Why isListeria monocytogenessuch a potent inducer of CD8+ T‐cells?

Abstract

Listeria monocytogenes is a rapidly growing, Gram‐positive, facultative intracellular pathogen that has been used for over 5 decades as a model to study basic aspects of infection and immunity. In a murine intravenous infection model, immunisation with a sublethal infection of L. monocytogenes initially leads to rapid intracellular multiplication followed by clearance of the bacteria and ultimately culminates in the development of long‐lived cell‐mediated immunity (CMI) mediated by antigen‐specific CD8+ cytotoxic T‐cells. Importantly, effective immunisation requires live, replicating bacteria. In this review, we summarise the cell and immunobiology of L. monocytogenes infection and discuss aspects of its pathogenesis that we suspect lead to robust CMI. We suggest five specific features of L. monocytogenes infection that positively impact the development of CMI: (a) the bacteria have a predilection for professional antigen‐presenting cells; (b) the bacteria escape from phagosomes, grow, and secrete antigens into the host cell cytosol; (c) bacterial‐secreted proteins enter the major histocompatibility complex (MHC) class I pathway of antigen processing and presentation; (d) the bacteria do not induce rapid host cell death; and (e) cytosolic bacteria induce a cytokine response that favours CMI. Collectively, these features make L. monocytogenes an attractive vaccine vector for both infectious disease applications and cancer immunotherapy.

Safety of a Novel Listeria monocytogenes-Based Vaccine Vector Expressing NcSAG1 (Neospora caninum Surface Antigen 1)

“…Therefore, we created an antibiotic-resistance-free triple deletion mutant devoid of actA , inlA and inlB to minimize the likelihood of systemic infection. Deletion of actA causes a 1000-fold LD 50 increase of Lm via prevention of bacterial intercellular spread and, hence, systemic dissemination of infection, and additionally via promotion of autophagy ( Flickinger et al., 2018 ; Radoshevich and Cossart, 2018 ; D’Orazio, 2019 ; Chávez Arroyo and Portnoy, 2020 ). Co-deletion of actA and inlB results in a safe vaccine vector by preventing hepatocyte infection and systemic spread while eliciting a potent immune reaction upon injection ( Brockstedt et al., 2004 ; Flickinger et al., 2018 ).…”

“…During infection, Lm triggers potent innate and adaptive immune responses when phagocytosed by APCs ( Flickinger et al., 2018 ; D’Orazio, 2019 ). Importantly, proteins from bacteria that reach the cytosol of infected APCs are processed and loaded on major histocompatibility complex (MHC) class I molecules for presentation to CD8 + cytotoxic T-cells ( Ikonomidis et al., 1994 ; Pamer, 2004 ; Flickinger et al., 2018 ; Chávez Arroyo and Portnoy, 2020 ; Zeng et al., 2020 ), while bacterial proteins that are degraded within phagolysosomes of APCs are delivered to MHC class II associated epitope presentation for CD4 + T-cell priming ( D’Orazio, 2019 ).…”

“…By deleting one or more crucial virulence genes, Lm virulence is easily and significantly attenuated preventing systemic infection of the host, while immunogenicity is maintained ( Brockstedt et al., 2004 ). Thus, attenuated Lm is a promising vaccine vector to be used against diseases including neosporosis, for which a Th1-mediated immune response is required to confer protection ( Ikonomidis et al., 1994 ; Brockstedt et al., 2004 ; Johnson et al., 2011 ; Wood and Paterson, 2014 ; Flickinger et al., 2018 ; D’Orazio, 2019 ; Chávez Arroyo and Portnoy, 2020 ). Additionally, the Lm vector has the advantage over other microbial vectors to overcome pre-existent or vector-induced immunity in the host allowing homologous prime-boost vaccination schemes without compromising its efficacy in T-cell priming ( Leong et al., 2009 ).…”

Secondary structure of the mRNA encoding listeriolysin O is essential to establish the replicative niche of L. monocytogenes

“…Therefore, to become an intracellular pathogen requires both the intricate regulation of virulence factor expression and the avoidance of endogenous host cell mechanisms that promote cell death. Not surprisingly, the primary mechanism of adaptive immunity to L. monocytogenes is the induction of cell death mediated by antigen-specific cytotoxic T cells (42).…”

Nanoparticle‐based applications for cervical cancer treatment in drug delivery, gene editing, and therapeutic cancer vaccines

“…Bacterial such as Listeria monocytogenes (Lm) is another carrier type for the presentation of HPV antigens. Lm‐based therapeutic vaccines can activate both CD8 + T cells through MHC class I way and CD4 + T cells via secretion of cytokines (Chávez‐Arroyo & Portnoy, 2020 ). The safety of Lm‐E7 vaccine had been confirmed in a phase I clinical trial (Maciaga et al, 2009 ).…”