Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections

Abstract

bFollowing transmission through a mosquito bite to the mammalian host, Plasmodium parasites first invade and replicate inside hepatocytes before infecting erythrocytes and causing malaria. The mechanisms limiting Plasmodium reinfections in humans living in regions of malaria endemicity have mainly been explored by studying the resistance induced by the blood stage of infection. However, epidemiologic studies have suggested that in high-transmission areas, preerythrocytic stages also activate host resistance to reinfection. This, along with the recent discovery that liver infections trigger a specific and effective type I interferon (IFN) response, prompted us to hypothesize that this pre-erythrocyte-stage-induced resistance is linked to liver innate immunity. Here, we combined experimental approaches and mathematical modeling to recapitulate field studies and understand the molecular basis behind such resistance. We present a newly established mouse reinfection model and demonstrate that rodent malaria liver-stage infection inhibits reinfection. This protection relies on the activation of innate immunity and involves the type I IFN response and the antimicrobial cytokine gamma IFN (IFN-␥). Importantly, mathematical simulations indicate that the predictions based on our experimental murine reinfection model fit available epidemiological data. Overall, our study revealed that liver-stage-induced innate immunity may contribute to the preerythrocytic resistance observed in humans in regions of malaria hyperendemicity. Malaria accounts for over half a million deaths per year and is thus the most prevalent parasitic human disease worldwide (1). The disease is caused by an intracellular protozoan parasite of the genus Plasmodium that infects multiple hosts, such as Anopheles mosquitoes and humans and other mammalians (2). Infection begins with a bite of a female mosquito that injects a few Plasmodium sporozoites, which represent the mosquito-transmitted parasite form, into the skin of the mammalian host. After migrating through skin cells (3), sporozoites enter the bloodstream and are then rapidly and specifically retained in the liver sinusoids. Sporozoites then cross the sinusoidal barrier (4) and traverse several liver cells until individual parasites invade a final hepatocyte with the formation of a parasitophorous vacuole (5). Inside this vacuolar niche, sporozoites asymptomatically develop and replicate into thousands of erythrocyte-infective parasites, termed merozoites (6). Finally, merozoites are released into the bloodstream and rapidly infect erythrocytes, initiating the blood stage and the clinical phase of infection (7).Malaria reinfections are common, especially in regions of high malaria transmission. Plasmodium parasites present an extraordinarily high rate of polymorphism; consequently, the host can be reinfected by different parasites that repeatedly escape the immune response (8). Therefore, efficient immunity to reinfection in one individual is obtained only after many years of facing recurrent infe...

Malaria Parasites: The Great Escape

“…IFN-γ induces the inducible nitric oxide enzyme to produce nitric oxide which directly kills the liver parasites (48–51). Innate immune mechanisms involving type I interferon pathway induced by the parasite infection and active against late schizonts or against reinfection have been recently uncovered (52–54). …”

From within host dynamics to the epidemiology of infectious disease: Scientific overview and challenges

“…Innate immune responses are activated, which at present are largely unexplored [54]. Surviving sporozoites migrate to the liver, where they take temporary refuge in hepatocytes [55].…”

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

“…This second-generation GAP3KO showed a much better safety profile in more stringent preclinical tests [26], and has recently completed successful Phase I safety trials in humans in which it appears safe and immunogenic [ In addition to the development of novel vaccine strategies, the access to liver stages afforded by rodent models allows for the interrogation of innate immune responses. Once thought to be immunologically inert, the liver stages of the parasite have recently been found to indeed induce innate immune responses that are capable of limiting parasite growth [27][28][29]. How exactly the parasite is sensed is still under investigation [30], and it is also unknown how these early innate events could influence the ensuing adaptive response.…”

“…Once thought to be immunologically inert, the liver stages of the parasite have recently been found to indeed induce innate immune responses that are capable of limiting parasite growth [27][28][29]. How exactly the parasite is sensed is still under investigation [30], and it is also unknown how these early innate events could influence the ensuing adaptive response.…”