Why should cell biologists study microbial pathogens?

Welch, Matthew D.

One area of cell biology in which the study of pathogens has enabled fundamental advances is the cytoskeletal field. Extracellular bacterial pathogens often target actin or its regulators by secreting toxins that translocate across cellular membranes to inhibit phagocytosis by immune cells (Lemichez and Aktories, 2013 ). An example is Clostridium botulinum, which causes the paralytic illness botulism. C. botulinum produces several secreted toxins, including C3 toxin, which enters host cells and ADP-ribosylates and inactivates the Rho family GTPase Rho (paralysis is caused by a separate toxin, as discussed below; Narumiya et al., 1988; Aktories et al., 1989) . By examining the effect of microinjecting C3 toxin into cells, Alan Hall and coworkers discovered that Rho signals to promote the formation of focal adhesions and stress fibers (Chardin et al., 1989; Paterson et al., 1990; Ridley and Hall, 1992) . Sadly, Alan passed away earlier this year in the prime of his career. Similar studies showed that Rho family proteins are also required for phagocytosis (Hall, 2012) . Many bacteria, such as Clostridium difficile, the leading cause of hospitalacquired diarrhea, or Yersinia pestis, the causative agent of plague, FIGURE 1: Pathogen virulence factors influence cellular pathways and structures. Extracellular pathogens produce virulence factors that act at a distance or on contact with a host cell. These virulence factors inhibit cellular processes (indicated by red) including phagocytosis and secretion. In contrast, intracellular pathogens produce virulence factors that promote intimate interactions with host cells. These activate cellular processes (indicated by green), including phagocytosis, intracellular movement to a preferred compartment or organelle, and cell-to-cell spread. Virulence factors can also either activate or inactivate cellular processes (indicated by orange) to prevent microbial killing and enable growth and replication. These pathways include those involved in membrane trafficking, autophagy, cell death, and cell cycle regulation. (Martin, 2004) . Famous examples are the Rous sarcoma virus (RSV), which causes sarcomas in chickens, and Abelson murine leukemia virus (A-MuLV), which causes lymphosarcomas in mice. The capacity of RSV to transform normal cells into tumor cells was found to be associated with the viral src gene and its product v-Src (Brugge and Erikson, 1977; Weiss et al., 1977) . The v-Src protein and the v-Abl protein from A-MuLV were subsequently shown to be tyrosine kinases (Hunter and Sefton, 1980; Witte et al., 1980) , the first discovery of this protein class. Cellular homologues of these proteins, c-Src and c-Abl, were soon identified (Stehelin et al., 1976; Shalloway et al., 1981; Heisterkamp et al., 1982) , demonstrating that viral oncogenes are derived from cellular counterparts. It was also soon recognized that the human ABL1 gene, which encodes c-Abl, participates in the Philadelphia chromosomal translocation, which is commonly associated with leukemias (de Klein et al., 1982) . Thus viruses were key to demonstrating the importance of tyrosine kinases in signaling in normal and cancer cells and the roles of oncogenes in cancer. Future studies of pathogens will continue to reveal ways in which diverse signaling pathways and proteins influence normal cell physiology and disease.