Mechanisms and targets of Fcγ-receptor mediated immunity to malaria sporozoites

Feng, Gaoqian; Wines, Bruce D.; Kurtovic, Liriye; Chan, Jianxiong; Boeuf, Philippe; Mollard, Vanessa; Cozijnsen, Anton; Drew, Damien R.; Marshall, Daniel L; Chishimba, Sandra; McFadden, Geoffrey I.; Dent, Arlene E.; Chelimo, Kiprotich; Boyle, Michelle J.; Kazura, James W.; Hogarth, P Mark; Beeson, James G.

doi:10.1038/s41467-021-21998-4

Cited by 52 publications

(109 citation statements)

References 63 publications

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“…This association was observed in two independent experiments using both the PBLs and highly purified (>99%) neutrophils. These findings corroborate a recent study that showed that neutrophil opsonic phagocytosis of sporozoites is important in malaria immunity and suggest that the role of neutrophils in controlling parasitemia may transcend different stages of the parasite 18 . Since the PBL-phagocytosis assay developed here measures the phagocytic activity of all leukocytes, our analysis also demonstrated that the phagocytosis promoting activity of monocytes was significantly associated with a reduced risk of febrile malaria in this Ghanaian cohort.…”

Section: Discussionsupporting

confidence: 91%

“…While the role of monocytes in NAI against malaria is well established 12 – 14 , 23 , we show here that antibody-mediated phagocytosis of blood-stage P. falciparum by neutrophils is also involved in NAI. Due to their greater numbers, we predict that neutrophils are the main effector cells that control blood-stage malaria parasite multiplication in vivo a notion, which may also hold true for pre-erythrocytic stage infections 18 .…”

Section: Discussionmentioning

confidence: 91%

“…However, all the bioassays used in studying these mechanisms have mostly relied on the use of preselected cell types, such as monocytes 11 , 15 or neutrophils 11 , 16 , or cell lines belonging to definite lineages 13 , 14 , 16 , 17 , which may not clearly depict the peripheral blood environment. In a recent study, peripheral blood neutrophils in a whole-leukocyte assay were shown to play a prominent role in the clearance of P. falciparum sporozoites demonstrating their role in pre-erythrocytic stage malaria immunity 18 . The role of the different peripheral blood phagocytes in opsonic phagocytosis of blood-stage P. falciparum merozoites and their overall contribution to blood-stage malaria immunity is yet to be described using such unbiased in vitro bioassays.…”

Section: Introductionmentioning

confidence: 99%

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Neutrophils dominate in opsonic phagocytosis of P. falciparum blood-stage merozoites and protect against febrile malaria

et al. 2021

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Antibody-mediated opsonic phagocytosis (OP) of Plasmodium falciparum blood-stage merozoites has been associated with protection against malaria. However, the precise contribution of different peripheral blood phagocytes in the OP mechanism remains unknown. Here, we developed an in vitro OP assay using peripheral blood leukocytes that allowed us to quantify the contribution of each phagocytic cell type in the OP of merozoites. We found that CD14 + +CD16− monocytes were the dominant phagocytic cells at very low antibody levels and Fc gamma receptor (FcγR) IIA plays a key role. At higher antibody levels however, neutrophils were the main phagocytes in the OP of merozoites with FcγRIIIB acting synergistically with FcγRIIA in the process. We found that OP activity by neutrophils was strongly associated with protection against febrile malaria in longitudinal cohort studies performed in Ghana and India. Our results demonstrate that peripheral blood neutrophils are the main phagocytes of P. falciparum blood-stage merozoites.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Neutrophils dominate in opsonic phagocytosis of P. falciparum blood-stage merozoites and protect against febrile malaria

et al. 2021

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“…The lack of boosting for the vaccine-induced anti-CSP IgG Abs by the continuous natural exposure might be explained by the slow acquisition of pre-erythrocytic immunity in children [18]. Furthermore, there were no measurable levels of anti-CSP IgG among the controls, suggesting that natural P. falciparum infection does not induce substantial quantities of anti-CSP IgG specific memory B cells in children.…”

Section: Discussionmentioning

confidence: 98%

Seven-year kinetics of RTS, S/AS01-induced anti-CSP antibodies in young Kenyan children

