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SARS-CoV-2 infection causes COVID-19 disease, which can result in consequences ranging from undetectable to fatal, focusing attention on the modulators of outcomes. The respiratory tract microbiome is thought to modulate the outcomes of infections such as influenza as well as acute lung injury, raising the question to what degree does the airway microbiome influence COVID-19? Here, we review the results of 56 studies examining COVID-19 and the respiratory tract microbiome, summarize the main generalizations, and point to useful avenues for further research. Although the results vary among studies, a few consistent findings stand out. The diversity of bacterial communities in the oropharynx typically declined with increasing disease severity. The relative abundance of Haemophilus and Neisseria also declined with severity. Multiple microbiome measures tracked with measures of systemic immune responses and COVID outcomes. For many of the conclusions drawn in these studies, the direction of causality is unknown—did an alteration in the microbiome result in increased COVID severity, did COVID severity alter the microbiome, or was some third factor the primary driver, such as medication use. Follow-up mechanistic studies can help answer these questions. -hPNxGBEUu4dZv1p37KLx1 Video Abstract

An unexpected Diplorickettsia species closely related to the tickborne pathogen D. massieliensis was found in the microbiome of an Ixodes scapularis tick in Vermont, USA. This evidence of Diplorickettsia in North American ticks suggests a need for disease surveillance using molecular screening of ticks and serologic studies of humans.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory tract, results in highly variable outcomes ranging from minimal illness to death, but the reasons for this are not well understood. We investigated the respiratory tract bacterial microbiome and small commensal DNA viruses in hospitalized COVID-19 patients and found that each was markedly abnormal compared to that in healthy people and differed from that in critically ill patients without COVID-19. Viral infection of the respiratory tract can be associated with propagating effects on the airway microbiome, and microbiome dysbiosis may influence viral disease. Here, we investigated the respiratory tract microbiome in coronavirus disease 2019 (COVID-19) and its relationship to disease severity, systemic immunologic features, and outcomes. We examined 507 oropharyngeal, nasopharyngeal, and endotracheal samples from 83 hospitalized COVID-19 patients as well as non-COVID patients and healthy controls. Bacterial communities were interrogated using 16S rRNA gene sequencing, and the commensal DNA viruses Anelloviridae and Redondoviridae were quantified by qPCR. We found that COVID-19 patients had upper respiratory microbiome dysbiosis and greater change over time than critically ill patients without COVID-19. Oropharyngeal microbiome diversity at the first time point correlated inversely with disease severity during hospitalization. Microbiome composition was also associated with systemic immune parameters in blood, as measured by lymphocyte/neutrophil ratios and immune profiling of peripheral blood mononuclear cells. Intubated patients showed patient-specific lung microbiome communities that were frequently highly dynamic, with prominence of Staphylococcus . Anelloviridae and Redondoviridae showed more frequent colonization and higher titers in severe disease. Machine learning analysis demonstrated that integrated features of the microbiome at early sampling points had high power to discriminate ultimate level of COVID-19 severity. Thus, the respiratory tract microbiome and commensal viruses are disturbed in COVID-19 and correlate with systemic immune parameters, and early microbiome features discriminate disease severity. Future studies should address clinical consequences of airway dysbiosis in COVID-19, its possible use as biomarkers, and the role of bacterial and viral taxa identified here in COVID-19 pathogenesis. IMPORTANCE COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory tract, results in highly variable outcomes ranging from minimal illness to death, but the reasons for this are not well understood. We investigated the respiratory tract bacterial microbiome and small commensal DNA viruses in hospitalized COVID-19 patients and found that each was markedly abnormal compared to that in healthy people and differed from that in critically ill patients without COVID-19. Early airway samples tracked with the level of COVID-19 illness reached during hospitalization, and the airway microbiome also correlated with immune parameters in blood. These findings raise questions about the mechanisms linking SARS-CoV-2 infection and other microbial inhabitants of the airway, including whether the microbiome might regulate severity of COVID-19 disease and/or whether early microbiome features might serve as biomarkers to discriminate disease severity.

