Extensive Changes in Transcriptomic “Fingerprints” and Immunological Cells in the Large Organs of Patients Dying of Acute Septic Shock and Multiple Organ Failure Caused by Neisseria meningitidis

Abstract

Background: Patients developing meningococcal septic shock reveal levels of Neisseria meningitidis (10 6-10 8 /mL) and endotoxin (10 1-10 3 EU/mL) in the circulation and organs, leading to acute cardiovascular, pulmonary and renal failure, coagulopathy and a high case fatality rate within 24 h. Objective: To investigate transcriptional profiles in heart, lungs, kidneys, liver, and spleen and immunostain key inflammatory cells and proteins in post mortem formalin-fixed, paraffin-embedded (FFPE) tissue samples from meningococcal septic shock patients. Patients and Methods: Total RNA was isolated from FFPE and fresh frozen (FF) tissue samples from five patients and two controls (acute non-infectious death). Differential expression of genes was detected using Affymetrix microarray analysis. Lung and heart tissue samples were immunostained for T-and B cells, macrophages, neutrophils and the inflammatory markers PAI-1 and MCP-1. Inflammatory mediators were quantified in lysates from FF tissues. Results: The transcriptional profiles showed a complex pattern of protein-coding and non-coding RNAs with significant regulation of pathways associated with organismal death, cell death and survival, leukocyte migration, cellular movement, proliferation of cells, cell-to-cell signaling, immune cell trafficking, and inflammatory responses in an organ-specific clustering manner. The canonical pathways including acute phase response-, EIF2-, TREM1-, IL-6-, HMBG1-, PPAR signaling, and LXR/RXR activation were associated with acute heart, pulmonary, and renal failure. Fewer genes were regulated in the liver and particularly in the spleen. The main upstream regulators were TNF, IL-1β, IL-6, RICTOR, miR-6739-3p, and CD3. Increased numbers of inflammatory cells (CD68+, MPO+, CD3+, and CD20+) were found in lungs and heart. PAI-1 inhibiting Brusletto et al. Transcriptional Profiles in MSS Organs fibrinolysis and MCP-1 attracting leukocyte were found significantly present in the septic tissue samples compared to the controls. Conclusions: FFPE tissue samples can be suitable for gene expression studies as well as immunostaining of specific cells or molecules. The most pronounced gene expression patterns were found in the organs with highest levels of Neisseria meningitidis DNA. Thousands of protein-coding and non-coding RNA transcripts were altered in lungs, heart and kidneys. We identified specific biomarker panels both protein-coding and non-coding RNA transcripts, which differed from organ to organ. Involvement of many genes and pathways add up and the combined effect induce organ failure.

Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia

“…S3E). 37 In summary, this in vitro and in vivo evidence showed that hepatocytes recruited RMs to the liver via CCL2-mediated pathways during endotoxemia.…”

Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo

“…Here we propose an essential role for the highly conserved Ppp1r15a uORF in the outcomes of sepsis-induced kidney injury. Sepsis is a complex pathological state where multiple pathways are aberrantly activated [45][46][47][48][49][50] . While these changes are spatially and temporally diverse, one major driver that underlies this dynamic state is the activation of antiviral responses.…”

Topical issues of clinical symptoms and diagnostics of septic shock

“…Необходимо отметить, что септический шок, вызванный Neisseria meningitidis, является наиболее тяжелым из-за быстрой прогрессии клинических симптомов и раннего развития полиорганной недостаточности [12,20]. Для такого септического шока характерен наиболее выраженный дисбаланс между свертывающей и фибринолитической системами крови.…”

“…Микротромбоз и эндотелиальная дисфункция, связанные с провоспалительным ответом, снижают эндотелиальную экспрессию тромбомодулина и рецепторов эндотелиального протеина С, тем самым снижая и фибринолиз. Прокоагулянтное и провоспалительное состояние, связанное с этими изменениями, вызывает эндоваскулярное повреждение, микроваскулярный тромбоз, ишемию органов и в конечном итоге -полиорганную недостаточность [12]. Результаты исследования B.S.…”

“…Основными регуляторами развития полиорганной недостаточности являются TNFα, IL-1β, IL-6, RICTOR (Rapamycin-Insensitive Companion of Mammalian Target of Rapamycin -RICTOR), miR-6739-3p и CD3. Повышенное количество воспалительных клеток (CD68 + , CD3 + и CD20 + ) было обнаружено в легких и сердце [12].…”