Single-cell RNA sequencing reveals the sustained immune cell dysfunction in the pathogenesis of sepsis secondary to bacterial pneumonia

Wang, Teng; Zhang, Xianglong; Liu, Zhan‐Guo; Tong, Yao; Zheng, Dongying; Gan, Jianwei; Yu, Shuang; Li, Lin; Chen, Peng; Sun, Jian

doi:10.1016/j.ygeno.2021.01.026

Cited by 55 publications

(41 citation statements)

References 37 publications

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“…S4C and table S11). A similar reconfiguration of immune responses was associated with rapid disease progression, worse symptoms, and increased mortality in humans in both bacterial and viral [influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] pneumonia (43)(44)(45).…”

Section: Early-life Antibiotic Exposure Remodels Pulmonary Immune Res...mentioning

confidence: 98%

The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota

et al. 2022

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Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.

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Section: Early-life Antibiotic Exposure Remodels Pulmonary Immune Res...mentioning

confidence: 98%

The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota

et al. 2022

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“…The analysis of within-host evolution of P. aeruginosa and other bacterial pathogens is now possible by using single-cell transcriptomics, and may lead to the prediction of clinical progression of bacterial infections and options in therapy [ 461 ]. For example, single-cell RNA sequencing was used to examine immune cell dysfunction in the pathogenesis of bacterial pneumonia-derived sepsis [ 462 ]. A combined strategy could be used by following gene expression of P. aeruginosa lung infections using micro-biopsied lung samples and single bacterial cells isolated from tissues by laser microdissection.…”

Section: Future Perspectivesmentioning

confidence: 99%

An Organ System-Based Synopsis ofPseudomonas aeruginosaVirulence

et al. 2021

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Driven in part by its metabolic versatility, high intrinsic antibiotic resistance, and a large repertoire of virulence factors, Pseudomonas aeruginosa is expertly adapted to thrive in a wide variety of environments, and in the process, making it a notorious opportunistic pathogen. Apart from the extensively studied chronic infection in the lungs of people with cystic fibrosis (CF), P. aeruginosa also causes multiple serious infections encompassing essentially all organs of the human body, among others, lung infection in patients with chronic obstructive pulmonary disease, primary ciliary dyskinesia and ventilator-associated pneumonia; bacteremia and sepsis; soft tissue infection in burns, open wounds and postsurgery patients; urinary tract infection; diabetic foot ulcers; chronic suppurative otitis media and otitis externa; and keratitis associated with extended contact lens use. Although well characterized in the context of CF, pathogenic processes mediated by various P. aeruginosa virulence factors in other organ systems remain poorly understood. In this review, we use an organ system-based approach to provide a synopsis of disease mechanisms exerted by P. aeruginosa virulence determinants that contribute to its success as a versatile pathogen.

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“…2d and g) in dysbiotic newborn macaques after infection with S. pneumoniae. A similar reconfiguration of immune responses was associated with rapid disease progression, worse symptoms, and increased mortality in humans in both bacterial and viral (influenza and SARS-Cov2) pneumonia (39)(40)(41)(42)(43)(44).…”

Section: Resultsmentioning

confidence: 89%

Balance between protective and pathogenic immune responses to pneumonia in the neonatal lung enforced by gut microbiota

Stevens

Steinmeyer

Bonfield

et al. 2021

Preprint

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While modern clinical practices like cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure, mirroring current clinical practices, interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system as assessed by single-cell proteomic and transcriptomic analyses of the pulmonary immune response. Early-life antibiotic exposure rendered newborn macaques susceptible to bacterial pneumonia, mediated by profound changes in neutrophil senescence, inflammatory signaling, and macrophage dysfunction. Pathogenic reprogramming of pulmonary immunity was reflected by a hyperinflammatory signature in all pulmonary immune cell subsets. Distinct patterns of immunoparalysis, including dysregulated antigen presentation in alveolar macrophages, impaired costimulatory function in T helper cells, and dysfunctional cytotoxic responses in natural killer (NK) cells, were coupled with a global loss of tissue-protective, homeostatic pathways in lungs of dysbiotic newborns. Fecal microbiota transfer corrected the broad immune maladaptations and protected against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity. Gut microbiota promote balance between pathways driving tissue repair and inflammatory responses, thereby leading to clinical recovery from infection in infants.

show abstract

Single-cell RNA sequencing reveals the sustained immune cell dysfunction in the pathogenesis of sepsis secondary to bacterial pneumonia

Cited by 55 publications

References 37 publications

The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota

The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota

An Organ System-Based Synopsis ofPseudomonas aeruginosaVirulence

Balance between protective and pathogenic immune responses to pneumonia in the neonatal lung enforced by gut microbiota

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