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. While many people will be genetically predisposed to a given disease, the mechanical properties of the tissue or cellular environment can also contribute to disease progression or its onset. For instance, although mutations in certain genes make a person susceptible to developing cancer, the invasiveness of the cancer may be determined by the stiffness of the extracellular matrix (ECM). Therefore, integration of mechanical cues into current models of pathogenesis based on molecular and biochemical pathways will provide a holistic view as well as new avenues for therapy.
Tumors come in various sizes, shapes and affect multiple organs. However despite the diversity, every cancer shares certain hallmark features at a cellular level. These features define tumorigenesis and help to distinguish cancer cells from normal cells. An important hallmark feature of cancer cells that is particularly challenging in cancer treatment is cancer invasion and metastasis. This is the ability of cancer cells to break away from the primary site to invade neighboring tissues and eventually reach distant sites where they self-seed and grow new tumors.
To achieve metastasis, cancer cells simulate a normal process in embryonic development called epithelial to mesenchymal transition (EMT). During this process, cells lose their adhesive contacts with each other as well as with the ECM, assume an elongated conformation from the normal cuboidal shape and acquire mobility through the activation and appropriate alignment of cytoskeletal proteins. The elongated conformation is due to establishment of cell polarity with a leading and trailing edge following cytoskeletal rearrangement. This type of movement requires adhesion with the ECM through focal adhesions (FA), which enables the cell to pull itself forward and navigate via lamellipodia or filopodia. However, a remarkable feature of cancer cells is their plasticity which enables them to adopt an alternate amoeboid mode of migration that doesn’t require polarity or FAs. Nevertheless, proteins and processes normally involved in cytoskeletal remodeling underlying processes like cell-cell adhesion, cell-ECM adhesion and cell migration are key drivers of cancer metastasis. The tumor suppressor protein p53 elicits its anti-tumor function by suppressing cytoskeletal remodeling through multiple pathways .
During metastasis, the ECM is broken down by the matrix metalloproteases (MMP) through proteolysis, enabling cancer cells to manoeuvre with ease. The density and organization of ECM also determines invasiveness . The mechanical stiffness of cancer cells inversely correlates with their invasiveness  and the stiffness of the ECM affects cancer progression . In breast cancer patients, higher collagen 1 cross-linking increases mammographic density, promotes ECM stiffening and FA formation, eventually inducing invasiveness of cancer cells. ECM stiffness and topology also affect cancer cell proliferation . Therefore there is a mechanical basis for the underlying pathogenesis of cancer, and the cytoskeleton, adhesion and ECM components may be targeted to develop novel anti-cancer drugs/strategies.
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 . Some bacteria like L. monocytogenes, S. flexneri, Ricketssia spp., use actin tails to move within and between cells . 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 . 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 . The enterohaemorrhagic E. coli (EHEC) also forms actin pedestals through a molecular mechanism distinct from that of EPEC .
Viruses also reconfigure and reorganize actin upon entry into host cells . Tumor viruses like the human cytomegalovirus (HCMV) may have an oncomodulatory role depending on the state of Rho GTPase isoforms . Many viruses also exploit filopodia for entry into a host cell and for horizontal transmission between cells . The pathogenic fungi Candida albicans modify actin and alter cell migration to invade tissues .
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 . 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 .