An immune-cell signature of bacterial sepsis

Abstract

Dysregulation of the immune response to bacterial infection can lead to sepsis, a condition with high mortality. Multiple whole-blood gene expression studies have defined sepsis-associated molecular signatures but did not resolve changes in transcriptional states of specific cell types. Here, we used single-cell RNA sequencing to profile the blood of patients with sepsis (n = 29) across three clinical cohorts with corresponding controls (n = 36). We profiled total peripheral blood mononuclear cells (PBMCs, 106,545 cells) and dendritic cells (19,806 cells) across all patients and, based on clustering of their gene expression profiles, defined 16 immune cell states. We identified a unique CD14+ monocyte state that is expanded in septic patients and validated its power in discriminating septic patients from controls using public transcriptomic data from patients of different disease etiologies and multiple geographic locations (18 cohorts, n = 1,213 patients). We identified a panel of surface markers for isolation and quantification of the monocyte state, characterized its epigenomic and functional phenotypes, and propose a model for its induction from human bone marrow. This study demonstrates the utility of single cell genomics in discovering disease-associated cytologic signatures and provides insight into the cellular basis of immune dysregulation in bacterial sepsis.

Single-cell profiling of Ebola virus infectionin vivoreveals viral and host transcriptional dynamics

“…The accumulation of additional host-pathogen single-cell datasets promises to greatly enhance our understanding of infection by allowing us to determine which features of pathogenesis are shared between, or specific to, individual pathogens. For example, our scRNA-Seq and CyTOF data identified several molecular commonalities between EVD and immunosuppressive septic shock (Bray and Mahanty, 2003) , which is also characterized by loss of MHC-II expression in monocytes (Monneret and Venet, 2014;Reyes et al, 2020) , increased DP monocytes (Fingerle et al, 1993) , and emergency myelopoiesis (Bomans et al, 2018;Cuenca et al, 2015;Reyes et al, 2020) . Soluble mediators, including cytokines and glucocorticoids, could be key drivers of both EVD and sepsis pathophysiology.…”

Deciphering the state of immune silence in fatal COVID-19 patients

“…Immunoparalysis is likely the ground for the HSV-1 superinfection observed in some ICU patients in our study. Recently, scRNA-seq unveiled a cluster of immature CD14 + monocytes, with low HLA-DR and expressing MPO, PLAC8 and IL1R2, in the blood of COVID-19 patients and similar cells were reported in sepsis [20,33]. These ndings shed light on the practice to measure the levels of HLA-DR in monocytes as marker for sepsis, preconized but never de nitively proven as mortality biomarker for severe sepsis, especially in ICU patients [34,35].…”

“…More importantly, we found that loss of function in myeloid cells mirrors an immune pathological status progressing from immune paralysis to "immune silence" associated with higher susceptibility to death event (Figure 2e, Figure S2f). CD14 + HLA-DR low monocytes and ARG1 + MPO + BPI +, low density pre-neutrophils are expanded in severe COVID-19 patients, a likely consequence of the pervasive emergency myelopoiesis triggered by SARS-Cov2 infection [33]. Based on gene expression pro les, these cell subsets were deemed to have immune suppressive features, which were not functionally addressed in the study.…”

“…Further studies are necessary to de ne whether these cells are immature precursors of the granulocytic/monocytic lineage or a new subset of circulating monocytes, as well as the extent of their overlap with the immature CD14 + cells described in COVID-19 patients and sepsis [20,33]. Noteworthy, our study identi es, new markers associated with disease severity in the peripheral blood of patients, such as the proportion of activated/resting γδ-T cells ( Figure S3E), which integrate with others already described and con rmed in our study (i.e NK cells and neutrophils activation [38,39]), which might be responsible for healthy tissue damage [40].…”

Consensus transcriptional states describe human mononuclear phagocyte diversity in the lung across health and disease

“…(Blériot et al, 2020;Nutt and Chopin, 2020). To perform these functions, these cell types execute diverse and distinct transcriptional programs in response to local and systemic cues (Jaitin et al, 2019;Maier et al, 2020;Okabe and Medzhitov, 2016;Reyes et al, 2020). This transcriptional diversity has been particularly appreciated in macrophages, where the classically-defined dichotomous spectrum has been progressively expanded in favor of a complex spectrum both in vitro and in vivo (Gautier et al, 2012;Li et al, 2019;Rajab et al, 2019;Sica and Mantovani, 2012;Xue et al, 2014).…”