Rodriguez and Mota reply:

We previously showed that migration of Plasmodium berghei sporozoites through hepatocytes causes cell wounding and leads to the release of hepatocyte growth factor (HGF) and the activation of its tyrosine kinase receptor, MET. We also showed that MET activation boosts P. berghei infection in mice, whereas its depletion leads to a reduction in infection1,2. Now, Kaushansky and Kappe, although fully confirming our data with P. berghei, further show that neither Plasmodium yoelii nor Plasmodium falciparum sporozoite migration through hepatocytes activates MET. The authors use this system to highlight the similarities between P. falciparum and P. yoelii versus P. berghei. As the authors clearly state, P. berghei is less selective for its host cell than other Plasmodium species, as it is able to infect several hepatoma cell lines as well as several nonhepatocytic cells in a CD81-dependent or CD81-independent manner in vitro3. In contrast, P. yoelii and P. falciparum require CD81 to invade cells and are much more restricted in the range of cells they can infect in vitro. Nevertheless, P. falciparum and P. yoelii also differ quite markedly from each other. Although neither of them can infect HepG2 cells, expression of CD81 makes these cells susceptible to P. yoelii but not to P. falciparum infection. In contrast, certain aspects of the P. berghei model of liver stage infection resemble another important human pathogen, Plasmodium vivax. Indeed, like P. berghei, P. vivax readily infects HepG2 cells, indicating that both parasites are able to infect cells in a CD81-independent manner4. Altogether, although these studies emphasize the limitations of the currently available Plasmodium rodent models, these models are nevertheless very useful and often constitute the only possible approach to reveal and dissect the mechanisms underlying Plasmodium infection. Furthermore, all of these studies also highlight how the different Plasmodium species have evolved different mechanisms to infect their hosts. Understanding how these mechanisms were acquired and their role in virulence and infection will certainly contribute to improved design of future strategies to combat malaria.