa double knockout mice were highly resistant to high-dose challenge with Listeria. Decreased bacterial burden and decreased host cell apoptosis were found in the spleens of these mice. The ability of the BH3-deficient mice to clear bacterial infection more efficiently than WT was correlated with increased concentrations of ROS, neutrophil extracellular DNA trap release and downregulation of TNF-α. Our data show a novel pathway of infection-induced apoptosis that enhances our understanding of the mechanism by which BH3-only proteins control apoptotic host cell death during Listeria infection.Keywords: Apoptosis r Cytokines r Host-pathogens interactions r Immune evasion r TNF r Transgenic models Additional supporting information may be found in the online version of this article at the publisher's web-site

Apoptotic cell death in disease—Current understanding of the NCCD 2023

“…Of note, at least part of this effect may be due to the requirement for XIAP to activate NOD signaling, rather than its ability to inhibit caspases [ 459 , 471 , 472 ]. Moreover, mice lacking the genes encoding BIM and NOXA (i.e., Bcl2l11 −/− Pmaip1 −/− mice) display pronounced resistance to challenge with high doses of Listeria monocytogenes , as shown by a decreased bacterial burden and reduced apoptosis induction in the spleen [ 473 ]. The overexpression of BCL2 in the hematopoietic compartment increase the survival of mice infected with Ebola virus [ 474 ], while deletion of Bok promote resistance of lung epithelial cells to apoptosis induced by SARS-CoV-2 virus membrane (M) protein [ 475 ].…”

Listeria monocytogenes: The Impact of Cell Death on Infection and Immunity

“…Since these early studies it has been demonstrated by other groups that infected hepatocytes undergo apoptosis, likely in a TNFα dependent manner [ 88 , 89 ], although whether this is host protective or beneficial to the bacterium remains unclear. Both TRAIL-deficient mice, as well as mice deficient in a variety of proapoptotic BH3-only Bcl-2 family members, were significantly more resistant to L. monocytogenes challenge, although this was not definitively localized to the hepatocyte compartment [ 90 , 91 ]. While it is clear that hepatocytes can undergo apoptosis during infection, the mechanism by which this is mediated and the consequences of hepatocyte apoptosis on the outcome of L. monocytogenes infection remains to be fully defined.…”

Targeting apoptosis pathways in infections

“…39 So far, only a limited number of studies have reported the use of knockout mice to determine the role of BH3-only proteins in preclinical infection models. 49 In contrast, the BCL-2 pro-survival factors are essential for development resulting in death before or shortly after birth. 39 In the absence of knockout mice, studies to determine the role of BCL-2 family members in infections have been largely limited to cultured cell lines.…”