Biology subjects

Donnelly, H. K.

Publications and source records attributed to Donnelly, H. K..

3 recordsLinked to original sources

bioRxiv2026

Pathogen-specific host responses define distinct pneumonia endotypes in the human lung

Pneumonia is the leading cause of death from infectious disease worldwide. The diagnosis and treatment of patients with pneumonia lag behind other major conditions, relying on syndromic definitions that lack molecular resolution and ignore underlying endotypes. We sought to test the hypothesis that dynamic pathogen-specific host responses in the alveolar space represent distinct pneumonia endotypes linked to different clinical features and outcomes. We prospectively enrolled a cohort of 690 patients (including immunocompromised patients) with known or suspected pneumonia receiving mechanical ventilation in whom the etiology of pneumonia was determined by gold-standard analysis of distal lung fluid obtained by bronchoalveolar lavage (BAL) combined with clinical adjudication. From these patients, we analyzed 792 BAL fluid samples, including 310 serial samples, using flow cytometry (482 patients) and single-cell RNA-sequencing (170 patients; 263 samples, complemented by 9 healthy controls and 25 post-COVID-19 patients, yielding [~]2.4 million single cells across 28 cell types), and extracted daily clinical data from the electronic health record (>15,000 patient-days). We used machine learning models to identify pathogen-specific host responses in the transcriptome of alveolar immune cells that were associated with changes in alveolar cell abundance and clinical features. Our results suggest that therapeutic strategies for pneumonia should be individualized to specific host-pathogen interactions.

immunology↗

bioRxiv2023

Prolonged exposure to lung-derived cytokines is associated with inflammatory activation of microglia in patients with COVID-19

Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia1-4. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans5. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF-[a] and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-196, was associated with lower levels of CXCL10, CCL8, and CCL2--molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells7. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19.

immunology↗

bioRxiv2020

Alveolitis in severe SARS-CoV-2 pneumonia is driven by self-sustaining circuits between infected alveolar macrophages and T cells

Some patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) develop severe pneumonia and the acute respiratory distress syndrome (ARDS) [1]. Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from other types of pneumonia [2]. We collected bronchoalveolar lavage fluid samples from 86 patients with SARS-CoV-2-induced respiratory failure and 252 patients with known or suspected pneumonia from other pathogens and subjected them to flow cytometry and bulk transcriptomic profiling. We performed single cell RNA-Seq in 5 bronchoalveolar lavage fluid samples collected from patients with severe COVID-19 within 48 hours of intubation. In the majority of patients with SARS-CoV-2 infection at the onset of mechanical ventilation, the alveolar space is persistently enriched in alveolar macrophages and T cells without neutrophilia. Bulk and single cell transcriptomic profiling suggest SARS-CoV-2 infects alveolar macrophages that respond by recruiting T cells. These T cells release interferon-gamma to induce inflammatory cytokine release from alveolar macrophages and further promote T cell recruitment. Our results suggest SARS-CoV-2 causes a slowly unfolding, spatially-limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 transcripts and T cells form a positive feedback loop that drives progressive alveolar inflammation. This manuscript is accompanied by an online resource: https://www.nupulmonary.org/covid-19/ One sentence summarySARS-CoV-2-infected alveolar macrophages form positive feedback loops with T cells in patients with severe COVID-19.

immunology↗