Transcriptomic and Proteomic Insights into Host Immune Responses in Pediatric Severe Malarial Anemia: Dysregulation in HSP60-70-TLR2/4 Signaling and Altered Glutamine Metabolism
Clinton O. Onyango,
Samuel B. Anyona,
Ivy Hurwitz,
Evans Raballah,
Sharely A. Wasena,
Shamim W. Osata,
Philip Seidenberg,
Benjamin H. McMahon,
Christophe G. Lambert,
Kristan A. Schneider,
Collins Ouma,
Qiuying Cheng,
Douglas J. Perkins
Affiliations
Clinton O. Onyango
Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno 40100, Kenya
Samuel B. Anyona
Kenya Global Health Programs, University of New Mexico, Kisumu and Siaya 40100, Kenya
Ivy Hurwitz
Center for Global Health, Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Evans Raballah
Kenya Global Health Programs, University of New Mexico, Kisumu and Siaya 40100, Kenya
Sharely A. Wasena
Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno 40100, Kenya
Shamim W. Osata
Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno 40100, Kenya
Philip Seidenberg
Center for Global Health, Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Benjamin H. McMahon
Center for Global Health, Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Christophe G. Lambert
Center for Global Health, Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Kristan A. Schneider
Center for Global Health, Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Collins Ouma
Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno 40100, Kenya
Qiuying Cheng
Center for Global Health, Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Douglas J. Perkins
Center for Global Health, Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Severe malarial anemia (SMA, Hb Plasmodium falciparum transmission zones. This study explored the entire expressed human transcriptome in whole blood from 66 Kenyan children with non-SMA (Hb ≥ 6.0 g/dL, n = 41) and SMA (n = 25), focusing on host immune response networks. RNA-seq analysis revealed 6862 differentially expressed genes, with equally distributed up-and down-regulated genes, indicating a complex host immune response. Deconvolution analyses uncovered leukocytic immune profiles indicative of a diminished antigenic response, reduced immune priming, and polarization toward cellular repair in SMA. Weighted gene co-expression network analysis revealed that immune-regulated processes are central molecular distinctions between non-SMA and SMA. A top dysregulated immune response signaling network in SMA was the HSP60-HSP70-TLR2/4 signaling pathway, indicating altered pathogen recognition, innate immune activation, stress responses, and antigen recognition. Validation with high-throughput gene expression from a separate cohort of Kenyan children (n = 50) with varying severities of malarial anemia (n = 38 non-SMA and n = 12 SMA) confirmed the RNA-seq findings. Proteomic analyses in 35 children with matched transcript and protein abundance (n = 19 non-SMA and n = 16 SMA) confirmed dysregulation in the HSP60-HSP70-TLR2/4 signaling pathway. Additionally, glutamine transporter and glutamine synthetase genes were differentially expressed, indicating altered glutamine metabolism in SMA. This comprehensive analysis underscores complex immune dysregulation and novel pathogenic features in SMA.
