Abstract
Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only ‘adaptive’ but also ‘innate’ lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO+ CD62L- effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ+IL-2+) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field.
Highlights
Malaria is caused by parasites of the genus Plasmodium that are transmitted from one human host to the by Anopheline mosquitoes, putting an estimated 3.3 billion of the world’s population at risk [1]
We measured the development of immune responses against the malaria parasite Plasmodium falciparum in human volunteers undergoing experimental malaria infections for the first time, allowing a uniquely detailed analysis thereof
We found that cellular immune responses against two clinically-relevant life-stages of the parasite are rapidly acquired following even a single malaria infection, and remain virtually undiminished over a year later – an unprecedented measurement
Summary
Malaria is caused by parasites of the genus Plasmodium that are transmitted from one human host to the by Anopheline mosquitoes, putting an estimated 3.3 billion of the world’s population at risk [1]. Upon inoculation by a mosquito, sporozoites initiate an asymptomatic infection of hepatocytes from which blood-stage forms emerge to invade and multiply exponentially within erythrocytes The latter process underlies the full spectrum of morbidity and mortality associated with clinical malaria. Infants in endemic areas remain susceptible to multiple new symptomatic infections throughout childhood and early adulthood, and adults frequently still harbor sub-clinical parasitemia (reviewed in [2,3]) Both poor induction (priming) of immune responses by the parasite and rapid attrition of such responses have been proposed as explanations, the validity of both hypotheses has been brought into question (discussed in [4,5,6])
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