Testing in Mice the Hypothesis That Melanin Is Protective in Malaria Infections

Abstract

Malaria has had the largest impact of any infectious disease on shaping the human genome, exerting enormous selective pressure on genes that improve survival in severe malaria infections. Modern humans originated in Africa and lost skin melanization as they migrated to temperate regions of the globe. Although it is well documented that loss of melanization improved cutaneous Vitamin D synthesis, melanin plays an evolutionary ancient role in insect immunity to malaria and in some instances melanin has been implicated to play an immunoregulatory role in vertebrates. Thus, we tested the hypothesis that melanization may be protective in malaria infections using mouse models. Congenic C57BL/6 mice that differed only in the gene encoding tyrosinase, a key enzyme in the synthesis of melanin, showed no difference in the clinical course of infection by Plasmodium yoelii 17XL, that causes severe anemia, Plasmodium berghei ANKA, that causes severe cerebral malaria or Plasmodium chabaudi AS that causes uncomplicated chronic disease. Moreover, neither genetic deficiencies in vitamin D synthesis nor vitamin D supplementation had an effect on survival in cerebral malaria. Taken together, these results indicate that neither melanin nor vitamin D production improve survival in severe malaria.

Vitamin D Inhibits the Occurrence of Experimental Cerebral Malaria in Mice by Suppressing the Host Inflammatory Response

“…Earlier work showed that there was no effect of injection of vitamin D on P. berghei infection in mice (24, 25). Injection using the same protocol reported (25) offered no protection against ECM (Fig. S1A, B).…”

“…For injection, VD was dissolved in 100% ethanol and diluted to a working solution of 0.1 μg/ml in 0.02% Tween 80. Mice in the treatment group was injected with a 0.5 μg/kg every other day, starting three days before the PbA infection (25), while mice in the control group received equal volumes of 0.02% Tween 80. For oral administration, VD was dissolved in soybean oil before use.…”

“…In a rodent malaria model, oral VD treatment of mice for two weeks prior to P. berghei infection has been reported to decrease parasite growth and expand the life span of infected mice (24). However, a recent study showed that three weekly intraperitoneal injections of 0.5 μg/kg VD had no effect on susceptibility of wild-type mice to PbA infection (25). In this report, we explored the effect of VD on ECM and showed that oral supplementation with VD protected mice from ECM.…”

Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

“…C57BL/6 mice were infected with PbA and monitored for peripheral blood parasitemia (31) and ECM clinical scores (25). DON (1.3 mg/kg) was administered i.p.…”

“…Mice were evaluated for the development of neurological signs associated with ECM and were given clinical scores between 0 (no signs) to 10 (moribund) using previously described criteria (25). Nearly all the untreated mice that were infected with PbA developed neurological signs by day 5p p.i.…”