Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae post COVID-19 (preprint)

Post-acute sequelae of SARS-CoV-2 infection (PASC) represents an urgent public health challenge, with its impact resonating in over 60 million individuals globally. While a growing body of evidence suggests that dysregulated immune reactions may be linked with PASC symptoms, most investigations have primarily centered around blood studies, with few focusing on samples derived from post-COVID affected tissues. Further, clinical studies alone often provide correlative insights rather than causal relationships. Thus, it is essential to compare clinical samples with relevant animal models and conduct functional experiments to truly understand the etiology of PASC. In this study, we have made comprehensive comparisons between bronchoalveolar lavage fluid (BAL) single-cell RNA sequencing (scRNAseq) data derived from clinical PASC samples and relevant PASC mouse models. This revealed a strong pro-fibrotic monocyte-derived macrophage response in respiratory PASC (R-PASC) in both humans and mice, and abnormal interactions between pulmonary macrophages and respiratory resident T cells. IFN-g emerged as a key node mediating the immune anomalies in R-PASC. Strikingly, neutralizing IFN-g post the resolution of acute infection reduced lung inflammation, tissue fibrosis, and improved pulmonary gas-exchange function in two mouse models of R-PASC. Our study underscores the importance of performing comparative analysis to understand the root cause of PASC for developing effective therapies.

Reduction in circulating monocytes correlates with persistent post-COVID pulmonary fibrosis in multi-omic comparison of long-haul COVID and IPF (preprint)

Rationale: Up to 30% of COVID-19 patients experience persistent sequelae, including dyspnea, restrictive physiology, and early radiographic signs of pulmonary fibrosis (PF). The mechanisms that provoke post-COVID progressive PF are poorly understood, and biomarkers to identify at-risk patients are urgently needed. Methods: We evaluated a cohort of 14 symptomatic COVID survivors with impaired respiratory function and imaging worrisome for developing PF, including bilateral reticulation, traction bronchiectasis and/or honeycombing, and compared these to Idiopathic Pulmonary Fibrosis (IPF) patients and age-matched controls without respiratory disease. We performed single-cell RNA-sequencing and multiplex immunostaining on peripheral blood mononuclear cells collected at the COVID-19 patients first visit after ICU discharge. Six months later, symptoms, restriction and PF improved in some (Early-Resolving COVID PF), but persisted in others (Late-Resolving COVID PF). Results: Circulating monocytes were significantly reduced in Late-Resolving COVID PF patients compared to Early-Resolving COVID PF and non-diseased controls. Monocyte abundance correlated with pulmonary function tests FVC and DLCO. Differential expression analysis revealed MHC-II class molecules were upregulated on the CD8 T cells of Late-Resolving COVID PF patients but downregulated in monocytes. IPF patients had a similar decrease in monocyte abundance and marked decrease in monocyte HLA-DR protein expression compared to Late-Resolving COVID PF patients. Conclusion: Circulating monocyte abundance may distinguish between patients whose post-COVID PF resolves or persists. Furthermore, fibrotic progression coincided with decreases in HLA-DR expression on monocytes, a phenotype previously associated with dampened antigen stimulation and severe respiratory failure.

Trauma Exposure and Depression among Frontline Health Professionals During COVID-19 Outbreak in China: The Role of Intrusive Rumination and Organizational Silence (preprint)

Background: Healthcare professionals are a population exposed to especially high riskand stress during the COVID-19 outbreak. Several studies have demonstrated that healthcare professionals exposed to COVID-19 reported various affective disorders such as depressive symptoms, anxiety, insomnia, and distress. However, the mechanism underlying the association between trauma exposure and depressive symptom among frontline hospital staff has yet to be investigated. This study aims to assess the prevalence of depressive symptoms among frontline healthcare professionals in Shenzhen, China, particularly examining its association with trauma exposure, intrusive rumination and organizational silence. Methods: : Data of the study came from a time-lagged panel questionnaire survey with three waves of measurement from February, 2020 to May, 2020 at an infectious diseases hospital of Shenzhen which accommodated all the confirmed cases of COVID-19 patients. Using clustersampling design, a total of 134 frontline healthcare professionals directly involved inproviding diagnosis, treatment and nursing services for COVID-19 patients completed three wave web survey. A moderated mediation model was performed to examine the complex interplay among the major study variables. Results: : Trauma exposure was significantly related with depression of frontline healthcare professionals. Intrusive rumination mediated the effect of trauma exposure on depressive symptom, and organization silence moderated the relationship between intrusive rumination and depressive symptoms. Intrusive rumination showed stronger effect on depressive while organization silences was at a lower level. Conclusions: : This research demonstrates the pivotal role that intrusive rumination and organizational silence play in predicting the depressive symptoms among the frontline healthcare professionals coping with COVID-19.

Tissue-resident CD8+T cells drive age-associated chronic lung sequelae following viral pneumonia (preprint)

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic non-resolving lung pathology and exaggerated accumulation of CD8 + tissue-resident memory T cells (T RM ) in the respiratory tract of aged hosts. T RM accumulation relies on elevated TGF-β present in aged tissues. Further, we show that T RM isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, T RM cells from aged lungs were insufficient to provide heterologous protective immunity. Strikingly, the depletion of CD8 + T RM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated T RM cell malfunction supports chronic lung inflammatory and fibrotic sequelae following viral pneumonia in aged hosts.