Bacterial pathogens exploit normal host cell processes to cause gastrointestinal disease

Many bacterial pathogens exploit normal host cell processes to cause disease. S. flexneri, a causative agent of gastrointestinal infections, exploits the normal host processes of motility and paracytophagy to spread intercellularly. My work has demonstrated that the addition of a single gene, icsA, which is sufficient for actin based motility, from S. flexneri into a non-pathogenic bacteria allows it to spread intercellularly. Thus, actin-based motility is sufficient for protrusion formation and uptake by neighboring cells.; Salmonella, a causative agent of gastroenteritis and typhoid fever, exploits normal macrophage cell death pathways to cause apoptosis by injecting effector proteins into host cells. Salmonella typhimurium , induces a rapid cell death that requires the protein secretion apparatus encoded on Salmonella pathogenicity island 1, SPI1, to inject SipB into the host cytosol. SipB binds and activates the host protein caspase-1, a member of the pro-apoptotic caspase family of proteases, which leads to a rapid macrophage death. My research showed that S. typhimurium also triggers a delayed death that is dependent on SPI2 and caspase-1. Caspase-1 is unique among caspases because it also directly cleaves the proinflammatory cytokines Interleukin (IL)-1β and IL-18 to produce bioactive cytokines. To test the roles of caspase-1 and IL-1β in Salmonella infection, we infected mice that are deficient for these host proteins. I found that mice lacking caspase-1 or IL-1β had an oral S. typhimurium LD₅₀ that was 1000-fold or 30-fold higher than wild-type mice, respectively. There was a positive correlation between the frequency of TUNEL-positive nuclei, inflammation and S. typhimurium colonization of the gastrointestinal tract. Thus, caspase-1, which is both proapoptotic and proinflammatory, and IL-1β, which is responsible for eliciting a proinflammatory response, are essential for S. typhimurium to efficiently colonize the cecum and PP and subsequently cause systemic typhoid-like disease in mice. That bacterial pathogens, from those infecting plants to those infecting humans, use sophisticated molecular mechanisms to exploit host cell processes and host immune functions to cause disease inspires awe and gives us added respect for the adaptability of microorganisms.