Antibody Responses to Antigenic Targets of Recent Exposure Are Associated With Low-Density Parasitemia in Controlled Human Plasmodium falciparum Infections

Hoogen, Lotus L. van den; Walk, Jona; Oulton, Tate; Reuling, Isaie J.; Reiling, Linda; Beeson, James G.; Coppel, Ross L.; Singh, Susheel K.; Draper, Simon J.; Bousema, Teun; Drakeley, Chris; Sauerwein, Robert W.; Tetteh, Kevin K. A.

doi:10.3389/fmicb.2018.03300

Cited by 30 publications

(30 citation statements)

References 56 publications

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“…This relationship remained after removal of outliers ( Supplementary Figure 5). Neither antibody score, nor individual antibody responses, were associated with parasite biomass during infection (Supplementary Figure S6A/B), in contrast to previous reports (48)(49)(50).…”

Section: Antibody Induction Is Associated With Th2-ctfh Activation Ducontrasting

confidence: 99%

Th2-like T-follicular helper cells promote functional antibody production duringPlasmodium falciparuminfection

Chan

Rivera

Loughland

et al. 2020

Preprint

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The most advanced malaria vaccine only has approximately 30% efficacy in target populations, and avenues to improve next generation vaccines need to be identified. Functional antibodies are key effectors of both vaccine induced and naturally acquired immunity, with induction driven by T-follicular helper cells (TfH) CD4+ T cells. We assessed circulating TfH (cTfH) responses and functional antibody production in human volunteers experimentally infected with Plasmodium falciparum. Longitudinal single-cell RNA-sequencing of cTfH revealed peak transcriptional activation and clonal expansion of major cTfH subsets occurred at day 8 following infection and a population structure of cTfH capturing phenotypical subsets of Th1-and Th2-like cells. Among 40 volunteers, infection resulted in the emergence of activated ICOS+ cTfH cells. During peak infection, activation was restricted to Th2-like cTfH cells, while Th1-like cTfH cell activation occurred one week after treatment. To link cTfH activation to antibody induction, we assessed the magnitude and function of anti-malarial IgM and IgG after infection. The functional breadth and magnitude of parasite-specific antibodies was positively associated with Th2-cTfH activation. In contrast, Th1-cTfH activation was associated with the induction of plasma cells, which we have previously shown have a detrimental role in germinal cell formation and antibody development.Thus, we identified that during P. falciparum malaria infection in humans, the activation of Th2-cTfH but not other subsets correlates with the development of functional antibodies required for protective immunity. Data for the first time identify a specific cellular response that can be targeted by future malaria vaccines to improve antibody induction.

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Section: Antibody Induction Is Associated With Th2-ctfh Activation Ducontrasting

confidence: 99%

Th2-like T-follicular helper cells promote functional antibody production duringPlasmodium falciparuminfection

Chan

Rivera

Loughland

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In contrast between the positive association between Th2-cTfh and antibody induction, total antigen load was not associated with antibody development, in contrast to previous reported findings. 41 , 42 , 43 These differences between studies may be due to differences in experimental infection models (blood stage versus sporozoite stages) and differences in analytical approaches (including methods to define parasite exposure and antibodies tested). The results seen here indicate that parasite load alone cannot explain antibody development, which is instead governed by individual immune activation, including Th2-cTfh cells.…”

Section: Discussionmentioning

confidence: 99%

“…Neither antibody score nor antibody variables were associated with parasite biomass during infection ( Figures S5A and S5B), in contrast to previous reports. [41][42][43] Furthermore, antibody induction was not associated with EOS time point nor with infection cohort ( Figures S5C-S5E). It has been hypothesized that short-lived plasma cell differentiation may be driven by Th1-cTfh cells.…”

Section: Antibody Induction Is Associated With Th2-ctfh Cell Activatimentioning

confidence: 99%

Th2-like T Follicular Helper Cells Promote Functional Antibody Production during Plasmodium falciparum Infection

