Molecular Biology of Liver Stages
Plasmodium possess only a single pyruvate dehydrogenase enzyme (PDH) complex. This is localized to the plastid-like organelle known as the apicoplast. Unlike most eukaryotes, Plasmodium lacks a mitochondrial PDH. The PDH catalyzes the conversion of pyruvate to acetyl-CoA, an important precursor for the tricarboxylic acid cycle and type II fatty acid synthesis.
The process of maturation within the liver is still being investigated. In the species Plasmodium yoelli the exit from the liver appears to be dependent on type II fatty acid synthesis. Deletions in either the pyruvate dehydrogenase E1 alpha and E3 subunits produce a phenotype similar to that found in mutants of the type II fatty acid synthesis pathway. These mutants appear normal in blood stage development, mosquito stage development and early liver stage development but fail to exit the liver cells.
Plasmodium is unable to synthesize sterols they must obtain these from the host. However manipulation of cholesterol metabolism does not impede the development of the merozoites.
Invasion of the hepatocyte induces the production of CD81 - a member of the tetraspanin superfamily. CD81 also appears to play a role in liver invasion by Plasmodium species. It is required for Plasmodium vivax sporozoite entry into human hepatocytes and for Plasmodium yoelii sporozoite entry into murine hepatocytes.
The protein UIS3 is an essential protein for liver stage development. It is thought to be localised to the membrane of the parasitophorous vacuole of the infected cell.
Latency of sporozoites is controlled by the eIF2 alpha kinase IK2, a general inhibitor of protein synthesis. Puf2 participates in the regulation of IK2 and inhibits premature sporozoite transformation. In contrast Puf1 appears to be dispensable.
The RNA binding protein family PUF member Pumilio-2 (Puf2) appears to be involved in transformation of sporozoites into the hepatic stage of the life cycle. Knock out mutants of this gene exhibit genome wide transcriptional changes resulting in loss of gliding motility, cell traversal ability, reduction in infectivity and trigger metamorphosis typical of early Plasmodium intra-hepatic development.
Type II fatty acid biosynthesis is vital for this stage in the life cycle. This pathway may be inhibited by the antibiotic triclosan.
The host iron regulatory hormone hepcidin which is synthesised in the liver and spleen, appears to be able to inhibit growth of the liver stages. Levels of this hormone are elevated during infection and seem to correlate with the anaemia often found in malaria. Erythrocytic parasitaemia, above a minimum threshold, impairs the growth of subsequent liver cell sporozoite infection. The production of hepcidin leads to the redistributes iron away from hepatocytes thus slowing the development of the iron dependent liver stage.
Liver hepcidin expression is upregulated and downregulated during the early and late stages of malaria infection respectively. Inflammation and erythropoietin, rather than the iron sensing pathway, are involved in the regulation of hepcidin expression. Treatment of malaria infected mice with anti hepcidin neutralizing antibodies increased parasitemia and mortality rates. Overexpression of hepcidin improves the outcome.
Lipocalin 2, a host protein that sequesters iron, is upregulated during infection and appears to be involved in the host response. This protein increases both host macrophage function and granulocyte recruitment and decreases reticulocytosis.
Expression of the iron sequestering protein ferritin (ferritin H chain in mice) is associated with decreased tissue damage. The mechanism appears to be via prevention of activation of the proapoptotic c-Jun N-terminal kinase.
Invasion of the hepatocyte seems to require the RON4 protease.
Within the liver actin reorganization is a dynamic process in part controlled by the actin severing and capping protein - gelsolin. The hepatocyte cytoskeleton may contribute to parasite elimination.
Within the genome is encoded a homolog of macrophage migration inhibitory factor. This gene appears to be important for parasite development in the liver.
In Plasmodium bergei a protein - liver specific protein 2 (LISP2) - is expressed 24 hours after infection and rapidly increases during the liver stage schizogony. LISP2 is carried first to the parasitophorous vacuole and subsequently transported to the cytoplasm and nucleus of host hepatocytes. Mutations in this gene result in arrested development of the merozoites.
Two other proteins (p52 and p36)in Plasmodium bergei appear to be important in the formation of the parasitophorous vacuole membrane in the liver.
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