Malaria and the liver: immunological hide-and-seek or subversion of immunity from within?

Abstract

During the pre-erythrocytic asymptomatic phase of malarial infection, sporozoites develop transiently inside less than 100 hepatocytes that subsequently release thousands of merozoites. Killing of these hepatocytes by cytotoxic T cells (CTLs) confers protection to subsequent malarial infection, suggesting that this bottleneck phase in the parasite life cycle can be targeted by vaccination. During natural transmission, although some CTLs are generated in the skin draining lymph nodes, they are unable to eliminate the parasite, suggesting that the liver is important for the sporozoite to escape immune surveillance. The contribution of the organ to this process is unclear. Based on the known ability of several hepatic antigen-presenting cells (APCs) to induce primary activation of CD8 T cells and tolerance, malarial antigens presented by both infected hepatocytes and/or hepatic cross-presenting APCs should result in tolerance. However, our latest model predicts that due to the low frequency of infected hepatocytes, some T cells recognizing sporozoite epitopes with high affinity should differentiate into CTLs. In this review, we discuss two possible models to explain why CTLs generated in the liver and skin draining lymph nodes are unable to eliminate the parasite: (1) sporozoites harness the tolerogenic property of the liver; (2) CTLs are not tolerized but fail to detect infected cells due to sparse infection of hepatocytes and the very short liver stage. We propose that while malaria sporozoites might use the ability of the liver to tolerize both naive and effector cells, they have also developed strategies to decrease the probability of encounter between CTLs and infected liver cells. Thus, we predict that to achieve protection, vaccination strategies should aim to boost intrahepatic activation and/or increase the chance of encounter between sporozoite-specific CTLs and infected hepatocytes.

Keywords: Kupffer cells; LSEC; T cells; dendritic cells; hepatic stellate cells; hepatocytes; sporozoite; tolerance.

Figure 1

Sequence of events during the pre-erythrocytic phase of malaria parasite infection leading to the presentation of sporozoite antigens to CD8 T cells in several compartments. Some sporozoites injected by the mosquito migrate via the lymph into the skin draining lymph nodes (LNs). Migratory DCs or resident DCs capturing sporozoite proteins activate naive CD8 T cells and promote the generation of CTLs. Other sporozoites migrate via the blood to the liver where they are retained by hepatic stellate cells (HSC) and glide. After binding to a Kupffer cell (KC), they cross the liver sinusoidal endothelial cells (LSEC) barrier, traverse through several hepatocytes (H), before entering one in which they establish a parasitophorous vacuole. After a short period (2 days in mice for P. berghei/P. yoelii or 7 days in humans for P. falciparum), each infected hepatocyte releases thousands of merozoites that will subsequently infect red blood cells. While traversing hepatocytes, sporozoites leave a trail of CSP and possibly other proteins. Antigens shed by infected hepatocytes could also potentially be presented in the liver draining LNs.

Figure 2

Potential antigen presenting cells during the pre-erythrocytic phase of malaria parasite infection eliciting tolerance or effective immune responses (CTLs). Presentation of sporozoite antigens to CD8 T cells in the liver could occur either by hepatocytes or cross-presenting hepatic cells (LSEC and maybe KC). Although activation by all these cells should lead to tolerance, T cells recognizing sporozoite antigens expressed by infected hepatocytes with high affinity might differentiate into full effector cells. Malarial antigens can also be presented in skin and liver draining LNs by cross-presenting DCs. This activation should lead to efficient priming and CTLs. The fate of effector cells generated in the liver and lymphoid tissues and re-encountering tolerogenic APCs in the liver (red arrows) is unknown.

Figure 3

Different potential strategies used by sporozoites to evade immune surveillance by CTLs according to the “hide and seek” model. To avoid being eliminated by CTLs generated in the LNs or intrahepatically, malaria sporozoites might have developed several strategies: (i) the very low frequency of sporozoites lowers the probability of encountering CTLs; (ii) the short time spent in the liver (2–7 days) gives CTLs a very short time to kill all infected cells; (iii) infection of hepatocytes at a distance from the entry point might divert the CTLs to the wrong area; (iv) the trail of CSP left in non-infected hepatocytes during cell traversal by sporozoites might be used as a decoy to “buy” some precious time for the sporozoites.