---
title: "Transcriptome differences linked to delayed mortality in invasive group A Streptococcal (iGAS) dis"
id: "plos-one-13-transcriptome-profile-of-delayed-mortality-in-patients-with-invasive-group-a"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-13-transcriptome-profile-of-delayed-mortality-in-patients-with-invasive-group-a"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356286"
published_at: "2026-08-18T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Transcriptome differences linked to delayed mortality in invasive group A Streptococcal (iGAS) dis
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-13-transcriptome-profile-of-delayed-mortality-in-patients-with-invasive-group-a
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356286)
- **Published At:** 2026-08-18T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The study prospectively recruited adult patients with culture-confirmed **invasive group A Streptococcal (iGAS)** infection from two Finnish hospitals between June 2018 and June 2020. Whole blood was sampled at an early timepoint (within two days of admission, timepoint A) and again five to seven days later (timepoint B) for transcriptome profiling. - A total of 45 patients were enrolled; eight died within 90 days, including four within the first week. After RNA quality control, 34 samples at timepoint A and 31 samples at timepoint B were retained for analysis. - Gene expression differences associated with severe disease and death varied markedly between the two timepoints. Modules of co-expressed genes were identified using weighted gene correlation network analysis (WGCNA) and related to clinical traits (need for intensive care, death, severe disease). - At timepoint B, higher expression of genes implicated in **necroptosis** and lower expression of **HLA** genes were associated with death. The profile at timepoint A differed from timepoint B, suggesting temporal changes in host response during iGAS. - Transcriptome processing included normalization by spike-in controls, selection of variable endogenous protein-coding genes (p < 0.05, Benjamini-Hochberg adjusted), WGCNA (soft threshold 16, unadjusted p-values), and gene ontology enrichment via Enrichr with adjusted p-values. - HLA typing was performed computationally (arcasHLA and IMGT/HLA database v3.34.0) and potential associations to clinical traits were evaluated with Boruta. Confounders evaluated included age, sex, and Charlson comorbidity index. - The authors caution that the sample size was small and that findings should not be interpreted as predictive. Data are not publicly available due to legal restrictions but can be requested under controlled access from the University of Turku. - The study was approved by relevant ethics committees and registered at ClinicalTrials.gov (NCT03507101). Funding sources and competing interests are reported in the article.
## Clinical Analysis & Structured Key Points
Transcriptome profile of delayed mortality in patients with invasive group A Streptococcal disease | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Peer Review Reader Comments Figures Figures Abstract Background Our aim was to study the pathophysiological mechanisms of early ( 0 (= positive correlation) and −1 if r < 0 (= negative correlation). The asterisks signify statistical significance, * = p < 0.05, ** = p < 0.005. ICU = intensive care unit, SD = severe disease (a composite of the death and ICU categories), Leuk = total leukocyte count, Leuk-lymf = total leukocyte count minus lymphocyte count, CCI = Charlson comorbidity index. https://doi.org/10.1371/journal.pone.0356286.g001 At timepoint B, low expression of the brown module and high expression of the pink module had a strong correlation (p < 0.01) with delayed death ( Fig 1B ). Both were also associated (p < 0.05) with the composite category of severe disease, but neither with need for intensive care alone, although the pink module was also associated with the need for respiratory support. High expression of the pink module also correlated with advanced age and higher Charlson class, as well as higher total leukocyte count, and a higher total leukocyte count minus lymphocyte count. The pink module contained genes relating to neutrophil regulation and necroptosis, whereas the brown module had many HLA genes (HLA-C/-DMA/-DMB/-DOB/-DPA1/-DPB1/-DQA1/-DRA/-DRB1/-DRB5) ( Tables 1 and 2 ). Especially HLA-DMB*01 and HLA-DQA1*01 showed importance in association with death ( Fig 2 ). Download: PNG larger image TIFF original image Table 1. Genes with the strongest association to death in the brown and pink modules at timepoint B. https://doi.org/10.1371/journal.pone.0356286.t001 Download: PNG larger image TIFF original image Table 2. Top 10 gene ontology biological process terms for pink (first ten) and brown (lower ten) module genes at timepoint B. https://doi.org/10.1371/journal.pone.0356286.t002 Download: PNG larger image TIFF original image Fig 2. Association of expressed HLA-HMB and -DQA1 with death. (A) Importance scores of HLA types on the association with death. Shadows (blue) are references made by randomly shuffled data. Confirmed HLA types (green) had higher importance score than the shadows.(B) RNA-seq read counts on the confirmed HLA types and the association with death. Undef represents HLA typing failure, which may imply novel types or may be due to lower expression; therefore, for example, black dots in HLA-DQA1 represent other than DQA1*01. https://doi.org/10.1371/journal.pone.0356286.g002 The yellow module of timepoint A, that was associated with death, only had an overlap of one gene with the brown module of timepoint B, and no overlap with the pink module of timepoint B. The brown and magenta modules of timepoint A, that had an association with severe disease, but not with death, had 330 overlapping genes with the brown module of timepoint B, but only one with the pink module of timepoint B. Among the genes with the strongest association ( table 1 ), there was no overlap. Overlap was tested with Venny [ 17 ]. Discussion Our understanding of the pathophysiology of sepsis and the inflammatory mechanisms involved have increased greatly in recent years with the advent of metagenomics, but much is still unclear. Up to almost half of sepsis deaths happen in the first week after onset [ 7 ]. In a study of patients with surgical sepsis, mortality was 4% within the first 14 days, and patients who survived this period either recovered or developed what was termed chronic critical illness. Mortality was 20% among chronic critical illness patients [ 9 ]. Another study of four patients with sepsis conducted 14–21 days after onset demonstrated unique transcriptomic patterns of circulating immune cells when compared to healthy controls [ 8 ]. Upregulation of many HLA genes was demonstrated in the cases with chronic critical illness. Contrarily, in our study it was downregulation of many HLA genes that seemed to be associated with disease severity and death at timepoint B. This discrepancy can be explained by the small sample sizes in both studies, but can also be hypothesized to demonstrate a behavioral trend of HLA regulation over time, as the timepoints of the above study differed markedly from our timepoint B, with our timepoint B being 7–14 days earlier than the transcriptome studies conducted in the above study [ 8 ]. Interestingly, the HLA gene expression did not appear to be associated with advanced age, a known risk factor for chronic critical illness [ 9 ]. In our previous article [ 11 ], we showed downregulation of various genes of cytotoxic immunity to be associated with severe disease in the early stage. At timepoint A, no HLA types had a strong association with disease severity. None of the genes most strongly associated with disease severity at timepoint A had this same association at timepoint B, and when looking at only death, there was an overlap of only one gene. The cases who survived until timepoint B then seem to have either reached a more homeostatic state of immunomodulation or they may have a persistent low expression of differing lymphocyte functions, including antigen presentation, which seems to be associated with a poor prognosis. The module with overexpression of neutrophil regulators and necroptosis regulators having an association with death and severe disease could be seen to support the theory of an ongoing dysregulated immune response as a factor of poor prognosis. In another study of patients with septic shock, low monocyte HLA-DR expression at 3–4 days after onset was associated with mortality [ 18 ], which aligns with this possibility. The finding that this m
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