The Detweiler Lab – Sponsor Laboratory for MCDB 1171
We identified a new niche for the bacterial pathogen, Salmonella, during persistent infection. Salmonella resides both within and outside of cells to cause disease. With confocal microscopy, we showed that the bacteria lives in macrophages that have engulfed erythrocytes or leukocytes, called “hemophagocytic” macrophages (HMs). We developed a cell culture model of HMs and with it established that HMs are able to kill E. coli but not Salmonella, that Salmonella acquires the essential nutrient iron from HMs, and that Salmonella stimulates macrophages to engulf erythrocytes to become HMs. In addition, Salmonella-infected mice, like humans with typhoid fever, accumulate HMs. We also recently embarked on a complementary project to identify new antibacterial therapeutics.
How pathogens that live within professional phagocytes outwit innate immunity remains a black box. We recently carried out an in-host-cell screen of ~14,000 chemical compounds for those that disrupt host-pathogen interactions. We identified 295 compounds that kill bacteria in macrophages and a similar number that increase bacterial replication. We are currently unravelling whether these compounds target bacterial essential genes, bacterial virulence determinants, or the host. Then we plan to figure out what they target and what this tells us about biology. We are also interested in whether some of the compounds that decrease bacterial load could be used to fight bacterial infections.
The Su Lab – Sponsor Laboratory for MCDB 2171
Non-autonomous protective effects of dying cells
Earlier this year, we reported a phenomenon wherein induction of apoptosis by a variety of means in wing imaginal discs of Drosophila larvae resulted in the activation of an anti-apoptotic microRNA, bantam. Cells in the vicinity of apoptotic cells also become harder to kill by ionizing radiation (IR)-induced apoptosis. The protective effect spanned as much as 100 microns away from dying cells. Both ban activation and increased protection from IR required receptor tyrosine kinase Tie, which we identified in a genetic screen for modifiers of ban. Apoptotic cells showed increased expression of transcriptional reporters for Pvf1 and Pvf2, putative ligands for Tie. We proposed that apoptotic cells activate ban in surviving cells through Tie to make the latter cells harder to kill, thereby preserving tissues and ensuring organism survival.
Chemical modulators of radiation sensitivity
Drosophila larvae have an amazing capacity to regenerate. Even after half of the cells in larval organ precursors have been killed with X-rays, the remaining cells can regenerate to produce a healthy, fertile adult. We are using this system to screen for small chemical molecules that inhibit regeneration after radiation damage, thereby enhancing the killing effect of radiation. We have screened through several public and commercial chemical libraries. Some of the hits enhance the effect of radiation in both Drosophila and human cancer models in proof-of-concept studies. We are focusing on a family of molecules that act by blocking the elongation step of protein synthesis. Translation elongation remains under-utilized as a drug target in oncology despite emerging evidence that it is highly relevant to cancer and recovery after radiation damage (e.g. Kruiswijk et al., Science Signaling, 2012). We hope to exploit this space to develop new ways to improve the treatment of cancers such as head and neck cancers and glioblastoma where radiation remains a key therapy choice.