Mugo

Mwai

Mwacharo

et al. 2021

Malar J

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Background RTS,S/AS01, the leading malaria vaccine has been recommended by the WHO for widespread immunization of children at risk. RTS,S/AS01-induced anti-CSP IgG antibodies are associated with the vaccine efficacy. Here, the long-term kinetics of RTS,S/AS01-induced antibodies was investigated. Methods 150 participants were randomly selected from the 447 children who participated in the RTS,S/AS01 phase IIb clinical trial in 2007 from Kilifi-Kenya. Cumulatively, the retrospective follow-up period was 93 months with annual plasma samples collection. The levels of anti-CSP IgM, total IgG, IgG1, IgG2, IgG3, and IgG4 antibodies were then determined using an enzyme-linked immunosorbent assay. Results RTS,S/AS01 induced high levels of anti-CSP IgG antibodies which exhibited a rapid waning over 6.5 months post-vaccination, followed by a slower decay over the subsequent years. RTS,S/AS01-induced anti-CSP IgG antibodies remained elevated above the control group levels throughout the 7 years follow-up period. The anti-CSP IgG antibodies were mostly IgG1, IgG3, IgG2, and to a lesser extent IgG4. IgG2 predominated in later timepoints. RTS,S/AS01 also induced high levels of anti-CSP IgM antibodies which increased above the control group levels by month 3. The controls exhibited increasing levels of the anti-CSP IgM antibodies which caught up with the RTS,S/AS01 vaccinees levels by month 21. In contrast, there were no measurable anti-CSP IgG antibodies among the controls. Conclusion RTS,S/AS01-induced anti-CSP IgG antibodies kinetics are consistent with long-lived but waning vaccine efficacy. Natural exposure induces anti-CSP IgM antibodies in children, which increases with age, but does not induce substantial levels of anti-CSP IgG antibodies.

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“…We also examined antibody responses to the specific regions of CSP using several antigen constructs. These included synthetic peptides representing the N-terminal region between amino acids 19-104 (NT) ( 38 ) and the central-repeat region comprised of the NANP motif repeated 15 times (NANP), both synthesized and purified by Life Tein (USA). We also used a recombinant protein representing the C-terminal region between amino acids 237-383 (CT) and a truncated CSP that lacked the central-repeat region (N+C), both expressed in HEK293 cells as previously described ( 23 , 38 ).…”

Section: Methodsmentioning

confidence: 99%

Antibody Targets and Properties for Complement-Fixation Against the Circumsporozoite Protein in Malaria Immunity

et al. 2021

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The Plasmodium falciparum circumsporozoite protein (CSP) forms the basis of leading subunit malaria vaccine candidates. However, the mechanisms and specific targets of immunity are poorly defined. Recent findings suggest that antibody-mediated complement-fixation and activation play an important role in immunity. Here, we investigated the regions of CSP targeted by functional complement-fixing antibodies and the antibody properties associated with this activity. We quantified IgG, IgM, and functional complement-fixing antibody responses to different regions of CSP among Kenyan adults naturally exposed to malaria (n=102) and using a series of rabbit vaccination studies. Individuals who acquired functional complement-fixing antibodies had higher IgG, IgM and IgG1 and IgG3 to CSP. Acquired complement-fixing antibodies targeted the N-terminal, central-repeat, and C-terminal regions of CSP, and positive responders had greater antibody breadth compared to those who were negative for complement-fixing antibodies (p<0.05). Using rabbit vaccinations as a model, we confirmed that IgG specific to the central-repeat and non-repeat regions of CSP could effectively fix complement. However, vaccination with near full length CSP in rabbits poorly induced antibodies to the N-terminal region compared to naturally-acquired immunity in humans. Poor induction of N-terminal antibodies was also observed in a vaccination study performed in mice. IgG and IgM to all three regions of CSP play a role in mediating complement-fixation, which has important implications for malaria vaccine development.

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Mechanisms and targets of Fcγ-receptor mediated immunity to malaria sporozoites

Cited by 52 publications

References 63 publications

Neutrophils dominate in opsonic phagocytosis of P. falciparum blood-stage merozoites and protect against febrile malaria

Neutrophils dominate in opsonic phagocytosis of P. falciparum blood-stage merozoites and protect against febrile malaria

Seven-year kinetics of RTS, S/AS01-induced anti-CSP antibodies in young Kenyan children

Antibody Targets and Properties for Complement-Fixation Against the Circumsporozoite Protein in Malaria Immunity

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