Journal Article

Infection-induced plasmablasts are a nutrient sink that impairs humoral immunity to malaria

Chan, Jo-Anne, Butler, Noah S., Li, Fengyin, Webb, Lachlan, Surette, Fionna A., Sompallae, Ramakrishna R., Andrew, Dean, Vijay, Rahul, Pope, Rosemary L., Boyle, Michelle J., de Labastida Rivera, Fabian, Engwerda, Christian R., Guthmiller, Jenna J., Sturtz, Alexandria J., Maury, Wendy J., Rogers, Kai J., Xue, Hai-Hui, McCarthy, James S.

2020

Overview

Plasmodium parasite–specific antibodies are critical for protection against malaria, yet the development of long-lived and effective humoral immunity against Plasmodium takes many years and multiple rounds of infection and cure. Here, we report that the rapid development of short-lived plasmablasts during experimental malaria unexpectedly hindered parasite control by impeding germinal center responses. Metabolic hyperactivity of plasmablasts resulted in nutrient deprivation of the germinal center reaction, limiting the generation of memory B cell and long-lived plasma cell responses. Therapeutic administration of a single amino acid to experimentally infected mice was sufficient to overcome the metabolic constraints imposed by plasmablasts and enhanced parasite clearance and the formation of protective humoral immune memory responses. Thus, our studies not only challenge the current model describing the role and function of blood-stage Plasmodium -induced plasmablasts but they also reveal new targets and strategies to improve anti- Plasmodium humoral immunity. Early humoral responses to malaria fail to induce durable protective antibodies. Butler and colleagues report that low-affinity, short-lived plasmablasts become nutrient sinks for glutamine and starve germinal center B and T cells, thereby reducing the generation of high-affinity B cells and long-lived plasma cells and memory B cells.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/1619/40 / 631/250/2152/2153 / 631/250/255/1629 / 631/250/255/1715 / Adolescent / Adult / Affinity / Amino acids / Amino Acids - administration & dosage / Amino Acids - metabolism / Analysis / Animals / Antibodies / Antibodies, Protozoan - blood / Antibodies, Protozoan - immunology / Antibodies, Protozoan - metabolism / Antimalarials - administration & dosage / B cells / Biomedical and Life Sciences / Biomedicine / Control / Development and progression / Disease Models, Animal / Disease susceptibility / DNA, Protozoan - isolation & purification / Germinal Center - cytology / Germinal Center - immunology / Germinal Center - metabolism / Glutamine / Health aspects / Host-Parasite Interactions - immunology / Humans / Humoral immunity / Hyperactivity / Immune clearance / Immunity, Humoral / Immunological memory / Immunology / Infection / Infectious Diseases / Lymphocytes B / Lymphocytes T / Malaria / Malaria - blood / Malaria - drug therapy / Malaria - immunology / Malaria - parasitology / Memory cells / Metabolism / Mice / Mice, Transgenic / Middle Aged / Nutrients / Nutrients - metabolism / Parasite control / Parasites / Plasma cells / Plasma Cells - immunology / Plasma Cells - metabolism / Plasma Cells - parasitology / Plasmodium / Plasmodium falciparum - genetics / Plasmodium falciparum - immunology / Plasmodium falciparum - isolation & purification / Proof of Concept Study / T cells / Vector-borne diseases / Viral antibodies / Young Adult