Abstract
Malaria, caused by infection with Plasmodium parasites, drives multiple regulatory responses across the immune landscape. These regulatory responses help to protect against inflammatory disease but may in some situations hamper the acquisition of adaptive immune responses that clear parasites. In addition, the regulatory responses that occur during Plasmodium infection may negatively affect malaria vaccine efficacy in the most at-risk populations. Here, we discuss the specific cellular mechanisms of immunoregulatory networks that develop during malaria, with a focus on knowledge gained from human studies and studies that involve the main malaria parasite to affect humans, Plasmodium falciparum. Leveraging this knowledge may lead to the development of new therapeutic approaches to increase protective immunity to malaria during infection or after vaccination.
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References
World Health Organization. World malaria report 2023. WHO https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2023 (2023).
RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386, 31–45 (2015). This paper reports the final results from the phase III trial of RTS,S/AS01, leading to the world’s first licensed malaria vaccine.
Ally, O. et al. Seven-year efficacy of RTS,S/AS01 malaria vaccine among young African children. N. Engl. J. Med. 374, 2519–2529 (2016).
Stoute, J. A. et al. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. N. Engl. J. Med. 336, 86–91 (1997).
Seder, R. A. et al. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science 341, 1359–1365 (2013).
Oneko, M. et al. Safety, immunogenicity and efficacy of PfSPZ vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial. Nat. Med. 27, 1636–1645 (2021).
Cunnington, A. J. & Riley, E. M. Suppression of vaccine responses by malaria: insignificant or overlooked? Expert Rev. Vaccines 9, 409–429 (2014).
Murphy, S. C. et al. PfSPZ-CVac efficacy against malaria increases from 0% to 75% when administered in the absence of erythrocyte stage parasitemia: a randomized, placebo-controlled trial with controlled human malaria infection. PLoS Pathog. 17, e1009594 (2021). This study shows the negative impact of blood-stage infection on the efficacy of live, drug-attenuated P. falciparum sporozoite vaccination (PfSPZ-CVac).
Montes de Oca, M., Good, M. F., McCarthy, J. S. & Engwerda, C. R. The impact of established immunoregulatory networks on vaccine efficacy and the development of immunity to malaria. J. Immunol. 197, 4518–4526 (2016).
Jakobsen, P. H. et al. Inflammatory reactions in placental blood of Plasmodium falciparum‐infected women and high concentrations of soluble E‐selectin and a circulating P. falciparum protein in the cord sera. Immunology 93, 264–269 (1998).
Feeney, M. E. The immune response to malaria in utero. Immunol. Rev. 293, 216–229 (2019).
Lee, H. J. et al. Integrated pathogen load and dual transcriptome analysis of systemic host–pathogen interactions in severe malaria. Sci. Transl Med. 10, eaar3619 (2018).
Anyona, S. et al. Entire expressed peripheral blood transcriptome in pediatric severe malarial anemia. Preprint at Res. Sq. https://doi.org/10.21203/rs.3.rs-3150748/v1 (2023).
Day, N. P. J. et al. The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria. J. Infect. Dis. 180, 1288–1297 (1999).
Lyke, K. E. et al. Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1β), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect. Immun. 72, 5630–5637 (2004).
Portugal, S. et al. Exposure-dependent control of malaria-induced inflammation in children. PLoS Pathog. 10, e1004079 (2014). This study uses a systems biology approach to analyse paired PBMCs from Malian children, with results that suggest that children acquire P. falciparum-specific regulatory responses and enhanced anti-parasite responses in the setting of P. falciparum re-exposure.
Gonçalves, B. P. et al. Parasite burden and severity of malaria in Tanzanian children. N. Engl. J. Med. 370, 1799–1808 (2014).
Gupta, S., Snow, R. W., Donnelly, C. A., Marsh, K. & Newbold, C. Immunity to non-cerebral severe malaria is acquired after one or two infections. Nat. Med. 5, 340–343 (1999). This study shows that immunity to severe forms of malaria is acquired by children living in disease-endemic areas after only one or two P. falciparum infections.
Doolan, D. L., Dobaño, C. & Baird, J. K. Acquired immunity to malaria. Clin. Microbiol. Rev. 22, 13–36 (2009).
Jeffery, G. M. & Collins, W. E. A retrospective examination of secondary sporozoite- and trophozoite-induced infections with Plasmodium falciparum: development of parasitologic and clinical immunity following secondary infection. Am. J. Trop. Med. Hyg. 61, 20–35 (1999).
Ockenhouse, C. F. et al. Common and divergent immune response signaling pathways discovered in peripheral blood mononuclear cell gene expression patterns in presymptomatic and clinically apparent malaria. Infect. Immun. 74, 5561–5573 (2006).
Tran, T. M. et al. Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria. Sci. Rep. 6, 31291 (2016).
Boldt, A. B. W. et al. The blood transcriptome of childhood malaria. EBioMedicine 40, 614–625 (2019).
Prah, D. A. et al. Asymptomatic Plasmodium falciparum infection evades triggering a host transcriptomic response. J. Infect. 87, 259–262 (2023).
Nideffer, J. et al. Disease tolerance acquired through repeated plasmodium infection involves epigenetic reprogramming of innate immune cells. Preprint at bioRxiv https://doi.org/10.1101/2023.04.19.537546 (2023).
