Bacterial Pathogenesis

Pathogenesis is defined as the origination and development of a disease. Insights into disease etiology and progression, the two major aspects of pathogenesis, are paramount in the prevention, management and treatment of various diseases. In many cases the mechanical properties of the tissue or cellular environment  contribute to disease progression or its onset, and this is also true in diseases arising from bacterial infection. For instance, the ability of a bacteria to invade a cell or tissue, to establish an infection within the body and to avoid or even exploit the immune response is often dependent on the bacteria’s ability to manipulate the host cytoskeleton, and exploit various biochemical pathways that respond to changes in mechanical stimuli.

The mechanobiology of infection and bacterial pathogenesis

During an infection, an external virulent agent like bacteria, virus or fungi, invades into body tissues and proliferates, causing disease. These pathogens employ multiple mechanisms of invasion, evasion of host immune responses and survival or replication within the host. While some molecular mechanisms may be unique to a particular pathogen, some may be conserved across species. A component of the host cell that is modulated by pathogens, both extracellular and intracellular, is the plasma membrane, being the first point of contact between the pathogen and host cell. The nature and outcome of membrane modulation differs depending on the pathogen, for instance, some pathogenic bacteria produce pore-forming toxins that modulate the membrane, whereas some hijack the membrane trafficking pathways. Membrane modulation often leads to rearrangement of the host cell cytoskeleton that enables entry, transport and survival of the pathogens in the host cell.

The nature of cytoskeletal modification varies with the pathogen and stage of infection. While extracellular pathogens like Yersinia spp activate Rho GTPases to cause cell rounding and inhibition of phagocytosis, intracellular pathogens like Mycobacterium tuberculosis (MTb) exploit phagocytosis by alveolar macrophages for its entry into the host. In the case of the bacteriae Samonella typhimurium and Shigella flexneri, effectors of Type III secretion system 1 (T3SS-1), trigger host signaling pathways that rearrange the host actin cytoskeleton to induce membrane ruffling, thus invoking macropinocytosis and engulfment of the bacteria. The precise molecular mechanisms underlying bacterial uptake are not clear, although a mechanism involving direct activation of Rho GTPases leading to actin polymerization either through Arp2/3- or formin-dependent pathways is likely in the case of Salmonella [1]. Some bacteria like L. monocytogenes, S. flexneri, Ricketssia spp., use actin tails to move within and between cells [2]. Other cytoskeletal components like microtubules (Salmonella), intermediate filaments (Chlamydia) and septins are also recruited/altered for pathogenesis.

Once internalized, bacteria thrive within vacuoles formed both in phagocytic and non-phagocytic host cells. The Salmonella Containing Vacuole (SCV) is integrated with the early endocytic pathway, but they escape lysosomal fusion and lysis [3]. During SCV maturation, an F-actin meshwork is formed around bacterial vacuoles in a process known as vacuole-associated actin polymerization (VAP) that reinforces the integrity of the vacuolar membrane. Mature SCVs are found in a perinuclear position, proximal to the Golgi apparatus. Salmonellae within SCVs also induce the formation of tubular aggregates along a scaffold of microtubules called Salmonella-induced filaments (SIFs) that extend from SCVs throughout the cell. Therefore, an intricate link exists between the host cytoskeleton and Salmonella pathogenesis at various stages. Other intracellular bacteria like Mycobacteria, Coxiella, Legionella, and Brucella also reside within vacuoles and exploit different components of the endocytic and secretory pathways for pathogenesis.

The enteropathogenic Escherichia coli (EPEC) modulate the membrane and cytoskeleton through yet another unique mechanism. The EPEC T3SS encodes the translocated intimin receptor (Tir), which localizes to the plasma membrane to induce actin polymerization. This results in the formation of a pedestal structure beneath the bacterium [4]. The enterohaemorrhagic E. coli (EHEC) also forms actin pedestals through a molecular mechanism distinct from that of EPEC [5].

Viruses also reconfigure and reorganize actin upon entry into host cells [6]. Tumor viruses like the human cytomegalovirus (HCMV) may have an oncomodulatory role depending on the state of Rho GTPase isoforms [7]. Many viruses also exploit filopodia for entry into a host cell and for horizontal transmission between cells [8]. The pathogenic fungi Candida albicans modify actin and alter cell migration to invade tissues [9].

Ironically, the host cytoskeleton that pathogens exploit for virulence, is also utilized by the host cell in cell-autonomous immunity, whereby the host cell attempts to eliminate the pathogen [10]. In fact, the cytoskeletal rearrangements during bacterial infection aid in bacterial sensing and initiation of immune responses, providing scaffolds for compartmentalization of pathogens and carrying out autophagy or host cell death leading to elimination of the pathogen [11].

In this topic


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