Plasmodium attenuation: connecting the dots between early immune responses and malaria disease severity

Abstract

Sterile attenuation of Plasmodium parasites at the liver-stage either by irradiation or genetic modification, or at the blood-stage by chemoprophylaxis, has been shown to induce immune responses that can protect against subsequent wild-type infection. However, following certain interventions, parasite attenuation can be incomplete or non-sterile. Instead parasites are rendered developmentally stunted but still capable of establishing an acute infection. In experiments involving Plasmodium berghei ANKA, a model of experimental cerebral malaria, it has been observed that several forms of attenuated parasites do not induce cerebral pathology. In this perspective we collect evidence from studies on murine malaria in particular, and attempt to “connect the dots” between early immune responses and protection from severe cerebral disease, highlighting potential parallels to human infection.

TLR9 signalling inhibits Plasmodium liver infection by macrophage activation

“…While low liver-stage burden is usually associated with a delay in blood-stage patency, it is conceivable that the inflammatory environment-as exemplified by increase in serum levels of IL-12, IFN-γ, and MCP-1-induced following TLR9 activation can also impact blood stages as they egress out of the liver. Nonetheless, our findings that activation of TLR9 has an inhibitory effect on Pb pre-erythrocytic stages, are consistent with obser-vations that an altered, often inflammatory, pre-erythrocytic or early immune response at day 0-1 may change later host immune responses at days 5 and, thereby, reduce the incidence of ECM [49]. When we induced a TLR9-mediated immune response prior to infection with Pb iRBCs, which bypasses the liver stages of infection, animals had lower parasitemia and were completely protected against ECM.…”

“…Interestingly, the effect of TLR4 and ‐9 activation on ECM resembles observations in the context of experimental whole‐organism vaccine strategies that altered immune responses during the first 2 days after Pb ANKA infection paradoxically causes reduced inflammation and cerebral pathology 5 to 8 days postinfection [49, 59 – 62]. In contrast, our observation that TLR9 activation prevents ECM irrespective of the route of infection is counterintuitive to the recent report that depletion of γδ T cells and a liver stage‐directed IFN‐γ response are associated with protection against ECM following sporozoite but not iRBC infection [63].…”

Editorial: Breaking the cycle: attacking the malaria parasite in the liver

“…The observation that both antigen-specific and antigen-unrelated CD8 T cells cluster around infected hepatocytes led to the proposal that antigen-specific effector CD8 T cells recruit other T cells to the site of infection and that the resulting inflammatory microenvironment augments parasite killing by antigen-specific and antigen-unrelated bystander cells (Bayarsaikhan et al, 2015 ). The significance of antigen-dependent focal inflammation and its consequences for the elimination of the intracellular parasites is discussed (Fernandes et al, 2014 ).…”