Bediako, Y. et al. Repeated clinical malaria episodes are associated with modification of the immune system in children. BMC Med. 17, 60 (2019). This study uses whole-blood transcriptomics, cellular phenotyping and cytokine analysis among Kenyan children and reports that those who had experienced multiple prior episodes of malaria had upregulation of interferon-inducible genes, increases in circulating IL-10 and activation of B cells, neutrophils and CD8+ T cells.
Bach, F. A. et al. A systematic analysis of the human immune response to Plasmodium vivax. J. Clin. Invest. 133, e152463 (2023).
Feintuch, C. M. et al. Activated neutrophils are associated with pediatric cerebral malaria vasculopathy in Malawian children. mBio 7, e01300–e01315 (2016).
Nallandhighal, S. et al. Whole-blood transcriptional signatures composed of erythropoietic and NRF2-regulated genes differ between cerebral malaria and severe malarial anemia. J. Infect. Dis. 219, 154–164 (2018).
Tran, T. M. et al. A molecular signature in blood reveals a role for p53 in regulating malaria-induced inflammation. Immunity 51, 750–765.e10 (2019).
Kirosingh, A. S. et al. Malaria-specific type 1 regulatory T cells are more abundant in first pregnancies and associated with placental malaria. EBioMedicine 95, 104772 (2023).
Studniberg, S. I. et al. Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria. Mol. Syst. Biol. 18, e10824 (2022).
Gazzinelli, R. T., Kalantari, P., Fitzgerald, K. A. & Golenbock, D. T. Innate sensing of malaria parasites. Nat. Rev. Immunol. 14, 744–757 (2014).
Dobbs, K. R. et al. Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria. JCI Insight 2, e95352 (2017).
Dooley, N. L. et al. Single cell transcriptomics shows that malaria promotes unique regulatory responses across multiple immune cell subsets. Nat. Commun. 14, 7387 (2023).
Stanisic, D. I. et al. γδ T cells and CD14+ monocytes are predominant cellular sources of cytokines and chemokines associated with severe malaria. J. Infect. Dis. 210, 295–305 (2014).
Reyes, M. et al. An immune-cell signature of bacterial sepsis. Nat. Med. 26, 333–340 (2020).
Guha, R. et al. Plasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype. PLoS Pathog. 17, e1009430 (2021). This study finds that monocytes of malaria-exposed Malian adults expressed lower levels of inflammatory cytokines and higher levels of regulatory molecules CD163, CD206, IL-10 and arginase 1, following in vitro P. falciparum stimulation in comparison with monocytes from Malian children or malaria-naive US adults.
Fontana, M. F. et al. A novel model of asymptomatic Plasmodium parasitemia that recapitulates elements of the human immune response to chronic infection. PLoS ONE 11, e0162132 (2016).
Biswas, S. K. & Lopez-Collazo, E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 30, 475–487 (2009).
Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).
Wimmers, F. et al. The single-cell epigenomic and transcriptional landscape of immunity to influenza vaccination. Cell 184, 3915–3935.e21 (2021).
Schrum, J. E. et al. Cutting edge: Plasmodium falciparum induces trained innate immunity. J. Immunol. 200, 1243–1248 (2018).
Crabtree, J. N. et al. Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum. J. Clin. Invest. 132, e139298 (2022).
Walk, J. et al. Controlled human malaria infection induces long-term functional changes in monocytes. Front. Mol. Biosci. 7, 604553 (2020).
Pinzon-Charry, A. et al. Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria. J. Exp. Med. 210, 1635–1646 (2013).
Loughland, J. R. et al. Profoundly reduced CD1c+ myeloid dendritic cell HLA-DR and CD86 expression and increased tumor necrosis factor production in experimental human blood-stage malaria infection. Infect. Immun. 84, 1403–1412 (2016).
Woodberry, T. et al. Low-level Plasmodium falciparum blood-stage infection causes dendritic cell apoptosis and dysfunction in healthy volunteers. J. Infect. Dis. 206, 333–340 (2012).
Turner, T. C. et al. Dendritic cell responses to Plasmodium falciparum in a malaria-endemic setting. Malar. J. 20, 9 (2021).
Wilson, N. S. et al. Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat. Immunol. 7, 165–172 (2006).
Ashayeripanah, M. et al. Systemic inflammatory response syndrome triggered by blood-borne pathogens induces prolonged dendritic cell paralysis and immunosuppression. Cell Rep. 43, 113754 (2023).
Knackstedt, S. L. et al. Neutrophil extracellular traps drive inflammatory pathogenesis in malaria. Sci. Immunol. 4, eaaw0336 (2019).
Feng, G. et al. Mechanisms and targets of Fcγ-receptor mediated immunity to malaria sporozoites. Nat. Commun. 12, 1742 (2021).
Ofori, E. A. et al. Human blood neutrophils generate ROS through FcγR-signaling to mediate protection against febrile P. falciparum malaria. Commun. Biol. 6, 743 (2023).
Amulic, B., Moxon, C. A. & Cunnington, A. J. A more granular view of neutrophils in malaria. Trends Parasitol. 36, 501–503 (2020).
Moorlag, S. J. C. F. M. et al. BCG vaccination induces long-term functional reprogramming of human neutrophils. Cell Rep. 33, 108387 (2020).
