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Malaria, folates and PABA

March 30, 2016 - 17:38 -- Pierre Lutgen

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 A1Food Nutr Bull. 2016 Mar 4. pii: 0379572116634511).

The detrimental role of PABA (para-amino benzoic acid) on malaria has already been described 60 years ago (F Hawking, British Medical Journal, 1954, Feb, 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 (A Bhatia et al Indian J Malariol 1991, 28 237-42). The same effect had already been inadvertely noticed in in vitro trials (CF Gilks et al., Parasitology, 1989 89 175-177).

Another research team showed that dietary folate deficiency protects primates against malaria (KC Das et al., Blood, 1992, 80-281). Blood infected with Plasmodium cynomolgi was injected into-folate deficient animals and folate-replete control animal. All control animals developed malaria and several died.

A more recent study extensively studies the effect of dietary PABA on murine Plasmodium yoelii infection (GA Kiczska et al., JID, 2003, 188, 1776-81). 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 P.yoelii. The initiation of a PABA-deficient diet after P.yoelii infection is established, 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 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 (MB van Hensbroek et al., Trans R Soc Prop Med Hyg 1995,89, 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 et al., Lancet. 2006 28;367(9507):302.

Another more recent study confirmed that high dietary folate in mice alters immune response and reduces survival after malarial infection (DN. Meadows, et al., PLOS One 2015 Nov 24. doi: 10.1371/journal.pone.0143738)

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 Echo Research Note No 1, 2012). Moringa is rich in glutamic acid – 5 times more than Artemisia- and para-aminobenzoic acid (PABA), two of the building blocks of folate (G Magnani et al., Biochem J, 2013455, 149-155). PABA is a major constituent in Moringa oleifera and soya (L Mbanga et al., Adv Biochem & Biotechnol., 2015, 1, 1-13). It was never detected in Artemisia annua. A recent paper studied the relative bioavailability of folate from the traditional food plant Moringa oleifera L. as evaluated in a rat model. The bioavailability of folate from dried leaves was 81.9%, which is much higher than the values of 50% known for other plants (Saini RK et al., J Food Sci Technol. 2016 ;53:511-20).

Several recent large scale trials in RDCongo (see “Breaking news from clinical trials with Artemisia plants, have shown that Artemisia annua and Artemisia afra completely eliminate gametocytes from malaria infected patients.

This is very encouraging for those who really want to eradicate malaria.  

But another research team found that PABA administered to gametocyte-carrying mice increased the number of oocysts in mosquitoes fed on them (W Peters Ann Trop Med Parasitol 1980, 74, 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 (B Merkli et al., Exp Parasit 1983 55, 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.