Therapeutic Potential of Phosphodiesterase Inhibitors in Parasitic Diseases - Phosphodiesterases as Drug Targets - page 490

1.1.1 Trypanosoma brucei
Human African trypanosomiasis (HAT) is caused by the kinetoplastid Trypa-
nosoma brucei ( T. brucei ) and transmitted to humans by the bite of the blood-
sucking tsetse fly. Two subspecies, T. brucei rhodesiense and T. brucei gambiense ,
are responsible for acute and chronic forms of HAT, known as East and West
African trypanosomiasis, respectively. A third subspecies, T. brucei brucei , causes
animal trypanosomiasis, also known as nagana, as do the closely related species
T. congolense , T. evansi , and T. vivax . The first sign of infection may be the for-
mation of a chancre at the bite site. During the first stage, or hemolymphatic stage of
the disease, trypanosomes invade the host bloodstream. The accompanying symp-
toms are often nonspecific (fever, headaches, enlarged lymph nodes, joint pain,
and itching). Indeed, patients may be asymptomatic, making early diagnosis diffi-
cult. The disease is characterized by waves of parasitemia, during which parasite
numbers peak and then decline almost to zero. Parasite survival is ensured due to
surface coat antigenic variants that are not recognized by the host immune system.
Each successive wave of parasitemia represents a new antigenic variant. In the
second phase, or neurological phase of the disease, which may occur within weeks
or months (East African trypanosomiasis), or years later (West African trypano-
somiasis), the trypanosomes invade the host central nervous system. Symptoms
during this phase include pancarditis, meningoencepahalitis, confusion, sensory
disturbance, disruption of the sleep-wake cycle, loss of coordination, and coma
and are fatal if not treated. HAT is endemic in 36 sub-Saharan countries: there are
50 million people at risk of contracting HAT and approximately 30,000 HAT-
related deaths per year (Stuart et al. 2008 ; Brun et al. 2010 ).
1.1.2 Trypanosoma cruzi
American trypanosomiasis is caused by the kinetoplastid Trypanosoma cruzi
( T. cruzi ) and is mainly transmitted in the feces of the blood-sucking triatomine
bugs. Other routes of infection are via blood transfusion and vertical transmission
from mother to fetus. Acute phase symptoms are generally mild and nonspecific and
often include a swelling at the site of infection, known as a chagoma or Roma ˜ a's
sign. Following the acute phase, the disease generally enters a life-long latent phase.
In approximately 30% of cases, however, life-threatening symptoms develop decades
after the initial infection, most often as complications of the heart or gut. The disease
is endemic in 19 Central and South American countries and is estimated to affect
8-11 million people (Stuart et al. 2008 ). Chagas disease is the leading cause of heart
failure in Central and South America and the cause of approximately 14,000 deaths
annually (Barrett et al. 2003 ; Stuart et al. 2008 ). Immigration of large populations of
Latin Americans to other countries has spread the risk of T. cruzi infection to regions
outside Central and South America. In recent years, T. cruzi contamination has been
identified in blood banks in the USA and other countries following blood donations
by individuals unaware they were infected.