An immune-cell signature of bacterial sepsis

Reyes, Miguel; Filbin, Michael R.; Bhattacharyya, Roby P.; Billman, Kianna; Eisenhaure, Thomas; Hung, Deborah T.; Levy, Bruce D.; Baron, Rebecca M.; Blainey, Paul C.; Goldberg, Marcia B.; Hacohen, Nir

doi:10.1038/s41591-020-0752-4

Cited by 283 publications

(334 citation statements)

References 52 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Kotliar

Lin

Logue

et al. 2020

Preprint

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Ebola virus (EBOV) causes epidemics with high case fatality rates, yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. To better understand EBOV infection in vivo , we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cell activity during EBOV infection in rhesus monkeys. We obtained 100,000 transcriptomes and 15,000,000 protein profiles, providing insight into pathogenesis. We find that immature, proliferative monocyte-lineage cells with reduced antigen presentation capacity replace conventional circulating monocyte subsets within days of infection, while lymphocytes upregulate apoptosis genes and decline in abundance. By quantifying viral RNA abundance in individual cells, we identify molecular determinants of tropism and examine temporal dynamics in viral and host gene expression. Within infected cells, we observe that EBOV down-regulates STAT1 mRNA and interferon signaling, and up-regulates putative pro-viral genes (e.g., DYNLL1 and HSPA5 ), nominating cellular pathways the virus manipulates for its replication. Overall, this study sheds light on EBOV tropism, replication dynamics, and elicited immune response, and provides a framework for characterizing interactions between hosts and emerging viruses in a maximum containment setting. over-activation of innate and adaptive immunity underlies much of EVD pathology, rather than solely virus-mediated cytotoxicity (Geisbert et al., 2003a(Geisbert et al., , 2003b .

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Section: Discussionmentioning

confidence: 99%

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

Kotliar

Lin

Logue

et al. 2020

Preprint

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“…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].…”

Section: Discussionmentioning

confidence: 86%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Amit

Bost

Sanctis

et al. 2020

Preprint

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Since the beginning of the SARS-CoV-2 pandemic, COVID-19 has appeared as a unique disease with unconventional tissue and systemic immune features. While COVID-19 severe forms share clinical and laboratory aspects with various pathologies such as hemophagocytic lymphohistiocyto-sis, sepsis or cytokine release syndrome, their exact nature remains unknown. This is severely imped-ing the ability to treat patients facing severe stages of the disease. To this aim, we performed an in-depth, single-cell RNA-seq analysis of more than 150.000 immune cells isolated from matched blood samples and broncho-alveolar lavage fluids of COVID-19 patients and healthy controls, and integrated it with clinical, immunological and functional ex vivo data. We unveiled an immune sig-nature of disease severity that correlated with the accumulation of naïve lymphoid cells in the lung and an expansion and activation of myeloid cells in the periphery. Moreover, we demonstrated that myeloid-driven immune suppression is a hallmark of COVID-19 evolution and arginase 1 expression is significantly associated with monocyte immune regulatory features. Noteworthy, we found mon-ocyte and neutrophil immune suppression loss associated with fatal clinical outcome in severe pa-tients. Additionally, our analysis discovered that the strongest association of the patients clinical outcome and immune phenotype is the lung T cell response. We found that patients with a robust CXCR6+ effector memory T cell response have better outcomes. This result is line with the rs11385942 COVID-19 risk allel, which is in proximity to the CXCR6 gene and suggest effector memory T cell are a primary feature in COVID-19 patients. By systemically quantifying the viral landscape in the lung of severe patients, we indeed identified Herpes-Simplex-Virus 1 (HSV-1) as a potential opportunistic virus in COVID-19 patients. Lastly, we observed an unexpectedly high SARS-CoV-2 viral load in an immuno-compromised patient, allowing us to study the SARS-CoV-2 in-vivo life cycle. The development of myeloid dysfunctions and the impairment of lymphoid arm establish a condition of immune paralysis that supports secondary bacteria and virus infection and can progress to “immune silence” in patients facing death.

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“…(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).…”

Section: Introductionmentioning

confidence: 99%

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

Peters

Blainey

Bryson

2020

Preprint

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SUMMARYMonocytes, dendritic cells, and macrophages, commonly referred to as mononuclear phagocytes (MNPs), are innate immune cells capable of adopting diverse homeostatic and pathogenic phenotypes. Recent single-cell RNA-sequencing studies across many diseases in the lung have profiled this diversity transcriptionally, defining new cellular states and their association with disease. Despite these massive cellular profiling efforts, many studies have focused on defining myeloid dysfunction in specific diseases without identifying common pan-disease trends in the mononuclear phagocyte compartment within the lung. To address these gaps in our knowledge, we collate, process, and analyze 561,390 cellular transcriptomes from 12 studies of the human lung across multiple human diseases. We develop a computational framework to identify and compare dominant gene markers and gene expression programs and characterize MNP diversity in the lung, proposing a conserved dictionary of gene sets. Utilizing this reference, we efficiently identify disease-associated and rare MNP populations across multiple diseases and cohorts. Furthermore, we demonstrate the utility of this dictionary in characterizing a recently published dataset of bronchoalveolar lavage cells from COVID-19 patients and healthy controls which further reveal novel transcriptional shifts directly relatable to other diseases in the lung. These results underline conserved MNP transcriptional programs in lung disease, provide an immediate reference for characterizing the landscape of lung MNPs and establish a roadmap to dissecting MNP transcriptional complexity across tissues.

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An immune-cell signature of bacterial sepsis

Cited by 283 publications

References 52 publications

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

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

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

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

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