Transcriptional profiling and immunophenotyping show sustained activation of blood monocyte in subpatent Plasmodium falciparum infection

Loughland, Jessica R., Woodberry, Tonia, Field, Matt, Andrew, Dean W., SheelaNair, Arya, Dooley, Nicholas L., Piera, Kim A., Amante, Fiona H., Kenangalem, Enny, Price, Ric N., Engwerda, Christian R., Anstey, Nicholas M., McCarthy, James S., Boyle, Michelle J., and Minigo, Gabriela (2020) Transcriptional profiling and immunophenotyping show sustained activation of blood monocyte in subpatent Plasmodium falciparum infection. Clinical & Translational Immunology, 9. pp. 1-18.

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Abstract

Objectives Malaria, caused by Plasmodium infection, remains a major global health problem. Monocytes are integral to the immune response, yet their transcriptional and functional responses in primary Plasmodium falciparum infection and in clinical malaria are poorly understood.

Methods The transcriptional and functional profiles of monocytes were examined in controlled human malaria infection with P. falciparum blood stages and in children and adults with acute malaria. Monocyte gene expression and functional phenotypes were examined by RNA sequencing and flow cytometry at peak infection and compared to pre‐infection or at convalescence in acute malaria.

Results In subpatent primary infection, the monocyte transcriptional profile was dominated by an interferon (IFN) molecular signature. Pathways enriched included type I IFN signalling, innate immune response and cytokine‐mediated signalling. Monocytes increased TNF and IL‐12 production upon in vitro toll‐like receptor stimulation and increased IL‐10 production upon in vitro parasite restimulation. Longitudinal phenotypic analyses revealed sustained significant changes in the composition of monocytes following infection, with increased CD14+CD16− and decreased CD14−CD16+ subsets. In acute malaria, monocyte CD64/FcγRI expression was significantly increased in children and adults, while HLA‐DR remained stable. Although children and adults showed a similar pattern of differentially expressed genes, the number and magnitude of gene expression change were greater in children.

Conclusions Monocyte activation during subpatent malaria is driven by an IFN molecular signature with robust activation of genes enriched in pathogen detection, phagocytosis, antimicrobial activity and antigen presentation. The greater magnitude of transcriptional changes in children with acute malaria suggests monocyte phenotypes may change with age or exposure.

Item ID: 63613
Item Type: Article (Research - C1)
ISSN: 2050-0068
Keywords: CHMI; interferon; malaria; monocytes; Plasmodium falciparum; RNA sequencing
Copyright Information: © 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Funders: National Health and Medical Research Council (NHMRC), Channel 7 Children’s Research Foundation, Wellcome Trust (WT)
Projects and Grants: NHMRC grant 141632, NHMRC grant 1135955, NHMRC grant 1037304, NHMRC grant 1092789, NHMRC grant 1132975, NHMRC grant 1045156, NHMRC grant 1125656, NHMRC grant 1042072, NHMRC grant 1154265, NHMRC grant APP5121190, Channel 7 Children's Research Foundation grant 151016, WT Senior Fellowship in Clinical Science grant 200909
Date Deposited: 07 Aug 2020 01:41
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 50%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060406 Genetic Immunology @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920120 Zoonoses @ 100%
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