Septic shock is the common endpoint of uncontrolled infection, with 750,000 cases and $17 billion spent each year in the United States alone. During Gram negative sepsis, LPS hyperactivates innate immune sensors, driving the systemic inflammation and vascular collapse seen in septic shock. Beginning 17 years ago, TLR4 was shown to sense extracellular and vacuolar LPS, and to contribute to septic shock. Nevertheless, despite intensive research into the immune dysfunction underlying TLR4 activation and septic shock, new treatments have repeatedly failed to show clinical efficacy. Using Burkholderia thailandensis, we have now shown that LPS is sensed in the cytosol through caspase- 11, the noncanonical inflammasome. Indeed, Dr. Shao demonstrated that the lipid A portion of LPS is directly detected by interaction with the CARD domain of murine caspase-11, and its human homologues caspases-4 and -5. We further showed that caspase-11 is essential for host defense, including B. thailandensis and B. pseudomallei - the latter of which is a potential biologic weapon and etiologic agent of melioidosis. Nevertheless, while many advances have been made, many mechanisms within this novel cytosolic LPS surveillance system remain poorly characterized, including the importance of priming upstream of caspase-11/4/5, the structural features of lipid A that are detected, and the clearance mechanisms engaged downstream of the caspases. Without establishing the normal operation of the noncanonical inflammasome, it will be difficult to understand the pathological hyperactivation of this pathway during sepsis.
In AIM 1, we propose to study the structural features of lipid A that are required for detection by caspase- 11, -4, and -5. Structures that bind to the caspase, but fail to activateit are potential competitive inhibitors for the treatment of septic shock. Other structures that activate caspase-4/5 but show minimal TLR4 activity could be novel adjuvants.
In AIM 2 we use B. thailandensis as an in vivo probe to explore the potential effector mechanisms downstream of cytosolic LPS detection that enable resistance to cytosolic infection. Many mechanisms have been advanced based on in vitro work, but none have been thoroughly explored in vivo. We investigate the hypothesis that pyroptosis is the primary effector mechanism of caspase-11. If valid, this insight would promote sepsis therapies aimed at ameliorating the consequences of large-scale cellular pyroptotic lysis. Finally, in AIM 3 we explore caspase-4 and -5 in vivo, using mice that are humanized for the cytosolic LPS surveillance pathway. These results will determine how these two caspases are similar and dissimilar to their murine homolog caspase-11, and will instruct the translational relevance of murine studies with respect to human disease.
The innate immune system can tell the difference between a bacterium that invades into the inside compartment of our immune cells (the cytosol) compared to one that remains outside our cells. This is accomplished through the caspase-11 pathway, which detects a component of the bacterial cell wall, lipopolysaccharide, in the cytosol. We will study how this is helps us defend against infection by cytosol- invasive bacteria.
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| Cheng, Kwong Tai; Xiong, Shiqin; Ye, Zhiming et al. (2017) Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest 127:4124-4135 |
| Kovacs, Stephen B; Miao, Edward A (2017) Gasdermins: Effectors of Pyroptosis. Trends Cell Biol 27:673-684 |
| Tubbs, Alan L; Liu, Bo; Rogers, Troy D et al. (2017) Dietary Salt Exacerbates Experimental Colitis. J Immunol 199:1051-1059 |
| Hagar, Jon A; Edin, Matthew L; Lih, Fred B et al. (2017) Lipopolysaccharide Potentiates Insulin-Driven Hypoglycemic Shock. J Immunol 199:3634-3643 |
| Jorgensen, Ine; Lopez, Joseph P; Laufer, Stefan A et al. (2016) IL-1?, IL-18, and eicosanoids promote neutrophil recruitment to pore-induced intracellular traps following pyroptosis. Eur J Immunol 46:2761-2766 |
| Maltez, Vivien I; Miao, Edward A (2016) Reassessing the Evolutionary Importance of Inflammasomes. J Immunol 196:956-62 |
| Jorgensen, Ine; Zhang, Yue; Krantz, Bryan A et al. (2016) Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis. J Exp Med 213:2113-28 |
| Wang, Xiaowei; Shaw, Dana K; Hammond, Holly L et al. (2016) The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. PLoS Pathog 12:e1005803 |
| Aachoui, Youssef; Miao, Edward A (2016) Down with doublespeak: NAIP/NLRC4 inflammasomes get specific. J Exp Med 213:646 |
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