Biomedical Engineering Reference
In-Depth Information
million people in developing countries and is a major cause of iron-deficiency
anemia in the tropics.
Proteases present in the alimentary canal or actively secreted by hookworms
are pivotal to the parasitic way of life. Because of their essential roles in the
parasite life cycle and exposure to the host immune system, these proteases offer
promise as targets for immune and chemotherapeutic intervention. Our group
has a particular interest in targeting hookworm proteases that are central to
blood-feeding, and developing subunit vaccines based on these molecules. The
disruption of life-sustaining processes (leading, hopefully, to parasite killing or
attenuation) by antibody-mediated neutralization of the proteases that drive
them has long been a core concept influencing vaccine development against
infectious organisms; there are numerous examples of proteases involved in both
pathogenesis of infectious diseases and injuries being neutralized by antibodies.
Indeed, we recently described the ecacy of a vaccine targeting an aspartic
protease from N. americanus, Na-APR-1, by vaccinating canines with recom-
binant protein and showed that the protective effect was likely due to the pro-
duction of neutralizing anti-Na-APR-1 antibodies that caused conformational
or steric changes to the protease and inhibited its enzymatic activity, thereby
impairing the parasite's capacity to digest host blood proteins (Figure 8.1).
2,3
Diseases caused by parasitic helminths represent a considerable portion of
the global burden of illness, affecting over one billion people worldwide and
causing tens of thousands of deaths annually. The diculty of eradication in
developing countries where helminths are endemic and the limited sustain-
ability of current drug administration regimes and emergence of drug resistance
in these areas make the development of vaccines against these parasites a highly
desirable goal.
4
Moreover, recent evidence that will be described in this chapter
highlights the likelihood that proteases of blood-feeding helminths are indeed
suitable targets for the development of such vaccines.
8.2 Proteases of Adult-Stage Hookworms
Hematophagous parasites express enormous repertoires of intestinal proteases
that are thought to be involved in the digestion of blood. Indeed, recent surveys
of the adult-stage transcriptomes or excretory/secretory (ES) proteomes of a
number of pathogenic helminths including the hookworms N. americanus
5
and
Ancylostoma caninum
6
has revealed an abundance of proteases implicated in
nutrient digestion. These digestive enzymes have been a major focus of vaccine
development due to their pivotal roles in parasite nutrient acquisition and,
therefore, survival. In fact, the vast majority of reports on helminth proteases
as vaccine antigens describe enzymes involved (or putatively involved) in
nutrient acquisition.
7-11
In order to live and reproduce inside their host, mature, hookworms utilize
amino acids derived from the degradation of ingested serum proteins and lysed
erythrocytes. Hemoglobin (Hb) is the most abundant protein in red blood cells,
and a battery of proteases are employed by the parasite in order to digest Hb
