Alejandro Aballay, PhD
Assistant Professor

This laboratory uses genetic and functional genomic methodologies to study the genetic bases of innate immunity. We infect the Caenorhabditis elegans model host with different human bacterial pathogens to understand what makes bacteria pathogenic and hosts resistant. The complex and tractable C. elegans system is excellent to study all aspects of the molecular basis of pathogenesis. From the perspective of the pathogen, the experimental advantage of using C. elegans as a host is that thousands of bacterial clones from a mutagenized library can be individually screened for avirulent mutants on separate Petri plates seeded with C. elegans. On the other hand, the advantages of using C. elegans to study host responses to pathogen attack are the extensive genetic and genomic resources available, and the relative ease of identifying C. elegans mutants that exhibit altered susceptibility to pathogen attack. We take advantage of the Caenorhabditis elegans system as a fast track to identify and initially characterize both host and pathogen genes involved in the pathogenic relationship. We also study the role of these genes in a variety of mammalian systems.

Recent genetic screens have identified bacterial virulence factors required for virulence in both nematodes and mammals. For example, components of the Type III secretory system were identified, as well as several effector proteins. Effector proteins are virulence factors that are translocated through the Type III apparatus to the cytosol of host cells, where they alter several signaling pathways. In an attempt to identify the host signaling pathways targeted by bacterial pathogens, we are expressing bacterial effector proteins and toxins to screen for worm mutants capable of suppressing the phenotypes imposed by the expression of the virulence factors.

We are also interested in studying the parallels between innate immune response in vertebrates and invertebrates. Little is known about the C. elegans innate immune response to bacterial pathogens. One candidate for a marker of an innate immune response that is observed in evolutionarily disparate species is programmed cell death (PCD). Interestingly, we found that S. enterica colonization of the C. elegans intestine leads to an increased level of cell death in the worm gonad. Using a variety of C. elegans mutants in which cell death is blocked, we observed that S. enterica-induced germ line cell death is dependent on the CED-9/CED-4/CED-3 pathway, homologous to the BCL2/APAF-1/CASPASE pathway in mammalian cells. ced-3 and ced-4 mutants are hypersensitive to S. enterica-mediated killing, suggesting that programmed cell death (or the CED-9/CED-4/CED-3 signal transduction pathway) may be involved in a C. elegans defense response to pathogen attack. We are currently using high throughput analysis to find virulence factors capable of inducing PCD and other host-defense mechanisms, and to identify upstream and downstream components of the CED cell death pathway.