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 The
outcome of the interaction between a pathogen
and a host depends on the interplay between virulence
factors of the microorganism and host responses
to the infection. Some virulence factors are induced
only in the host and may therefore require specialized
techniques to be identified, based on detection
of these genes in vivo or the survival of mutagenized
strains within specific host environments. Previous
studies have shown that non-vertebrate hosts can
be used to study established and identify novel
virulence determinants in a variety of microbial
animal pathogens. The hypothesis is that selection
for genes involved in interactions with both mammalian
and non-mammalian hosts may specifically identify
genes of fundamental relevance to pathogenesis
independent of the model system used (read
more).
Therefore, investigators have increasingly turned
to invertebrates as facile and inexpensive hosts
to model a variety of human pathogens. If killing
of invertebrate hosts by pathogens mimics key
features of mammalian pathogenesis, then it should
be possible to use invertebrates as facile and
inexpensive hosts for high throughput study of
microbial pathogenesis.
We developed three invertebrate systems for the
study of the fungal pathogens. These non-mammalian
hosts are:
- Caenorhabditis elegans
- Drosophila
melanogaster and
- Galleria mellonella.
Each of these systems provides some unique
advantages. We are using non-mammalian hosts
and especially Caenorhabditis
elegans to study host-pathogen interactions. C.
elegans is a facile model (read
more)
and has enabled us to study virulence factors
of the model fungal pathogen Cryptococcus
neoformans.
Using this system we have ascertained a number
of C.
neoformans mutants that are hypovirulent
in C. elegans (read
more).
More recently, we found that Candida albicans
as well as other Candida species are ingested
by C. elegans and establish a persistent lethal
infection in the C. elegans intestinal track.
Importantly, key components of Candida pathogenesis
in mammals, such as biofilm and filament formation,
are also involved in nematode killing. The assay
is performed in liquid media using standard 96-well
plate technology. A screen of 1,266 compounds
with known pharmaceutical activities identified
15 (~1.2%) that prolonged survival of C. albicans-infected
nematodes and inhibited in vivo filamentation
of C. albicans. We have tested three of these
compounds in the murine model of candidiasis and
two of these compounds identified, caffeic acid
phenethyl ester (CAPE), a major active component
of honeybee propolis, and the fluoroquinolone
agent enoxacin, exhibited anti-fungal activity
in mice. (read
more) These surrogate hosts fill an important
niche in microbial pathogenesis research and,
along with established mammalian models provide
us with a unique opportunity to identify and study
basic, evolutionarily conserved aspects of microbial
virulence and host response.
Eleftherios Mylonakis, M.D.
Division of Infectious Diseases
55 Fruit Street
Gray Jackson 5, Room GRJ-504
Boston, Massachusetts 02114-2696
(617) 726-3812
E-mail: emylonakis@partners.org
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