Goodier, M. R., Lundqvist, C., Hammarström, M., Troye‐Blomberg, M. & Langhorne, J. Cytokine profiles for human Vγ9+ T cells stimulated by Plasmodium falciparum. Parasite Immunol. 17, 413–423 (1995).
Behr, C. & Dubois, P. Preferential expansion of Vγ9 Vδ2 T cells following stimulation of peripheral blood lymphocytes with extracts of Plasmodium falciparum. Int. Immunol. 4, 361–366 (1992).
Jagannathan, P. et al. Loss and dysfunction of Vδ2+ γδ T cells are associated with clinical tolerance to malaria. Sci. Transl Med. 6, 251ra117 (2014). This study finds that repeated malaria during childhood results in progressive loss and dysfunction of pro-inflammatory, malaria-responsive γδ T cells and that this may have a role in facilitating anti-disease immunity in children.
Jagannathan, P. et al. Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure. Sci. Rep. 7, 11487 (2017).
Costa, G. et al. Control of Plasmodium falciparum erythrocytic cycle: γδ T cells target the red blood cell-invasive merozoites. Blood 118, 6952–6962 (2011).
Junqueira, C. et al. γδ T cells suppress Plasmodium falciparum blood-stage infection by direct killing and phagocytosis. Nat. Immunol. 22, 347–357 (2021).
Ishizuka, A. S. et al. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat. Med. 22, 614–623 (2016).
Zaidi, I. et al. γδ T cells are required for the induction of sterile immunity during irradiated sporozoite vaccinations. J. Immunol. 199, 3781–3788 (2017).
Lautenbach, M. J. et al. Systems analysis shows a role of cytophilic antibodies in shaping innate tolerance to malaria. Cell Rep. 39, 110709 (2022).
Schofield, L. et al. Synergistic effect of IL-12 and IL-18 induces TIM3 regulation of γδ T cell function and decreases the risk of clinical malaria in children living in Papua New Guinea. BMC Med. 15, 114 (2017).
Farrington, L. A. et al. Frequent malaria drives progressive Vδ2 T-cell loss, dysfunction, and CD16 up-regulation during early childhood. J. Infect. Dis. 213, 1483–1490 (2016).
Farrington, L. A. et al. Opsonized antigen activates Vδ2+ T cells via CD16/FCγRIIIa in individuals with chronic malaria exposure. PLoS Pathog. 16, e1008997 (2020).
Borstel, Avon et al. Repeated Plasmodium falciparum infection in humans drives the clonal expansion of an adaptive γδ T cell repertoire. Sci. Transl Med. 13, eabe7430 (2021).
Hviid, L. et al. Perturbation and proinflammatory type activation of Vδ1+ γδ T cells in African children with Plasmodium falciparum malaria. Infect. Immun. 69, 3190–3196 (2001).
Hviid, L. et al. High frequency of circulating γδ T cells with dominance of the Vδ1 subset in a healthy population. Int. Immunol. 12, 797–805 (2000).
Goodier, M. R., Wolf, A. S. & Riley, E. M. Differentiation and adaptation of natural killer cells for anti‐malarial immunity. Immunol. Rev. 293, 25–37 (2019).
Artavanis-Tsakonas, K. & Riley, E. M. Innate immune response to malaria: rapid induction of IFN-γ from human NK cells by live Plasmodium falciparum-infected erythrocytes. J. Immunol. 169, 2956–2963 (2002).
Horowitz, A. et al. Cross-talk between T cells and NK cells generates rapid effector responses to Plasmodium falciparum-infected erythrocytes. J. Immunol. 184, 6043–6052 (2010).
Horowitz, A. et al. Antigen-specific IL-2 secretion correlates with NK cell responses after immunization of Tanzanian children with the RTS,S/AS01 malaria vaccine. J. Immunol. 188, 5054–5062 (2012).
Kazmin, D. et al. Systems analysis of protective immune responses to RTS,S malaria vaccination in humans. Proc. Natl Acad. Sci. USA 114, 2425–2430 (2017).
Arora, G. et al. NK cells inhibit Plasmodium falciparum growth in red blood cells via antibody-dependent cellular cytotoxicity. eLife 7, e36806 (2018).
Odera, D. O. et al. Anti-merozoite antibodies induce natural killer cell effector function and are associated with immunity against malaria. Sci. Transl Med. 15, eabn5993 (2023).
Moebius, J. et al. PD-1 expression on NK cells in malaria-exposed individuals is associated with diminished natural cytotoxicity and enhanced antibody-dependent cellular cytotoxicity. Infect. Immun. 88, e00711–e00719 (2020).
Hart, G. T. et al. Adaptive NK cells in people exposed to Plasmodium falciparum correlate with protection from malaria. J. Exp. Med. 216, 1280–1290 (2019).
Ty, M. et al. Malaria-driven expansion of adaptive-like functional CD56-negative NK cells correlates with clinical immunity to malaria. Sci. Transl Med. 15, eadd9012 (2023). This longitudinal study profiles NK cells in cohorts of Ugandan children and identifies an atypical CD56– subset that expands in response to repeated P. falciparum stimulation and correlates with protection against symptomatic malaria.
Mavilio, D. et al. Characterization of CD56–/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc. Natl Acad. Sci. USA 102, 2886–2891 (2005).