SARS-CoV-2 continues to transmit and evolve in humans and animals. White-tailed deer ( Odocoileus virginianus ) have been previously identified as a zoonotic reservoir for SARS-CoV-2 with high rates of infection and probable spillback into humans. Here we report sampling 1,127 white-tailed deer (WTD) in Pennsylvania, and a genomic analysis of viral dynamics spanning 1,017 days between April 2021 and January 2024. To assess viral load and genotypes, RNA was isolated from retropharyngeal lymph nodes and analyzed using RT-qPCR and viral whole genome sequencing. Samples showed a 14.64% positivity rate by RT-qPCR. Analysis showed no association of SARS-CoV-2 prevalence with age, sex, or diagnosis with Chronic Wasting Disease. From the 165 SARS-CoV-2 positive WTD, we recovered 25 whole genome sequences and an additional 17 spike-targeted amplicon sequences. The viral variants identified included 17 Alpha, 11 Delta, and 14 Omicron. Alpha largely stopped circulating in humans around September 2021, but persisted in WTD as recently as March of 2023. Phylodynamic analysis of pooled genomic data from Pennsylvania documents at least 12 SARS-CoV-2 spillovers from humans into WTD, including a recent series of Omicron spillovers. Prevalence was higher in WTD in regions with crop coverage rather than forest, suggesting an association with proximity to humans. Analysis of seasonality showed increased prevalence in winter and spring. Multiple examples of recurrent mutations were identified associated with transmissions, suggesting WTD-specific evolutionary pressures. These data document ongoing infections in white-tailed deer, probable onward transmission in deer, and a remarkable rate of new spillovers from humans.

Background The majority of bacteria in the vertebrate gut harbor integrated bacterial viruses (“bacteriophages” or “phages”; integrated phage are termed “prophages”). To probe phage replication strategies in the mammalian gut microbiome, we investigated phage activity in a large longitudinal study of diversity outbred mice (913 animals) undergoing extreme dietary restriction with detailed phenotypic characterization across lifespan. Results We assembled 54,119 candidate DNA viral genomes from 2997 longitudinal metagenomes, forming 6462 viral operational taxonomic units (vOTUs). Over 85% of vOTUs annotated as novel. Viruses annotated predominantly as prophages in the Caudoviricetes class. We detected no eukaryotic DNA viruses, and none of the strictly lytic Crassvirales order that is abundant in human gut. The most prevalent phages had the widest predicted host ranges. The relative abundance of most phages was highly correlated to that of their inferred host bacteria, suggesting quiescent prophages dominate viral metagenomes, consistent with “piggyback-the-winner” dynamics. After accounting for close phage-bacterial covariation, we did identify a subset of phages changing in relative abundance and prevalence relative to their hosts in response to dietary restriction and aging. In particular, phages with larger genomes become less common in diets with restricted calories, potentially reflecting a higher fitness cost to their host. Generalist phages were enriched for a gene encoding a single-strand DNA binding protein which is reportedly involved in DNA repair and protection from nucleases encoded by host cells. Lytic phages became more common with aging, and we observed a reduction in phage richness with age, both findings previously observed in human cohorts. Conclusion These studies enrich our understanding of DNA phage dynamics in gut while emphasizing the predominance of “piggyback-the-winner” strategies.

