Controlled Human Malaria Infection Leads to Long-Lasting Changes in Innate and Innate-like Lymphocyte Populations

Abstract

Animal model studies highlight the role of innate-like lymphocyte populations in the early inflammatory response and subsequent parasite control following Plasmodium infection. IFNγ production by these lymphocytes likely plays a key role in the early control of the parasite and disease severity. Analyzing human innate-like T cell and natural killer (NK) cell responses following infection with Plasmodium has been challenging since the early stages of infection are clinically silent. To overcome this limitation, we examined blood samples from a controlled human malaria infection (CHMI) study in a Tanzanian cohort, in which volunteers underwent CHMI with a low or high CHMI dose of Plasmodium falciparum sporozoites (PfSPZ challenge). The CHMI differentially affected NK, natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cell populations in a dose-dependent manner resulting in an altered composition of this innate-like lymphocyte compartment. While these innate-like responses are typically thought of as short-lived, we found that changes persisted for months after the infection was cleared leading to significantly increased frequencies of MAIT cells 6 months post-infection. We used single-cell RNAseq and TCR αβ chain usage analysis to define potential mechanisms for this expansion. These single-cell data suggest that this increase was mediated by homeostatic expansion-like mechanisms. Together these data demonstrate that CHMI leads to previously unappreciated long-lasting alterations in the human innate-like lymphocyte compartment. We discuss the consequences of these changes for recurrent parasite infection and infection-associated pathologies and highlight the importance of considering host immunity and infection history for vaccine design.

Unravelling the roles of innate lymphoid cells in cerebral malaria pathogenesis

“…The crosstalk of NK cells and macrophages with effector T cells controlling P. falciparum ‐infected erythrocytes was further emphasized before the emergence of the ILC paradigm. Mpina et al reported interesting data from blood samples from a controlled human malaria infection (CHMI) study with P. falciparum sporozoites in a Tanzanian cohort with volunteers showing an altered composition of the innate‐like lymphocyte compartment including NK, NKT and mucosal‐associated invariant T (MAIT) cells. The data of this controlled infection suggest the emergence of long‐lasting changes of the human innate‐like lymphocyte compartment .…”

“…Mpina et al reported interesting data from blood samples from a controlled human malaria infection (CHMI) study with P. falciparum sporozoites in a Tanzanian cohort with volunteers showing an altered composition of the innate‐like lymphocyte compartment including NK, NKT and mucosal‐associated invariant T (MAIT) cells. The data of this controlled infection suggest the emergence of long‐lasting changes of the human innate‐like lymphocyte compartment . Therefore, the innate immune response on host immunity with recurrent parasite infection and associated pathologies requires more investigations which include human ILCs.…”

The MAIT conundrum – how human MAIT cells distinguish bacterial colonization from infection in mucosal barrier tissues

“…Overall, it has become clear that there is more heterogeneity in the MAIT cell population than initially appreciated[45]. A small fraction of MAIT cells isolated from the blood can also secrete IL-17 ex vivo following short term stimulation with via CD3/CD28 or PMA and ionomycin[12,46,47]. It is noteworthy that a large fraction of MAIT cells in the blood expresses the transcription factor RORγt[37], which drives T-cells towards IL-17 production[48].…”

“…Finally, MAIT cells in the blood can be divided into different subsets based on CD8 and CD4 co-receptor expression. The relationship of these subsets is unclear, but single cell gene expression analysis from the two major MAIT subsets, CD8 + and CD8 − (CD4 − ) cells, isolated from the blood demonstrated distinct transcriptional differences[44] and their respective frequencies can change independently following infection[46]. …”

“…Most MAIT cells in the blood express CCR6[12,44,46,66], which is implicated in trafficking to mucosal tissues and liver, since its ligand CCL20 is expressed in steady state conditions in organs like gut, lung and liver. Interestingly, CCL20 is typically considered to be the sole ligand for CCR6, but some evidence suggests that beta-defensins may bind to CCR6 as well[67].…”