Gonzalez, V. D. et al. Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-α and ribavirin treatment. J. Immunol. 183, 6612–6618 (2009).
Forconi, C. S. et al. Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas. Blood Adv. 2, 1101–1114 (2018).
Björkström, N. K., Ljunggren, H.-G. & Sandberg, J. K. CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol. 31, 401–406 (2010).
Osier, F. H. et al. Opsonic phagocytosis of Plasmodium falciparum merozoites: mechanism in human immunity and a correlate of protection against malaria. BMC Med. 12, 108 (2014).
Musasia, F. K. et al. Phagocytosis of Plasmodium falciparum ring-stage parasites predicts protection against malaria. Nat. Commun. 13, 4098 (2022).
Nziza, N. et al. Accumulation of neutrophil phagocytic antibody features tracks with naturally acquired immunity against malaria in children. J. Infect. Dis. 228, 759–768 (2023).
Engwerda, C. R., Ng, S. S. & Bunn, P. T. The regulation of CD4+ T cell responses during protozoan infections. Front. Immunol. 5, 498 (2014).
Montes de Oca, M. et al. Type I interferons regulate immune responses in humans with blood-stage Plasmodium falciparum infection. Cell Rep. 17, 399–412 (2016).
Roestenberg, M. et al. Protection against a malaria challenge by sporozoite inoculation. N. Engl. J. Med. 361, 468–477 (2009).
Mordmüller, B. et al. Sterile protection against human malaria by chemoattenuated PfSPZ vaccine. Nature 542, 445–449 (2017).
de Jong, S. E. et al. Systems analysis and controlled malaria infection in Europeans and Africans elucidate naturally acquired immunity. Nat. Immunol. 22, 654–665 (2021).
Boyle, M. J. et al. Effector phenotype of Plasmodium falciparum-specific CD4+ T cells is influenced by both age and transmission intensity in naturally exposed populations. J. Infect. Dis. 212, 416–425 (2015).
Boyle, M. J. et al. The development of Plasmodium falciparum-specific IL10 CD4 T cells and protection from malaria in children in an area of high malaria transmission. Front. Immunol. 8, 1329 (2017).
Odorizzi, P. M. et al. In utero priming of highly functional effector T cell responses to human malaria. Sci. Transl Med. 10, eaat6176 (2018). This study profiles cord blood from Ugandan infants and finds that placental malaria is associated with generation of pro-inflammatory malaria-responsive fetal T cells.
Gitau, E. N. et al. CD4+ T cell responses to the Plasmodium falciparum erythrocyte membrane protein 1 in children with mild malaria. J. Immunol. 192, 1753–1761 (2014).
Ghazanfari, N., Mueller, S. N. & Heath, W. R. Cerebral malaria in mouse and man. Front. Immunol. 9, 2016 (2018).
Sakaguchi, S. et al. Regulatory T cells and human disease. Annu. Rev. Immunol. 38, 541–566 (2020).
Minigo, G. et al. Parasite-dependent expansion of TNF receptor II-positive regulatory T cells with enhanced suppressive activity in adults with severe malaria. PLoS Pathog. 5, e1000402 (2009).
Kurup, S. P. et al. Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4. Nat. Med. 23, 1220–1225 (2017).
Todryk, S. M. et al. Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4+CD25high T cells with susceptibility in Kenyans. PLoS ONE 3, e2027 (2008).
Walther, M. et al. Upregulation of TGF-β, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23, 287–296 (2005).
Torcia, M. G. et al. Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria. Proc. Natl Acad. Sci. USA 105, 646–651 (2008).
Boyle, M. J. et al. Decline of FoxP3+ regulatory CD4 T cells in peripheral blood of children heavily exposed to malaria. PLoS Pathog. 11, e1005041 (2015).
Jagannathan, P. et al. IFNγ/IL-10 co-producing cells dominate the CD4 response to malaria in highly exposed children. PLoS Pathog. 10, e1003864 (2014).
Walther, M. et al. Distinct roles for FOXP3+ and FOXP3− CD4+ T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog. 5, e1000364 (2009).
Brustoski, K. et al. IFN-gamma and IL-10 mediate parasite-specific immune responses of cord blood cells induced by pregnancy-associated Plasmodium falciparum malaria. J. Immunol. 174, 1738–1745 (2005).
Edwards, C. L. et al. IL-10-producing Th1 cells possess a distinct molecular signature in malaria. J. Clin. Invest. 133, e153733 (2023). This study describes the heterogeneity of co-inhibitory receptor expression by Treg cells during P. falciparum infection, highlighting the difficulty in targeting these regulatory pathways for favourable clinical outcomes in malaria.
Sumida, T. S. et al. Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells. Nat. Immunol. 23, 632–642 (2022).
Wang, Y. et al. STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria. J. Clin. Invest. 133, e169417 (2023).
Chughlay, M. F. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of coadministered ruxolitinib and artemether–lumefantrine in healthy adults. Antimicrob. Agents Chemother. 66, e0158421 (2021).
Junqueira, C. et al. Cytotoxic CD8+ T cells recognize and kill Plasmodium vivax-infected reticulocytes. Nat. Med. 24, 1330–1336 (2018).
Bijker, E. M. et al. Cytotoxic markers associate with protection against malaria in human volunteers immunized with plasmodium falciparum sporozoites. J. Infect. Dis. 210, 1605–1615 (2014).
