Host cell transcriptional profiling during malaria liver stage infection reveals a coordinated and sequential set of biological events.

BACKGROUND: Plasmodium sporozoites migrate to the liver where they traverse several hepatocytes before invading the one inside which they will develop and multiply into thousands of merozoites. Although this constitutes an essential step of malaria infection, the requirements of Plasmodium parasites in liver cells and how they use the host cell for their own survival and development are poorly understood. RESULTS: To gain new insights into the molecular host-parasite interactions that take place during malaria liver infection, we have used high-throughput microarray technology to determine the transcriptional profile of P. berghei-infected hepatoma cells. The data analysis shows differential expression patterns for 1064 host genes starting at 6 h and up to 24 h post infection, with the largest proportion correlating specifically with the early stages of the infection process. A considerable proportion of those genes were also found to be modulated in liver cells collected from P. yoelii-infected mice 24 and 40 h after infection, strengthening the data obtained with the in vitro model and highlighting genes and pathways involved in the host response to rodent Plasmodium parasites. CONCLUSION: Our data reveal that host cell infection by Plasmodium sporozoites leads to a coordinated and sequential set of biological events, ranging from the initial stage of stress response up to the engagement of host metabolic processes and the maintenance of cell viability throughout infection.

HGF/MET signalling protects Plasmodium-infected host cells from apoptosis.

Plasmodium, the causative agent of malaria, migrates through several hepatocytes before initiating a malaria infection. We have previously shown that this process induces the secretion of hepatocyte growth factor (HGF) by traversed cells, which renders neighbour hepatocytes susceptible to infection. The signalling initiated by HGF through its receptor MET has multifunctional effects on various cell types. Our results reveal a major role for apoptosis protection of host cells by HGF/MET signalling on the host susceptibility to infection. Inhibition of HGF/MET signalling induces a specific increase in apoptosis of infected cells leading to a great reduction on infection. Since HGF/MET signalling is capable of protecting cells from apoptosis by using both PI3-kinase/Akt and, to a lesser extent, MAPK pathways, we determined the impact of these pathways on Plasmodium sporozoite infection. Although inhibition of either of these pathways leads to a reduction in infection, inhibition of PI3-kinase/Akt pathway caused a stronger effect, which correlated with a higher level of apoptosis in infected host cells. Altogether, the results show that the HGF/MET signalling requirement for infection is mediated by its anti-apoptotic signal effects. These results demonstrate for the first time that active inhibition of apoptosis in host cell during infection by Plasmodium is required for a successful infection.

Survival of protozoan intracellular parasites in host cells.

The most common human diseases are caused by pathogens. Several of these microorganisms have developed efficient ways in which to exploit host molecules, along with molecular pathways to ensure their survival, differentiation and replication in host cells. Although the contribution of the host cell to the development of many intracellular pathogens (particularly viruses and bacteria) has been unequivocally established, the study of host-cell requirements during the life cycle of protozoan parasites is still in its infancy. In this review, we aim to provide some insight into the manipulation of the host cell by parasites through discussing the hurdles that are faced by the latter during infection.