ObjectiveThe immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological, and molecular features.MethodsEndobronchial biopsies (n=295) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via autofluorescence bronchoscopy and CT, were profiled by RNA-seq. We applied the TCR Repertoire Utilities for Solid Tissue/Tumor tool to the RNA-seq data to identify TCR CDR3 sequences across all samples. In the biopsies, we measured the correlation of TCR diversity with previously derived immune-associated PML transcriptional signatures and PML outcome. We also quantified the spatial and temporal distribution of shared and clonally expanded TCRs. Using the biopsies and brushes, the ratio of private (ie, found in one patient only) and public (ie, found in two or more patients) TCRs was quantified, and the CDR3 sequences were compared with those found in curated databases with known antigen specificities.ResultsWe detected 39,303 unique TCR sequences across all samples. In PML biopsies, TCR diversity was negatively associated with a transcriptional signature of T cell mediated immune activation (p=4e-4) associated with PML outcome. Additionally, in lesions of the proliferative molecular subtype, TCR diversity was decreased in regressive versus progressive/persistent PMLs (p=0.045). Within each patient, TCRs were more likely to be shared between biopsies sampled at the same timepoint than biopsies sampled at the same anatomic location at different times. Clonally expanded TCRs, within a biopsied lesion, were more likely to be expanded at future time points than non-expanded clones. The majority of TCR sequences were found in a single sample, with only 3396 (8.6%) found in more than one sample and 1057 (2.7%) found in two or more patients (ie, public); however, when compared with a public database of CDR3 sequences, 4543 (11.6%) of TCRs were identified as public. TCRs with known antigen specificities were enriched among public TCRs (p<0.001).ConclusionsDecreased TCR diversity may reflect nascent immune responses that contribute to PML elimination. Further studies are needed to explore the potential for immunoprevention of PMLs.

Respiratory tract diseases represent some of the most common causes of mortality worldwide, yet the role of the respiratory tract’s resident microbiome is still underexplored in many of these diseases. In the present study, we examined the role of the respiratory microbiome in two diseases, COVID-19 and Chronic Lung Allograft Disfunction, as well as one related environmental exposure, the reuse of facemasks during the COVID-19 pandemic. In our COVID-19 cohort, we found that more severe disease was correlated with a loss of oropharyngeal microbiome diversity, and a reduction in the genera Haemophilus and Neisseria. Examining other COVID-19 cohorts from published literature found that this was a consistent signature, suggesting a possible indicator of severe disease that is consistent across patients. In our mask reuse study, we looked for changes in the respiratory tract microbiome associated with the reuse of disposable facemasks during the COVID-19 pandemic. We recruited two cohorts of participants, one group wearing a new facemask each day, another wearing one mask for a whole week. We found that while the bacterial burden on facemasks increased substantially with repeated use, this was not associated with any changes in the respiratory tract microbiome. Finally, in our CLAD cohort, we identified factors associated with lung function decline in lung transplant recipients. We collected microbiome samples during the first year post-transplant, and tracked lung function over the next eight years. We found three factors that correlated strongly with time to CLAD onset; expression of the cytokine IP10/CXCL10 immediately post-transplant, total bacterial burden at six weeks post-transplant, and the Streptococcus to Prevotella ratio at six months post-transplant. This work indicates that long term survival following lung allograft is dependent on microbiome alterations that during the first months, weeks, and even hours post-transplant. Ultimately, these three cohort studies lay the foundation for mechanistic studies of the respiratory tract microbiome in both acute and chronic lung conditions.

Introduction Interstitial lung abnormalities (ILA) often represent early fibrotic changes that can portend a progressive fibrotic phenotype. In particular, the fibrotic subtype of ILA is associated with increased mortality and rapid decline in lung function. Understanding the differential gene expression that occurs in the lungs of participants with fibrotic ILA may provide insight into development of a useful biomarker for early detection and therapeutic targets for progressive pulmonary fibrosis. Methods Measures of ILA and gene expression data were available in 213 participants in the Detection of Early Lung Cancer Among Military Personnel (DECAMP1 and DECAMP2) cohorts. ILA was defined using Fleischner Society guidelines and determined by sequential reading of computed tomography (CT) scans. Primary analysis focused on comparing gene expression in ILA with usual interstitial pneumonia (UIP) pattern with those with no ILA. Results ILA was present in 51 (24%) participants, of which 16 (7%) were subtyped as ILA with a UIP pattern. One gene, pro platelet basic protein (PPBP) and seventeen pathways (e.g. TNF-α signalling) were significantly differentially expressed between those with a probable or definite UIP pattern of ILA compared to those without ILA. 16 of these 17 pathways, but no individual gene, met significance when comparing those with ILA to those without ILA. Conclusion Our study demonstrates that abnormal inflammatory processes are apparent in the bronchial airway gene expression profiles of smokers with and without lung cancer with ILA. Future studies with larger and more diverse populations will be needed to confirm these findings.