Antimalarial Diets - by Loren Cordain
Editor's note: Dr. Cordain originally wrote the following article as a grant proposal to the Bill and Melinda Gates Foundation entitled Identification of ?-aminobenzoic acid (PABA) concentrations in food to formulate antimalarial diets.
Section I. Strategies for the treatment, prevention and control of malaria typically involve pharmaceuticals, insecticides and nettings. Rarely has diet been considered as an effective therapy to prevent or attenuate malarial morbidity and mortality. This proposal is novel because we show how diets that maintain low concentrations of ?-aminobenzoic acid (PABA) and folate represent an untapped tactic to thwart malarial infection.
An Achilles heel in the lifecycle of Plasmodia species is it’s reliance upon the availability of folate, an essential nutrient for these rapidly growing parasites. Pharmaceuticals such as pyrimethamine and sulfa drugs are effective anti-malarials because they interfere with the conversion of PABA to folate (depicted in the Shikimate pathway below). In vitro (test-tube) experiments indicate that Plasmodia species have the ability to synthesize limited amounts of folate endogenously, however further experiments show that these parasites cannot synthesize sufficient quantities of folate to survive in living animals (in vivo)1. Hence, without adequate supplemental stores of PABA and folate from their host’s tissues, Plasmodia species have no capacity to cause lethal infections. In support of this scenario is an extensive, but older literature reviewed in references2, 3 showing that exclusive milk diets suppress malarial infections in birds, rodents, and primates. Milk contains very little PABA and yields low concentrations of folate (60-90 µg/1000 kcal; ~ 20 % of the DRI for a 3 year old child). The suppression of malarial symptoms is abrogated when supplemental PABA is added to all milk diets of infected animals2, 3. Further, rodent models of malaria demonstrate that dietary PABA and folate reduce the efficacy of sulfa drugs4 and in humans, high blood concentrations of folate also impair the efficacy of pyrimethamine and sulfa drugs5. An experimental study of 20 West African infants, up to 2 years of age who were naturally infected with Plasmodia falciparum demonstrated that exclusive milk diets reduced parasite density and decreased disease symptoms within a few days in a manner similar to those (n=12) serving as controls and treated with chloroquine therapy2.
The pastoralist Fulani of West and Central Africa exhibit a well established resistance to malaria compared to other non-milk drinking African sympatric ethnic groups that is unexplained by known genetic resistance factors6, but rather by enhanced immunity7. Displacement of PABA and folate rich foods by milk in this population may attenuate malaria infection while allowing immune exposure, serving to prevent serious disease sequelae and facilitate the establishment of protective immunity. In support of this concept are data showing a high prevalence of adult lactase persistence (~68 % of the population)8 in the Fulani which may represent a previously unrecognized genetic factor that indirectly reduces malarial mortality. Accordingly, in high malarial regions where adult lactase persistence is widespread, reduced dietary PABA and folate intake caused by high milk consumption may disrupt the life cycle of Plasmodia species by impairing folate metabolism, thereby reducing childhood malaria fatalities and overall morbidity within adults.
Except for a single modern study1, research involving the efficacy of PABA deficient diets in preventing or attenuating malaria symptoms effectively stopped in the early 1970s with the widespread use of insecticides, nettings and pharmaceuticals9. One of the major shortcomings in all of these early experiments was the failure to report milk PABA concentrations2, 3 which conceivably could have been quite variable – perhaps caused by various fodders fed to the cows or by different milk processing procedures. Additionally, because PABA is not an essential human nutrient, no tables of the PABA concentrations in common foods have ever been published. To our knowledge only a single study has reported the PABA concentrations in any food items (five vegetables: carrots, spinach, brussel sprouts, endive, and lettuce)10, whereas extensive USDA tables exist showing the folate concentrations in foods. Consequently, a crucial need exists to determine the PABA content of foods so that anti-malarial diets can be formulated and eventually tested.
The formulation of PABA deficient diets for humans will have no adverse health consequences as PABA is not required in human nutrition. Because about 80% of all deaths attributed to malaria occur in sub-Saharan Africa, mainly among children less than 5 years of age2, the greatest risk to their lives comes not from inadequate folate intake, but rather from malaria5. At a meeting hosted by the World Health Organization in 2006, five expert reports concluded that reducing folic acid supplementation in sub-Saharan African children may reduce fatal malarial infections11.
Section II. Phase I of the experiment will be descriptive in nature with the goal of characterizing the PABA content of a wide variety of foodstuffs, including sub-Saharan African ethnic foods. This PABA database along with pre-existing folate databases will be employed to formulate low PABA and folate diets that will be nutritionally adequate in other respects. We will assess PABA concentrations in ~500 pre-selected foods using multiple samples3-5 per food using HPLC/tandem mass spectrometry10, a procedure by which food compounds can be measured with great sensitivity and minimal preparation. Foods will be classified as high, medium or low PABA content. The estimated in house cost per food (~$150 - $200; ~$75,000 - $100,000 total) for the analyses (foods, reagents, technicians) will determine the extent of our PABA database. Once the pilot data garnered from Phase 1 is complete we plan to implement these diets first in rodent models of malaria and then in humans living in malarial regions of the world and contrast morbidity and mortality rates to those achieved by pharmaceutical intervention. Further, it may be possible to formulate low PABA and folate diets without the use of milk which is contraindicated in many sub-Saharan African populations because of their inability to digest the milk sugar lactose without gastric upset.
References:
1. Kicska GA et al. Infect. Dis. 2003; 188: 1776-1781.
2. Kretschmar, W, Voller AZ. Tropenmed. Parasit. 1973; 24: 51-59.
3. Nowell, F. Parasitology. 1970; 61: 425-433.
4. Jacobs, R.L. Exp. Parasitol. 1964; 15: 213-225.
5. Carter JY et al. Am J Trop Med Hyg 2005;73:166-170.
6. Modiano, D. et al. Proc. Natl. Acad. Sci.1996; 93: 13206-13211.
7. Bereczky, S. et al. Trans. R. Soc. Trop. Med. Hyg. 2006; 100: 248-257.
8. Swallow, DM. Ann. Rev. Genet. 2003; 37: 197-219.
9. Walther B, Walther M. Ann Trop Med Parasitol. 2007;101:657-72.
10. Zhang GF et al. Rapid Commun Mass Spectrom. 2005;19:963-9.
11. Oppenheimer S. Food Nutr Bull. 2007;28(4 suppl):S550-9.
