Para-aminobenzoic acid and folates enhance malaria

Malaria, folates and PABA : beware Folates combine three molecules : pretidine & para-aminobenzoic acid (PABA) & glutamate. They were discovered around 1940 and first isolated from spinach leaves. The term folate is derived from the latin word folium. The malaria parasite has a unique feature of being able to salvage exogenous folate derivatives and/or synthesize them de novo. Due to its high rate of replication, the parasite has a high demand for folates. Folate metabolism is the target of several antimalarials. Food fortified with folic acid has been available for consumption in North America for over two decades. African countries are now embracing this concept; however, because folate promotes malaria parasite division, as it does in cancer cells, there is a possibility of malaria exacerbation if folate intake is increased. Nzila A, Okombo J, Hyde J. Malaria in the Era of Food Fortification With Folic Acid. Food Nutr Bull. 2016 Jun; 37(2):153-63. doi: 10.1177/0379572116634511. The detrimental role of PABA (para-amino benzoic acid) on malaria has already been described 60 years ago F. Hawking. Milk, p-Aminobenzoate, and Malaria of Rats and Monkeys. Br Med J. 1954 Feb 20; 1(4859): 425–429. Rats fed on a milk diet were insusceptible to infection with Plasmodium berghei. Milk does not contain PABA or only traces. This insusceptibility was reversed by the addition of PABA or folic acid. The same experiences were repeated on monkeys and gave the same results. It is likely that the relative immunity to malaria shown by infants in many parts of the tropics may be due to a deficiency of PABA in their mother’s milk. In 1991 it was found that feeding wistar albino rats on low protein and low energy diet caused suppression of P berghei parasitaemia. When PABA was added to the diet parasitaemia re-elevated. Bhatia A, Vinayak VK. Dietary modulation of malaria infection in rats. Indian J Malariol. 1991 Dec;28(4):237-42. The same effect had already been inadvertely noticed in in vitro trials. Gilks CF, Jarra W, Harvey-Wood K, McLean SA, Schetters T. Host diet in experimental rodent malaria: a variable which can compromise experimental design and interpretation. Parasitology. 1989 Apr; 98 Pt 2:175-7. Another research team showed that dietary folate deficiency protects primates against malaria Anuraj H. Shankar. Nutritional Modulation of Malaria Morbidity and Mortality. The Journal of Infectious Diseases 2000;182 (Suppl 1):S37–53 Kretschmar W, Voller A. Suppression of Plasmodium falciparum malaria in Aotus monkeys by milk diet. Z Tropenmed Parasitol. 1973 Mar;24(1):51-9. Kicska GA, Ting LM, Schramm VL, Kim K. Effect of dietary p-aminobenzoic acid on murine Plasmodium yoelii infection. J Infect Dis. 2003 Dec 1;188(11):1776-81 Blood infected with Plasmodium cynomolgi was injected into-folate deficient animals and folate-replete control animal. All control animals developed malaria and several died. Plasmodium species, unlike humans, can utilize PABA for de novo generation of folate. The authors show that, despite the presence of biosynthetioc machinery to synthesize PABA, Plasmodium yoelii, a rodent malaria species, requires exogenous dietary PABA for survival. Mice fed low-PABA-diets do not die from lethal doses of Plasmodium yoelii. The initiation of a PABA-deficient diet after P.yoelii infection leads to the clearance of parasites and subsequent resistance to infection by P. yoelii. An intact immune system is not necessary for protection given that mice with severe combined immunodeficiency were also protected by PABA-deficient diet. In a randomized, placebo-controlled, double blind trial in Kenya with 488 pregnant women the authors conclude that the concomitant use of 5 mg FA supplementation compromises the efficacy of SP Peter Ouma, Monica E Parise, Anna M van Eijk. A Randomized Controlled Trial of Folate Supplementation When Treating Malaria in Pregnancy with Sulfadoxine-Pyrimethamine. PLOS One Clinical trials, October 20, 2006 http://dx.doi.org/10.1371/journal.pctr.0010028 In a trial made in The Gambia involving 600 children with uncomplicated falciparum malaria, among children who received the antifolate sulfadoxine-pyrimethamine, the treatment failure rate was significantly higher in those given folic acid than those given placebo van Hensbroek MB1, Morris-Jones S, Meisner S, Jaffar S, Bayo L, Dackour R, Phillips C, Greenwood BM. Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria. Trans R Soc Trop Med Hyg. 1995 Nov-Dec;89(6):672-6. And the authors suggest that the WHO recommendation of universal folic acid supplementation should exclude children in areas of high prevalence. In a randomized, double blind prophylactic trial in Zanzibar the authors had to conclude that the routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, Dhingra U, Kabole I, Deb S, Othman MK, Kabole FM. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006 Jan 14;367(9505):133-43. Another more recent study confirmed that high dietary folate in mice alters immune response and reduces survival after malarial infection Meadows DN1, Bahous RH1, Best AF2, Rozen R1,3. High Dietary Folate in Mice Alters Immune Response and Reduces Survival after Malarial Infection. PLoS One. 2015 Nov 24;10(11):e0143738. doi: 10.1371/journal.pone.0143738. Food fortified with folic acid has been available for consumption in North America for over a decade. Many African countries are now embracing this concept; however, because folate promotes malaria parasite division, as it does in cancer cells, there is a possibility of malaria exacerbation if folate intake is increased. Thus, the introduction of food fortification with folic acid in malaria-endemic areas should be attended by precautionary programs to monitor the risk of malaria. Nzila A, Okombo J, Hyde J. Malaria in the Era of Food Fortification With Folic Acid. Food Nutr Bull. 2016 Jun;37(2):153-63. doi: 10.1177/0379572116634511 In case of malaria infection, diet should be low in folates or PABA. Swamping Africa with multiple micronutrient powders (MNPs) from Switzerland, nutraceuticals from the US, “compléments alimentaires” from France, all containing folates, is questionable. The folic acid fortified milk market is booming. Business on the verge of crime. A plant which could be detrimental during malaria infection is Moringa oleifera. The average folate in vegetables is 40 microg/100g but in Moringa oleifera it goes up to 540 microg/100g DW. K Witt. The Nutrient Content of Moringa oleifera Leaves. Echo Research Note No 1, 2012. But another research team found that PABA administered to gametocyte-carrying mice increased the number of oocysts in mosquitoes fed on them. Peters W, Ramkaran AE. The chemotherapy of rodent malaria, XXXII. The influence of p-aminobenzoic acid on the transmission of Plasmodium yoelii and P. berghei by Anopheles stephensi. Ann Trop Med Parasitol. 1980 Jun;74(3):275-82. High PABA content in the diet leads to the selection of drug resistant parasites in mice. A higher yield of resistance was related to the higher parasitaemia generated by PABA Merkli B, Richle R. Plasmodium berghei: diet and drug dosage regimens influencing selection of drug-resistant parasites in mice. Exp Parasitol. 1983 Jun;55(3):372-6. That is worrying. We are supposed to know. But the malaria experts from WHO and Tropical Medicine Institutes close their eyes on it.