The liver’s role in malaria survival

An anti-malaria vaccination in mice causes chemical modifications to liver DNA that seem to be necessary to overcome the disease. Understanding which genes and mechanisms in the liver intervene against malaria could help to design an efficient vaccine for humans.

The liver is the hub where malaria parasites multiply before invading red blood cells in the bloodstream, but it is also involved in counteracting the disease. The details of this protection mechanism are not completely clear. 

KACST-funded research investigated how vaccination and subsequent malaria infection affected the addition of methyl groups to liver DNA. This so-called ‘methylation’ of DNA regions called promoter sites typically leads to the repression of gene expression. Reduction in methylation (hypo-methylation), increasing gene expression, seems to be critical for vaccination efficacy. 

The scientists used the membrane of red blood cells infected with the rodent malaria parasite Plasmodium chabaudi as a vaccine. Studies have shown this vaccine increases the survival rate of mice from 0% to 80%. 

By analysing DNA extracted from liver tissues, the researchers found that vaccination induced the methylation of 256 gene promoters and the down-methylation of 345 promoters. 

When mice were then injected with the malaria parasite, the team found that some promoters reversed from hyper- to hypo-methylation (and vice-versa), just one day after the infection, indicating that some of the epigenetic effects brought in by the vaccine were temporary. 

After eight days of infection, 571 and 1,013 liver gene promoters were hyper- and hypo-methylated respectively. 

Both vaccination and malaria infection modified promoters controlling genes related to the regulation of gene transcription, and a minority of genes related to the immune response. 

Genes associated with hyper-methylated promoters in vaccinated mice were mostly related to the transport of nucleic acids and DNA binding. 

Genes with hypo-methylated promoters included: Cx3cl1, Gata2 and Gp130. Cx3cl1 enhances the liver’s capacity to remove red blood cells infected with P. chabaudi. These are replaced with new immature red blood cells, which are not P. chabaudi’s favourite host, likely through Gata2’s intervention. Finally, Gp130 plays a role in accelerating liver recovery from damage caused by the parasite. 

These self-healing strategies could contribute to long-lasting protective immunity in mice against future P. chabaudi infections. 

The data, say the researchers in their study published in the journal Parasitology Research, provides evidence that the vaccination-induced potency to survive P. chabaudi infection is associated with modifications in DNA methylation of promoters of numerous genes. This may ultimately impact the expression of genes involved in immune-related mechanisms in the liver, contributing to the survival of malaria.

1. Al-Quraishy, S., Dkhil, M. A., Abdel-Baki, A. A. S., Ghanjati, F., Erichsen, L., et al. Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice. Parasitology Research, 116(5), 1463-1477 (2017). | article