Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c+Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation.
Plasmodium vivaxmalaria remains a major public health problem. The requirements for acquisition of protective immunity to the species are not clear. Dendritic cells (DC) are essential for immune cell priming but also perform immune regulatory functions, along with regulatory T cells (Treg). An important function of DC involves activation of the kynurenine pathway via indoleamine 2,3-dioxygenase (IDO). Using a controlled human experimental infection study with blood-stageP. vivax, we characterized plasmacytoid DC (pDC) and myeloid DC (mDC) subset maturation, CD4+CD25+CD127loTreg activation, and IDO activity. Blood samples were collected from six healthy adults preinoculation, at peak parasitemia (day 14; ∼31,400 parasites/ml), and 24 and 48 h after antimalarial treatment. CD1c+and CD141+mDC and pDC numbers markedly declined at peak parasitemia, while CD16+mDC numbers appeared less affected. HLA-DR expression was selectively reduced on CD1c+mDC, increased on CD16+mDC, and was unaltered on pDC. Plasma IFN-γ increased significantly and was correlated with an increased kynurenine/tryptophan (KT) ratio, a measure of IDO activity. At peak parasitemia, Treg presented an activated CD4+CD25+CD127loCD45RA-phenotype and upregulated TNFR2 expression. In a mixed-effects model, the KT ratio was positively associated with an increase in activated Treg. Our data demonstrate that a primaryP. vivaxinfection exerts immune modulatory effects by impairing HLA-DR expression on CD1c+mDC while activating CD16+mDC. Induction of the kynurenine pathway and increased Treg activation, together with skewed mDC maturation, suggestP. vivaxpromotes an immunosuppressive environment, likely impairing the development of a protective host immune response.
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia.
Tonia
T
Woodberry
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia jessica.loughland@menzies.edu.au.
Jessica R
JR
Loughland
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia.
Gabriela
G
Minigo
QIMR Berghofer Institute of Medical Research, Brisbane, Queensland, Australia.
Julie G
JG
Burel
QIMR Berghofer Institute of Medical Research, Brisbane, Queensland, Australia.
Fiona H
FH
Amante
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia.
Kim A
KA
Piera
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia.
Yvette
Y
McNeil
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia.|Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.|Communicable Disease Centre, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.
Tsin W
TW
Yeo
Glycomics Institute, Griffith University, Queensland, Australia.
Michael F
MF
Good
QIMR Berghofer Institute of Medical Research, Brisbane, Queensland, Australia.|Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
Denise L
DL
Doolan
QIMR Berghofer Institute of Medical Research, Brisbane, Queensland, Australia.
Christian R
CR
Engwerda
QIMR Berghofer Institute of Medical Research, Brisbane, Queensland, Australia.
James S
JS
McCarthy
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia.|Royal Darwin Hospital, Darwin, Australia.
Nicholas M
NM
Anstey
D000328:Adult; D015415:Biomarkers / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D064368:Healthy Volunteers; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D008213:Lymphocyte Activation; D016780:Malaria, Vivax / Q000276:immunology*; D008297:Male; D010966:Plasmodium vivax; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014364:Tryptophan / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
D015415:Biomarkers; D006684:HLA-DR Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan
Plasmodium vivax; Treg; dendritic cells; indoleamine 2,3-dioxygenase