ActA of Listeria monocytogenes and Its Manifold Activities as an Important Listerial Virulence Factor

Abstract

Listeria monocytogenes is a ubiquitously occurring gram-positive bacterium in the environment that causes listeriosis, one of the deadliest foodborne infections known today. It is a versatile facultative intracellular pathogen capable of growth within the host's cytosolic compartment. Following entry into the host cell, L. monocytogenes escapes from vacuolar compartments to the cytosol, where the bacterium begins a remarkable journey within the host cytoplasm, culminating in bacterial spread from cell to cell, to deeper tissues and organs. This dissemination process depends on the ability of the bacterium to harness central components of the host cell actin cytoskeleton using the surface bound bacterial factor ActA (actin assembly inducing protein). Hence ActA plays a major role in listerial virulence, and its absence renders bacteria intracellularly immotile and essentially non-infectious. As the bacterium, moving by building a network of filamentous actin behind itself that is often referred to as its actin tail, encounters cell-cell contacts it forms double-vacuolar protrusions that allow it to enter the neighboring cell where the cycle then continues. Recent studies have now implicated ActA in other stages of the life cycle of L. monocytogenes. These include extracellular properties of aggregation and biofilm formation to mediate colonization of the gut lumen, promotion and enhancement of bacterial host cell entry, evasion of autophagy, vacuolar exit, as well as nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) activation. These novel properties provide a new view of ActA and help explain its role as an essential virulence factor of L. monocytogenes.

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

“…Upon entering the host cell cytosol, L. monocytogenes dramatically up-regulates the expression of a cell surface transmembrane protein called actin assembly-inducing protein (ActA), which recruits and activates the host Arp2/3 complex to induce the polymerisation of host actin filaments leading to intracellular and intercellular spread (Gouin, Welch, & Cossart, 2005;Pillich, Puri, & Chakraborty, 2017). ActA mutants grow normally within the cytosol of infected cells but are incapable of cell-to-cell spread and are approximately 1,000-fold less virulent in mouse models (Brundage, Smith, Camilli, Theriot, & Portnoy, 1993).…”

Recent advances in understanding Listeria monocytogenes infection: the importance of subcellular and physiological context

“…The bacterium then subverts the host cytoskeleton, inducing characteristic actin “comet tails” to drive both intracellular and intercellular movements. The most important virulence factor (in addition to actin assembly-inducing protein [ActA] 2 responsible for the actin-based motility, and the two invasion proteins internalin A [InlA] and internalin B [InlB]), is certainly listeriolysin O (LLO) 3 . This pore-forming toxin appears to be a multifaceted factor involved in several steps of infection, before bacterial entry into cells, at the level of the escape from the vacuole, and in the cytosol.…”

TetR‐dependent gene regulation in intracellular Listeria monocytogenes demonstrates the spatiotemporal surface distribution of ActA

“…In contrast to InlA and InlB, ActA was initially believed to be non-essential for initiation of the infection, i.e., invasion, internalization, and escape from the primary vacuole. However, since its discovery more than 25 years ago, the role of ActA has been studied in much detail, and it became clear that ActA not only drives bacterial movement and cell-to-cell spread by actin-based motility, but it can also initiate cellular TetR-dependent gene regulation in intracellular L. monocytogenes 417 uptake, support escape from the vacuole, and enhance bacterial persistence in the colon of mice (Pillich et al, 2017). Its presence and function, i.e., recruitment of cellular actin and tail formation, can be conveniently visualized within infected host cells employing fluorescence microscopy.…”