Hodgson, S. H. et al. Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals. J. Infect. Dis. 211, 1076–1086 (2015).
Lefebvre, M. N. & Harty, J. T. You shall not pass: memory CD8 T cells in liver-stage malaria. Trends Parasitol. 36, 147–157 (2020).
Noé, A. et al. Deep immune phenotyping and single-cell transcriptomics allow identification of circulating TRM-like cells which correlate with liver-stage immunity and vaccine-induced protection from malaria. Front. Immunol. 13, 795463 (2022).
Howland, S. W., Claser, C., Poh, C. M., Gun, S. Y. & Rénia, L. Pathogenic CD8+ T cells in experimental cerebral malaria. Semin. Immunopathol. 37, 221–231 (2015).
Riggle, B. A. et al. CD8+ T cells target cerebrovasculature in children with cerebral malaria. J. Clin. Invest. 130, 1128–1138 (2019).
Barrera, V. et al. Comparison of CD8+ T cell accumulation in the brain during human and murine cerebral malaria. Front. Immunol. 10, 1747 (2019).
Kaminski, L.-C. et al. Cytotoxic T cell-derived granzyme B is increased in severe plasmodium falciparum malaria. Front. Immunol. 10, 2917 (2019).
Noble, A., Giorgini, A. & Leggat, J. A. Cytokine-induced IL-10–secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage. Blood 107, 4475–4483 (2006).
Cohen, S., McGregor, I. A. & Carrington, S. Gamma-globulin and acquired immunity to human malaria. Nature 192, 733–737 (1961). This pivotal study shows the crucial role of anti-parasite antibody in controlling parasitaemia and clinical symptoms in malaria.
Kurtovic, L. et al. Multi-functional antibodies are induced by the RTS,S malaria vaccine and associated with protection in a phase I/IIa trial. J. Infect. Dis. 365, 1863 (2020).
White, M. T. et al. Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial. Lancet Infect. Dis. 15, 1450–1458 (2015).
RTS,S Clinical Trials Partnership. Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med. 11, e1001685 (2014).
Opi, D. H. et al. Multi-functional antibody profiling for malaria vaccine development and evaluation. Expert Rev. Vaccines 20, 1257–1272 (2021).
Tan, J. et al. Functional human IgA targets a conserved site on malaria sporozoites. Sci. Transl Med. 13, eabg2344 (2021).
Boyle, M. J. et al. Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against malaria. Immunity 42, 580–590 (2015). This study shows that antibodies that target merozoite-stage parasites require complement to inhibit parasite growth and that complement-fixing antibodies are strongly associated with protection from malaria.
Boyle, M. J. et al. IgM in human immunity to Plasmodium falciparum malaria. Sci. Adv. 5, eaax4489 (2019).
Behet, M. C. et al. The complement system contributes to functional antibody-mediated responses induced by immunization with Plasmodium falciparum malaria sporozoites. Infect. Immun. 86, e00920-17 (2018).
Kurtovic, L. et al. Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children. BMC Med. 16, 61 (2018).
Opi, D. H. et al. Reduced risk of placental parasitemia associated with complement fixation on Plasmodium falciparum by antibodies among pregnant women. BMC Med. 19, 201 (2021).
Reiling, L. et al. Targets of complement-fixing antibodies in protective immunity against malaria in children. Nat. Commun. 10, 610 (2019).
Joos, C. et al. Clinical protection from falciparum malaria correlates with neutrophil respiratory bursts induced by merozoites opsonized with human serum antibodies. PLoS ONE 5, e9871 (2010).
Garcia-Senosiain, A. et al. Neutrophils dominate in opsonic phagocytosis of P. falciparum blood-stage merozoites and protect against febrile malaria. Commun. Biol. 4, 984 (2021).
Hill, D. L. et al. Merozoite antigens of Plasmodium falciparum elicit strain-transcending opsonizing immunity. Infect. Immun. 84, 2175–2184 (2016).
Larsen, M. D. et al. Afucosylated Plasmodium falciparum-specific IgG is induced by infection but not by subunit vaccination. Nat. Commun. 12, 5838 (2021). This paper shows that afucosylated IgG targeting the pregnancy-associated red blood cell surface antigen PfEMP1 induces Fc-dependent NK cell degranulation and that these afucosylated antibodies develop during natural infection but not vaccination.
Tarlinton, D. M., Ding, Z., Tellier, J. & Nutt, S. L. Making sense of plasma cell heterogeneity. Curr. Opin. Immunol. 81, 102297 (2023).
White, M. T. et al. Dynamics of the antibody response to Plasmodium falciparum infection in African children. J. Infect. Dis. 210, 1115–1122 (2014). This study models the kinetics of SLPC and LLPC induction and maintenance following malaria infection.
Vijay, R. et al. Infection-induced plasmablasts are a nutrient sink that impairs humoral immunity to malaria. Nat. Immunol. 21, 790–801 (2020).
Fowkes, F. J. I., McGready, R., Johnstone-Robertson, S., Nosten, F. & Beeson, J. G. Antibody boosting and longevity following tetanus immunization during pregnancy. Clin. Infect. Dis. 56, 749–750 (2013).
Fowkes, F. J. I. et al. New insights into acquisition, boosting, and longevity of immunity to malaria in pregnant women. J. Infect. Dis. 206, 1612–1621 (2012).
