Humoral immunity prevents clinical malaria during Plasmodium relapses without eliminating gametocytes

Abstract

Plasmodium relapses are attributed to the activation of dormant liver-stage parasites and are responsible for a significant number of recurring malaria blood-stage infections. While characteristic of human infections caused by P. vivax and P. ovale, their relative contribution to malaria disease burden and transmission remains poorly understood. This is largely because it is difficult to identify ‘bona fide’ relapse infections due to ongoing transmission in most endemic areas. Here, we use the P. cynomolgi–rhesus macaque model of relapsing malaria to demonstrate that clinical immunity can form after a single sporozoite-initiated blood-stage infection and prevent illness during relapses and homologous reinfections. By integrating data from whole blood RNA-sequencing, flow cytometry, P. cynomolgi-specific ELISAs, and opsonic phagocytosis assays, we demonstrate that this immunity is associated with a rapid recall response by memory B cells that expand and produce anti-parasite IgG1 that can mediate parasite clearance of relapsing parasites. The reduction in parasitemia during relapses was mirrored by a reduction in the total number of circulating gametocytes, but importantly, the cumulative proportion of gametocytes increased during relapses. Overall, this study reveals that P. cynomolgi relapse infections can be clinically silent in macaques due to rapid memory B cell responses that help to clear asexual-stage parasites but still carry gametocytes.

Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer

“…In immune system, B cells are classically recognized as positive modulators to regulate inflammation and immune responses by releasing antibodies and activating T cells through antigen presentation (1)(2)(3). Generally, B cells produce antibodies which are a critical part of the host immunity against infection, that can neutralize pathogens, opsonize pathogens for subsequent phagocytosis and mediate antibody-dependent cellular cytotoxicity (4)(5)(6). Besides, B cells also act to suppress immune responses.…”

A dual fluorescent Plasmodium cynomolgi reporter line reveals in vitro malaria hypnozoite reactivation

“…In vivo , P. cynomolgi M is a fast relapsing parasite. While low-dose inoculations (2000 sporozoites) followed by subcurative treatment of blood stages gave rise to somewhat delayed relapses 24,25 , high-dose sporozoite inoculations (10 5 –10 6 ) resulted in early relapses around days 18–33 post infection as assessed by thin film analysis 26,27 . It is thus expected that activation of hypnozoites in this parasite may start relatively soon after the completion of liver stage development (merosome release) of the primary schizonts.…”

Modeling Relapsing Malaria: Emerging Technologies to Study Parasite-Host Interactions in the Liver

“…In addition, it was shown that P. cynomolgi relapses can be clinically silent. This is likely to be due to the rapid development of memory B cell responses that help to clear asexual blood stage parasites but not gametocytes (Joyner et al, 2019).…”