Plasmodium, the causative agent of malaria, must first infect hepatocytes to initiate a mammalian infection. Sporozoites migrate through several hepatocytes, by breaching their plasma membranes, before infection is finally established in one of them. Here we show that wounding of hepatocytes by sporozoite migration induces the secretion of hepatocyte growth factor (HGF), which renders hepatocytes susceptible to infection. Infection depends on activation of the HGF receptor, MET, by secreted HGF. The malaria parasite exploits MET not as a primary binding site, but as a mediator of signals that make the host cell susceptible to infection. HGF/MET signaling induces rearrangements of the host-cell actin cytoskeleton that are required for the early development of the parasites within hepatocytes. Our findings identify HGF and MET as potential targets for new approaches to malaria prevention.
SummaryPlasmodium , 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.
Malaria starts with infection of the host liver by Plasmodium sporozoites. Inoculation with radiation-attenuated Plasmodium sporozoites induces complete protection against malaria. Protection is mediated by dendritic cells (DCs) and CD8(+) T cells, but the source of parasite antigens mediating this response remains unclear. Here, we show that hepatocytes infected with irradiated Plasmodium sporozoites undergo apoptosis shortly after infection. Infection with irradiated sporozoites induces the recruitment of DCs to the liver, where they phagocytose apoptotic infected hepatocytes containing parasite antigens. We propose that apoptotic Plasmodium-infected hepatocytes provide a source of parasite antigens for the initiation of the protective immune response.
Monocytes have the capacity to differentiate into macrophages or dendritic cells (DCs) after extravasation into lymphoid and nonlymphoid tissues. They have thus been consequently considered as precursors, but not effector cells, recirculating exclusively through the blood. In this report, we demonstrate for the first time that, after subcutaneous injection, activated monocytes migrate through the lymphatics from the dermis into the draining lymph nodes by a CCR7-dependent mechanism. LPS-activated monocytes were less efficient than DCs in stimulating CD4(+) T cells, but unexpectedly, they were highly efficient in inducing antigen-specific CD8(+) T-cell proliferation by cross-presentation, both in vitro and in vivo. Interestingly, CD8(+) T cells stimulated in vivo by activated monocytes expressed a high level of CD62L, suggesting that they had undergone an unconventional activation process. In conclusion, our data strongly support the concept that monocytes can behave not only as precursor cells for macrophages and DCs, but also as effector cells with the capacity to migrate from the periphery to the lymph nodes through the lymph and to cross-present antigens to CD8(+) T cells. These results suggest that monocytes can play an important role in the induction and regulation of CD4(+) and CD8(+) T-cell responses.
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.
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