Bioactive lipids in trypanosoma cruzi infection

Fabiana S. Machado, Shankar Mukherjee, Louis M. Weiss, Herbert B. Tanowitz, Anthony W. Ashton

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite. Chagas disease remains a serious health problem in large parts of Mexico and Central and South America, where it is a major cause of morbidity and mortality. This disease is being increasingly recognized in non-endemic regions due to immigration. Heart disease develops in 10-30% of infected individuals. It is increasingly clear that parasite- and host-derived bioactive lipids potently modulate disease progression. Many of the changes that occur during acute and chronic Chagas disease can be accounted for by the effects of arachidonic acid (AA)-derived lipids such as leukotrienes, lipoxins, H(P)ETEs, prostaglandins (PGs) and thromboxane. During the course of infection with T. cruzi, changes in circulating levels of AA metabolites are observed. Antagonism of PG synthesis with cyclooxygenase (COX) inhibitors has both beneficial and adverse effects. Treatment with COX inhibitors during acute infection may result in increased parasite load and mortality. However, treatment instituted during chronic infection may be beneficial with no increase in mortality and substantial improvement with cardiac function. Recently, T. cruzi infection of mice deficient in AA biosynthetic enzymes for various pathways has yielded more insightful data than pharmacological inhibition and has highlighted the potential deleterious effects of inhibitors due to "off-target" actions. Using COX-1 null mice, it was observed that parasite biosynthesis is dependent upon host metabolism, that the majority of TXA 2 liberated during T. cruzi infection is derived from the parasite and that this molecule may act as a quorum sensor to control parasite growth/differentiation. Thus, eicosanoids present during acute infection may act as immunomodulators aiding the transition to, and maintenance of, the chronic stage of the disease. It is also likely that the same mediators that initially function to ensure host survival may later contribute to cardiovascular damage. Collectively, the eicosanoids represent a new series of targets for therapy in Chagas disease with defined potential therapeutic windows in which to apply these agents for greatest effect. A deeper understanding of the mechanism of action of non-steroidal anti-inflammatory drugs may provide clues to the differences between host responses in acute and chronic T. cruzi infection.

Original languageEnglish (US)
Pages (from-to)1-31
Number of pages31
JournalAdvances in Parasitology
Volume76
DOIs
StatePublished - 2011

Fingerprint

Trypanosoma cruzi
Chagas Disease
Lipids
Infection
Parasites
Arachidonic Acid
Cyclooxygenase Inhibitors
Eicosanoids
Prostaglandins
Mortality
Chronic Disease
Lipoxins
Parasite Load
Communicable Disease Control
Central America
Cyclooxygenase 1
South America
Leukotrienes
Thromboxanes
Emigration and Immigration

Keywords

  • Chagas disease
  • Chagas heart disease
  • Eicosanoids
  • Inflammation
  • Lipoxins
  • Thromboxane
  • Trypanosoma cruzi

ASJC Scopus subject areas

  • Parasitology

Cite this

Bioactive lipids in trypanosoma cruzi infection. / Machado, Fabiana S.; Mukherjee, Shankar; Weiss, Louis M.; Tanowitz, Herbert B.; Ashton, Anthony W.

In: Advances in Parasitology, Vol. 76, 2011, p. 1-31.

Research output: Contribution to journalArticle

Machado, Fabiana S. ; Mukherjee, Shankar ; Weiss, Louis M. ; Tanowitz, Herbert B. ; Ashton, Anthony W. / Bioactive lipids in trypanosoma cruzi infection. In: Advances in Parasitology. 2011 ; Vol. 76. pp. 1-31.
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