Baird, J. K. et al. Age-dependent acquired protection against Plasmodium falciparum in people having two years exposure to hyperendemic malaria. Am. J. Med. Trop. Hyg. 45, 65–76 (1991). This study identifies the key role of host age in acquisition of protective immunity to P. falciparum malaria.
Baird, J. K. Age dependent characteristics of protection v. susceptibility to Plasmodium falciparum. Ann. Trop. Med. Parasitol. 92, 367–390 (2017).
Oyong, D. A. et al. Adults with Plasmodium falciparum malaria have higher magnitude and quality of circulating T-follicular helper cells compared to children. EBioMedicine 75, 103784 (2022).
Rodriguez-Barraquer, I. et al. Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure. eLife 7, e35832 (2018). This study uses detailed clinical and entomological data to quantify the development of anti-disease and anti-parasite immunity, showing independent effects of age and parasite exposure.
Ssewanyana, I. et al. Impact of a rapid decline in malaria transmission on antimalarial IgG subclasses and avidity. Front. Immunol. 11, 576663 (2021).
Chan, J.-A. et al. Age-dependent changes in circulating Tfh cells influence development of functional malaria antibodies in children. Nat. Commun. 13, 4159 (2022).
Ssewanyana, I. et al. Avidity of anti-malarial antibodies inversely related to transmission intensity at three sites in Uganda. Malar. J. 16, 67 (2017).
Urban, B. C. et al. Fatal Plasmodium falciparum malaria causes specific patterns of splenic architectural disorganization. Infect. Immun. 73, 1986–1994 (2005).
Dechkhajorn, W. et al. The activation of BAFF/APRIL system in spleen and lymph nodes of Plasmodium falciparum infected patients. Sci. Rep. 10, 3865 (2020).
Kho, S. et al. Hidden biomass of intact malaria parasites in the human spleen. N. Engl. J. Med. 384, 2067–2069 (2021). This study identifies a hidden biomass of P. falciparum and P. vivax in the spleens of asymptomatic adults from a malaria-endemic area of Papua, Indonesia.
Kho, S. et al. Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: a prospective human splenectomy study. PLoS Med. 18, e1003632 (2021).
Joice, R. et al. Plasmodium falciparum transmission stages accumulate in the human bone marrow. Sci. Transl Med. 6, 244re5 (2014).
Aguilar, R. et al. Molecular evidence for the localization of Plasmodium falciparum immature gametocytes in bone marrow. Blood 123, 959–966 (2014).
Obaldia, N. et al. Bone marrow is a major parasite reservoir in Plasmodium vivax infection. mBio 9, e00625-18 (2018).
Ndungu, F. M. et al. Memory B cells are a more reliable archive for historical antimalarial responses than plasma antibodies in no-longer exposed children. Proc. Natl Acad. Sci. USA 109, 8247–8252 (2012). This study shows that memory B cells survive longer than anti-parasite antibodies in serum, indicating that they are better maintained than LLPCs in children previously exposed to P. falciparum.
Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).
Weiss, G. E. et al. The Plasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections. PLoS Pathog. 6, e1000912 (2010).
Weiss, G. E. et al. Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area. J. Immunol. 183, 2176–2182 (2009). This study is the first to show that P. falciparum malaria drives expansion of ‘atypical’ memory B cells, previously identified as a hyporesponsive B cell subset in HIV-infected individuals.
Portugal, S. et al. Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function. eLife 4, 1748 (2015).
Sullivan, R. T. et al. FCRL5 delineates functionally impaired memory B cells associated with Plasmodium falciparum exposure. PLoS Pathog. 11, e1004894 (2015).
Sundling, C. et al. B cell profiling in malaria reveals expansion and remodelling of CD11c+ B cell subsets. JCI Insight 5, e126492 (2019).
Illingworth, J. et al. Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. J. Immunol. 190, 1038–1047 (2013).
Holla, P. et al. Shared transcriptional profiles of atypical B cells suggest common drivers of expansion and function in malaria, HIV, and autoimmunity. Sci. Adv. 7, eabg8384 (2021).
Sutton, H. J. et al. Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans. Cell Rep. 34, 108684 (2021).
Muellenbeck, M. F. et al. Atypical and classical memory B cells produce Plasmodium falciparum neutralizing antibodies B cell memory to Plasmodium falciparum. J. Exp. Med. 210, 389–399 (2013). This paper shows that both classical and ‘atypical’ memory B cells contribute to protective circulating antibodies in malaria.
Hopp, C. S. et al. Atypical B cells up-regulate costimulatory molecules during malaria and secrete antibodies with T follicular helper cell support. Sci. Immunol. 7, eabn1250 (2022).
Obeng-Adjei, N. et al. Malaria-induced interferon-γ drives the expansion of Tbethi atypical memory B cells. PLoS Pathog. 13, e1006576 (2017).
Hopp, C. S. et al. Plasmodium falciparum-specific IgM B cells dominate in children, expand with malaria, and produce functional IgM. J. Exp. Med. 218, e20200901 (2021).
Thouvenel, C. D. et al. Multimeric antibodies from antigen-specific human IgM+ memory B cells restrict Plasmodium parasites. J. Exp. Med. 218, e20200942 (2021).
