Elsevier

Medical Hypotheses

Volume 74, Issue 4, April 2010, Pages 676-678
Medical Hypotheses

Do long-chain unsaturated fatty acids function as endogenous anti-trypanosomal molecules?

https://doi.org/10.1016/j.mehy.2009.11.002Get rights and content

Summary

Trypanosomiasis is common in Africa and South America. The surface of trypanosomes is covered by glycosyl phosphatidylinositol (GPI)-anchored variant surface glycoprotein (VSG) that contains the fatty acid myristate (14:0) as its lipid moiety that is essential for its survival. Myristic acid, being a saturated fatty acid, is resistant to peroxidation. Hence, I propose that replacement of myristic acid of VSG–GPI of trypanosomes by unsaturated fatty acids may render them unviable due to the ease with which the latter undergo peroxidation. In addition, unsaturated fatty acids could kill trypanosomes by (1) activation of macrophages and release of reactive oxygen species; (2) high Ca2+ influx that may be lethal; (3) alteration in mitochondrial membrane potential and disruption of energy generation; and (4) direct disruption of the cell membrane. If this hypothesis proves to be correct, unsaturated fatty acids and its analogues could form a new approach to the management of trypanosomiasis and other intracellular parasitic infections.

Introduction

More than 66 million people in 36 countries of sub-Saharan Africa suffer from human African trypanosomiasis [1]. African sleeping sickness, caused by two different parasites include: Trypanosoma brucei gambiense, which causes a chronic infection lasting years and affecting countries of western and central Africa; Trypanosoma brucei rhodesiense, which causes acute illness lasting several weeks in countries of eastern and southern Africa. Human African trypanosomiasis can be fatal if not treated. It spreads by the bite of an infected tsetse fly (Glossina genus). The tsetse fly bite erupts into a red sore and within a few weeks the person can experience fever, swollen lymph glands, aching muscles and joints, headaches and irritability. In advanced stages, the disease attacks the central nervous system, causing changes in personality, alteration of the circadian rhythm, confusion, slurred speech, seizures, and difficulty walking and talking.

In South America, a different trypanosome, T. cruzi, causes Chagas disease that is transmitted by the arthropod, Triatoma infestans. The acute phase of the disease may have no or very mild symptoms while the chronic illness is characterized by cardiomyopathy, hepatosplenomegaly, lymphadenopathy, arrhythmias and tachycardia, megacolon, megaesophagus with swallowing difficulty, heart failure and malnutrition [2]. The two drugs that are used to treat this infection: benznidazole and nifurtimox are not without side-effects and drug resistance has been reported.

Despite many advances, trypanosomiasis continues to be a huge public health challenge. Since not all subjects exposed to the parasite develop the disease, it is likely that there could be some endogenous molecules that thwart the infection and show effective anti-trypanosomal properties. Identifying such natural molecules could pave way to develop new modalities of therapy and prevention.

Section snippets

Immune response against trypanosomal infection

C3H mice are relatively more trypanosusceptible, as evidenced by their reduced ability to control parasitemia and shorter survival time, than B6B-F1 mice, showed enhanced levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), nitric oxide (NO) and interleukin-10 (IL-10) in plasma and lymph nodes, and lower levels of plasma IgM, IgG1, IgG2a, IgG2b and IgG3 Abs against soluble variant surface glycoprotein (VSG in response to Trypanosoma brucei brucei). These results suggest that

Saturated fatty acid, myristic acid, is essential for the survival of trypanosomes

The blood stream form of Trypanosoma brucei covers its surface with ∼107 identical molecules of a glycosyl phosphatidylinositol (GPI)-anchored variant surface glycoprotein (VSG) that contains the fatty acid myristate (14:0) as its lipid moiety. Myristate is not abundant in host bloodstreams and so the trypanosome manufactures myristate by expressing fatty acid synthetase so that this fatty acid can be preferentially incorporated into GPIs and not into other lipids [13]. Myristate produced by

Unsaturated fatty acids may be lethal to trypanosomes and other intracellular parasites

The VSG–GPI that covers the surface of trypanosoma that contains the fatty acid myristate (14:0) as its lipid moiety is essential for its survival. Myristic acid, being a saturated fatty acid, is resistant to peroxidation and stabilizes the membrane. Several analogs of myristic acid are lethal to the parasite [14], [15]. Antibiotic thiolactomycin affects GPI remodeling by inhibiting the synthesis of myristate, has low toxicity in mice and is useful against bacterial infections, trypanosomiasis

Testing the hypothesis

The proposal that unsaturated fatty acids will be toxic to trypanosomes can be verified in vitro, in vivo and in the clinic.

Conclusion

The proposal that long-chain unsaturated fatty acids may be toxic to trypanosomal organisms is supported by the fact that these lipids have already been shown to be effective against malarial parasite; an intracellular pathogen. Since myristic acid, a saturated fatty acid, is an important constituent of VSG–GPI of trypanosomes that is essential for its survival in the host, its replacement by unsaturated fatty acids could render the parasite unviable due to an increase in the degree of

Conflict of interest statement

None declared.

Acknowledgement

Dr. U.N. Das is in receipt of Ramalingaswami fellowship of the Department of Biotechnology, India during the tenure of this study.

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