Audrey O.T. Lau, MPH, PhD
Audrey O.T. Lau, MPH, PhD
Disrupting the host-pathogen relationship often results in virulence, a
measure of pathogenesis. Such disruption can arise from many factors. No
single factor is responsible for all the differences that result in
virulence and pathogenic adaptation does not always occur. Understanding how
virulence arises, therefore, is crucial to developing better mechanisms for
controlling and possibly eliminating many infectious diseases.
Identifying the virulent factors involved is the first step in this process.
Advances in genome sequencing and molecular techniques have proven to be
critical in the identification of virulent factors and in understanding
host-pathogen relationships. Several apicomplexan genomes have recently been
sequenced including Babesia bovis
, a vector host-dependent mammalian
hemoparasites, similar to Plasmodium
1995; Mbati et al., 2002). Utilizing a model apicomplexan system such
as Babesia sp
. knowledge gained can be applicable to other pathogens. In the
case of Babesia, loss of virulence can be recovered by passage of the
attenuated strain through a competent tick vector
et al., 1990). The precise changes that occur resulting in attenuation
are currently unknown. A comprehensive genome-wide analysis of
multiple virulent and avirulent strains can identify these changes as well
as mechanisms of pathogenicity. Our laboratory will be the first to analyze
strains of the same species and strains to identify factors and mechanisms
responsible for either the acquisition or loss of virulence by in silico and
at the bench. This new knowledge is crucial to understand host-pathogen
interactions and has the potential to substantially improve human and animal
health and to reduce the economic impact of diseases.
Diseases caused by apicoplast-containing parasites (phylum Apicomplexans)
inflict much mortality and morbidity in humans and animals worldwide.
Drugs targeting the apicoplast, an organelle whose origin is prokaryotic,
have the potential to control and improve disease maintenance such as
babesiosis, cryptosporodiosis, East Coast fever and malaria. The role
this organelle plays in contributing to the survival of these parasites,
though essential, is not well known despite the recent sequencing of several
genomes from these species. A better understanding of the biochemical
processes that occur within the organelle, especially from a comparative
perspective, would help identify common treatments throughout the phylum.
Our long-term goal is to enhance drug discovery efforts for treating
Apicomplexan parasites. Utilizing a comparative approach, assessment of drug
sensitivity and genome analyses will help identify common drugs that are
effective against these Apicomplexans. My lab. focuses on the
determination of metabolic pathways within this prokaryotic derived
organelle through the identification of apicoplast targeted proteins and
drug sensitivity assays in a model Apicomplexan using Babesia bovis
recently sequenced the entire B. bovis
genome, including apicoplast DNA, and
have identified several putative metabolic pathways to occur within the B. bovis
apicoplast. Recent drug sensitivity studies targeting substrates
within these pathways in Apicomplexans including Babesia
suggest that not
all apicoplasts are alike. Comparative studies that utilize model systems
and recently developed genomic tools are needed to maximize drug development
efforts. Outcome of our work will include potential common drug targets
against Apicomplexans as well as specialized ones that will target Babesia
exclusively. In addition, results from this proposal will enhance our
understanding of the complex protein trafficking process that takes place in
apicoplasts since all apicoplasts contain three to four membranes ADDIN
EN.CITE ADDIN EN.CITE.DATA (Hopkins, et al. 1999; Kohler, et al. 1997) and
mechanisms governing protein translocation into this organelle are not well
Lau AOT, Pedroni MJ, Fretwell DL, Cereceres K,
Mosqueda J, Palmer GH, McElwain TF. Genotype diversity of Babesia
bovis merozoite surface antigen 1 among individual animal cohorts in
an endemic region of Mexico. (2009)(in submission to
International Journal of Parasitology)
Lau AOT, McElwain TF, Brayton KA, Knowles DP, and
Roalson EH. Babesia bovis: a comprehensive phylogenetic analysis of
plastid-encoded genes supports green algal origin of apicoplasts. (2009)(in
Laughery JM, Lau AOT, White SN, Howell JM and Suarez CE.
Transcriptional analysis of rRNA genes in distinct Babesia bovis life cycle
stages. (Jun., 2009)(in press in Experimental Parasitology)
Lau AOT. An overview of the
Babesia, Plasmodium and
Theileria genomes: a comparative perspective.
Molecular and Biochemical Parasitology (Mar., 2009) 164: 1-8.
Brayton KA, Lau AOT, Herndon D, Hannick L, Kappemeyer LS
et al. Genome sequence of Babesia bovis and comparative analysis of
PLoS Pathogens (Oct., 2007) 3: e148.
Lau AOT, Tibbals DL and McElwain TF. Babesia bovis: the
development of an expression oligonucleotide microarray. Experimental
Parasitology (Jul., 2007) 117: 93-98.