Chan

Loughland

Rivera

et al. 2020

Cell Reports Medicine

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Summary CD4 + T follicular helper cells (Tfh) are key drivers of antibody development. During Plasmodium falciparum malaria in children, the activation of Tfh is restricted to the Th1 subset and not associated with antibody levels. To identify Tfh subsets that are associated with antibody development in malaria, we assess Tfh and antibodies longitudinally in human volunteers with experimental P. falciparum infection. Tfh cells activate during infection, with distinct dynamics in different Tfh subsets. Th2-Tfh cells activate early, during peak infection, while Th1-Tfh cells activate 1 week after peak infection and treatment. Th2-Tfh cell activation is associated with the functional breadth and magnitude of parasite antibodies. In contrast, Th1-Tfh activation is not associated with antibody development but instead with plasma cells, which have previously been shown to play a detrimental role in the development of long-lived immunity. Thus, our study identifies the contrasting roles of Th2 and Th1-Tfh cells during experimental P. falciparum malaria.

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“…Total IgE was measured using a commercial ELISA kit (Thermo Fisher, Invitrogen, UK) according to manufacturer’s instructions and using a seropositivity cut-off of 7.8 ng/ml. Ascaris antigen was kindly provided by MariaYazdanbaksh (Leiden, Netherlands) and used to estimate reactivity with serum IgG using an in-house protein microarray assay ( 19 ).…”

Section: Methodsmentioning

confidence: 99%

Age-Related Dynamics of Circulating Innate Lymphoid Cells in an African Population

et al. 2020

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Innate lymphoid cell (ILC) lineages mirror those of CD4+ T helper cell subsets, producing type 1, 2 and 3 cytokines respectively. Studies in adult human populations have shown contributions of non-cytotoxic ILC to immune regulation or pathogenesis in a wide range of diseases and have prompted investigations of potential functional redundancy between ILC and T helper cell compartments in neonates and children. To investigate the potential for ILC to contribute to immune responses across the human lifespan, we examined the numbers and frequencies of peripheral blood ILC subsets in a cohort of Gambians aged between 5 and 73 years of age. ILC2 were the most abundant peripheral blood ILC subset in this Gambian cohort, while ILC1 were the rarest at all ages. Moreover, the frequency of ILC1s (as a proportion of all lymphocytes) was remarkably stable over the life course whereas ILC3 cell frequencies and absolute numbers declined steadily across the life course and ILC2 frequencies and absolute numbers declined from childhood until the age of approx. 30 years of age. Age-related reductions in ILC2 cell numbers appeared to be partially offset by increasing numbers of total and GATA3+ central memory (CD45RA-CCR7+) CD4+ T cells, although there was also a gradual decline in numbers of total and GATA3+ effector memory (CD45RA-CCR7-) CD4+ T cells. Despite reduced overall abundance of ILC2 cells, we observed a coincident increase in the proportion of CD117+ ILC2, indicating potential for age-related adaptation of these cells in childhood and early adulthood. While both CD117+ and CD117- ILC2 cells produced IL-13, these responses occurred predominantly within CD117- cells. Furthermore, comparison of ILC frequencies between aged-matched Gambian and UK young adults (25–29 years) revealed an overall higher proportion of ILC1 and ILC2, but not ILC3 in Gambians. Thus, these data indicate ongoing age-related changes in ILC2 cells throughout life, which retain the capacity to differentiate into potent type 2 cytokine producing cells, consistent with an ongoing role in immune modulation.

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Antibody Responses to Antigenic Targets of Recent Exposure Are Associated With Low-Density Parasitemia in Controlled Human Plasmodium falciparum Infections

Cited by 30 publications

References 56 publications

Th2-like T-follicular helper cells promote functional antibody production duringPlasmodium falciparuminfection

Th2-like T-follicular helper cells promote functional antibody production duringPlasmodium falciparuminfection

Th2-like T Follicular Helper Cells Promote Functional Antibody Production during Plasmodium falciparum Infection

Age-Related Dynamics of Circulating Innate Lymphoid Cells in an African Population

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