Krishnamurty, A. T. et al. Somatically hypermutated Plasmodium-specific IgM+ memory B cells are rapid, plastic, early responders upon malaria rechallenge. Immunity 45, 402–414 (2016).
Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607–612 (2015).
Han, X. et al. Potential role for regulatory B cells as a major source of interleukin-10 in spleen from Plasmodium chabaudi-infected mice. Infect. Immun. 86, e00016-18 (2018).
Soon, M. S. F., Nalubega, M. & Boyle, M. J. T-follicular helper cells in malaria infection and roles in antibody induction. Oxf. Open Immunol. 2, iqab008 (2021).
Sebina, I. et al. IFNAR1-signalling obstructs ICOS-mediated humoral immunity during non-lethal blood-stage Plasmodium infection. PLoS Pathog. 12, e1005999 (2016).
Zander, R. A. et al. Type I interferons induce T regulatory 1 responses and restrict humoral immunity during experimental malaria. PLoS Pathog. 12, e1005945 (2016).
Olatunde, A. C., Hale, J. S. & Lamb, T. J. Cytokine-skewed Tfh cells: functional consequences for B cell help. Trends Immunol. 42, 536–550 (2021).
Chan, J.-A. et al. Th2-like T follicular helper cells promote functional antibody production during Plasmodium falciparum infection. Cell Rep. Med. 1, 100157 (2020).
Bowyer, G. et al. CXCR3+ T follicular helper cells induced by co-administration of RTS,S/AS01B and viral-vectored vaccines are associated with reduced immunogenicity and efficacy against malaria. Front. Immunol. 9, 1660 (2018).
Minassian, A. M. et al. Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination. Med 2, 701–719.e19 (2021).
Wahl, I. et al. Clonal evolution and TCR specificity of the human TFH cell response to Plasmodium falciparum CSP. Sci. Immunol. 7, eabm9644 (2022).
Obeng-Adjei, N. et al. Circulating Th1-cell-type Tfh cells that exhibit impaired B cell help are preferentially activated during acute malaria in children. Cell Rep. 13, 425–439 (2015).
Solé, P. et al. A T follicular helper cell origin for T regulatory type 1 cells. Cell. Mol. Immunol. 20, 489–511 (2023).
Xin, G. et al. Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection. Nat. Commun. 9, 5037 (2018).
Wing, J. B., Lim, E. L. & Sakaguchi, S. Control of foreign Ag‐specific Ab responses by Treg and Tfr. Immunol. Rev. 296, 104–119 (2020).
Datoo, M. S. et al. Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial. Lancet 403, 533–544 (2024).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/search?term=NCT04978272 (2024).
Chandramohan, D. et al. Seasonal malaria vaccination with or without seasonal malaria chemoprevention. N. Engl. J. Med. 385, 1005–1017 (2021).
Kapulu, M. C. et al. Safety and PCR monitoring in 161 semi-immune Kenyan adults following controlled human malaria infection. Jci Insight 6, e146443 (2021).
Dejon-Agobe, J. C. et al. Controlled human malaria infection of healthy adults with lifelong malaria exposure to assess safety, immunogenicity, and efficacy of the asexual blood stage malaria vaccine candidate GMZ2. Clin. Infect. Dis. 69, 1377–1384 (2018).
Sissoko, M. S. et al. Safety and efficacy of a three-dose regimen of Plasmodium falciparum sporozoite vaccine in adults during an intense malaria transmission season in Mali: a randomised, controlled phase 1 trial. Lancet Infect. Dis. 22, 377–389 (2021).
van Dorst, M. M. A. R. et al. Immunological factors linked to geographical variation in vaccine responses. Nat. Rev. Immunol. 24, 250–263 (2024).
Australia New Zealand Trials Registry. ANZCTR.org.au https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12621000866808 (2022).
Pallikkuth, S. et al. A delayed fractionated dose RTS,S AS01 vaccine regimen mediates protection via improved T follicular helper and B cell responses. eLife 9, e51889 (2020).
Nielsen, C. M. et al. Delayed boosting improves human antigen-specific Ig and B cell responses to the RH5.1/AS01B malaria vaccine. JCI Insight 8, e163859 (2023).
Cowman, A. F., Tonkin, C. J., Tham, W.-H. & Duraisingh, M. T. The molecular basis of erythrocyte invasion by malaria parasites. Cell Host Microbe 22, 232–245 (2017).
Ngotho, P. et al. Revisiting gametocyte biology in malaria parasites. FEMS Microbiol. Rev. 43, 401–414 (2019).
Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).
Rausher, M. D. Co-evolution and plant resistance to natural enemies. Nature 411, 857–864 (2001).
Ayres, J. S., Freitag, N. & Schneider, D. S. Identification of Drosophila mutants altering defense of and endurance to Listeria monocytogenes infection. Genetics 178, 1807–1815 (2008).
Råberg, L., Sim, D. & Read, A. F. Disentangling genetic variation for resistance and tolerance to infectious diseases in animals. Science 318, 812–814 (2007).
Soares, M. P., Teixeira, L. & Moita, L. F. Disease tolerance and immunity in host protection against infection. Nat. Rev. Immunol. 17, 83–96 (2017).
Chovatiya, R. & Medzhitov, R. Stress, inflammation, and defense of homeostasis. Mol. Cell 54, 281–288 (2014).
