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.
Finally, we are interested in screening for C. elegans
mutants that are either more resistant or more susceptible
to pathogens. Since several components of innate immunity
are conserved among different organisms throughout
evolution, understanding the basis of the immune response
in C. elegans should provide new insight into some
aspects of immunity in mammals.