Ferreira, A. et al. Sickle hemoglobin confers tolerance to Plasmodium infection. Cell 145, 398–409 (2011).
Pamplona, A. et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat. Med. 13, 703–710 (2007).
Nahrendorf, W., Ivens, A. & Spence, P. J. Inducible mechanisms of disease tolerance provide an alternative strategy of acquired immunity to malaria. eLife 10, e63838 (2021).
Sandoval, D. M. et al. Adaptive T cells regulate disease tolerance in human malaria. Preprint at medRxiv https://doi.org/10.1101/2021.08.19.21262298 (2021).
Chiu, L. et al. Protective microbiota: from localized to long-reaching co-immunity. Front. Immunol. 8, 1678 (2017).
Tan, J. et al. Chapter three the role of short-chain fatty acids in health and disease. Adv. Immunol. 121, 91–119 (2014).
Mandal, R. K. & Schmidt, N. W. Mechanistic insights into the interaction between the host gut microbiome and malaria. PLOS Pathog. 19, e1011665 (2023).
Koyama, M. et al. Intestinal microbiota controls graft-versus-host disease independent of donor-host genetic disparity. Immunity 56, 1876–1893.e8 (2023).
Juraska, M. et al. Genotypic analysis of RTS,S/AS01E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5–17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(24)00179-8 (2024).
Bell, G. J. et al. Background malaria incidence and parasitemia during the three-dose RTS,S/AS01 vaccination series do not reduce magnitude of antibody response nor efficacy against the first case of malaria. BMC Infect. Dis. 23, 716 (2023).
Morter, R. et al. Impact of exposure to malaria and nutritional status on responses to the experimental malaria vaccine ChAd63 MVA ME-TRAP in 5-17 month-old children in Burkina Faso. Front. Immunol. 13, 1058227 (2022).
Tiono, A. B. et al. Plasmodium falciparum infection coinciding with the malaria vaccine candidate BK-SE36 administration interferes with the immune responses in Burkinabe children. Front. Immunol. 14, 1119820 (2023).
Mahon, B. E. et al. Baseline asymptomatic malaria infection and immunogenicity of recombinant vesicular stomatitis virus–Zaire Ebola virus envelope glycoprotein. J. Infect. Dis. 224, 1907–1915 (2021).
Snounou, G. & Pérignon, J.-L. Chapter six malariotherapy – insanity at the service of malariology. Adv. Parasitol. 81, 223–255 (2013).
Salkeld, J. et al. Repeat controlled human malaria infection of healthy UK adults with blood-stage Plasmodium falciparum: safety and parasite growth dynamics. Front. Immunol. 13, 984323 (2022).
Francis, T. On the doctrine of original antigenic sin. Proc. Am. Philos. Soc. 104, 572–578 (1960).
Camponovo, F. et al. Proteome-wide analysis of a malaria vaccine study reveals personalized humoral immune profiles in Tanzanian adults. eLife 9, e53080 (2020).
Taylor, R. R. et al. Selective recognition of malaria antigens by human serum antibodies is not genetically determined but demonstrates some features of clonal imprinting. Int. Immunol. 8, 905–915 (1996).
McNamara, H. A. et al. Antibody feedback limits the expansion of B cell responses to malaria vaccination but drives diversification of the humoral response. Cell Host Microbe 28, 572–585.e7 (2020).
Beutler, N. et al. A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum. PLoS Pathog. 18, e1010409 (2022).
Dobaño, C. et al. Concentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS,S/AS01E malaria vaccine efficacy. Nat. Commun. 10, 2174 (2019).
Chaudhury, S. et al. Breadth of humoral immune responses to the C-terminus of the circumsporozoite protein is associated with protective efficacy induced by the RTS,S malaria vaccine. Vaccine 39, 968–975 (2021).
Suscovich, T. J. et al. Mapping functional humoral correlates of protection against malaria challenge following RTS,S/AS01 vaccination. Sci. Transl Med. 12, eabb4757 (2020).
Sallusto, F., Cassotta, A., Hoces, D., Foglierini, M. & Lanzavecchia, A. Do memory CD4 T cells keep their cell-type programming: plasticity versus fate commitment?: T-cell heterogeneity, plasticity, and selection in humans. Cold Spring Harbor Perspect. Biol. 10, a029421 (2017).
Carpio, V. H. et al. T helper plasticity is orchestrated by STAT3, Bcl6 and Blimp-1 balancing pathology and protection in malaria. iScience 23, 101310 (2020).
Soon, M. S. F. et al. Transcriptome dynamics of CD4+ T cells during malaria maps gradual transit from effector to memory. Nat. Immunol. 21, 1597–1610 (2020).
Acknowledgements
M.J.B. is supported by a Snow Medical Fellowship and CSL Centenary Fellowship. P.J. is supported by the NIH (U01 AI15532, U01 AI150741, R01 AI 177377), the Bill and Melinda Gates Foundation (OPP 052649) and the Stanford Maternal and Child Health Faculty Scholars Program. C.R.E. has been supported by funding from the Australian National Health and Medical Research Council (1132975, 1154265).
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Boyle, M.J., Engwerda, C.R. & Jagannathan, P. The impact of Plasmodium-driven immunoregulatory networks on immunity to malaria. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01041-5
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DOI: https://doi.org/10.1038/s41577-024-01041-5
