Daily Respiratory Research Analysis
Analyzed 229 papers and selected 3 impactful papers.
Summary
Analyzed 229 papers and selected 3 impactful articles.
Selected Articles
1. Airway immune signatures of protection and disease progression in recent human tuberculosis household contacts.
Single-cell RNA-seq of bronchoalveolar lavage from recent TB contacts identified neutrophil-dominant, type I IFN–linked programs and inverse T-cell abundance with exhaustion in progressors, whereas nonprogressors displayed regulatory, quiescent, stem-like T-cell states. These airway programs delineate early human responses that may determine infection outcomes.
Impact: This mechanistic human study pinpoints airway cellular programs that segregate TB control vs progression, offering actionable targets for host-directed therapies and vaccine design.
Clinical Implications: Airway neutrophil dominance with T-cell exhaustion may serve as early biomarkers to risk-stratify recent contacts and to prioritize host-directed interventions restoring T-cell function or tempering type I IFN–neutrophil axes.
Key Findings
- Single-cell RNA-seq of BAL identified type I IFN–dependent and IFN-independent neutrophil signatures in active TB and progressors.
- An inverse relationship existed between airway neutrophils and T cells; progressors showed T-cell exhaustion, cytotoxicity, and cell death signatures.
- Nonprogressors exhibited protective T-cell programs enriched for regulation, quiescence, and stem-like states, suggesting mechanisms of natural control.
Methodological Strengths
- Single-cell transcriptomics directly on human bronchoalveolar lavage
- PET/CT-defined recent contacts enabling precise phenotypic stratification
Limitations
- Observational design without interventional validation of pathways
- Sample size and generalisability not detailed; causality cannot be inferred
Future Directions: Longitudinal validation in larger, diverse cohorts; interventional studies testing host-directed agents targeting neutrophil–IFN axes and T-cell exhaustion programs; integration with mucosal vaccine strategies.
The local immune factors dictating whether individuals who have been infected with Mycobacterium tuberculosis remain healthy or progress to active tuberculosis (TB) have not been defined. Here we interrogated the airway immune response at single-cell resolution in bronchoalveolar lavage from positron emission and computed tomography-characterized recent TB household contacts, who either controlled the infection or progressed to TB disease, as well as of patients with active TB at diagnosis. Single-cell RNA sequencing revealed type I IFN-depen
2. NF-κB-Dependent Transcriptional Regulation of Piezo1 Mediates Bacterial Clearance on Infected Lung Stiffness.
Using stiffness-relevant macrophage models, the study shows that NF-κB (p65)-MyD88 signaling increases Piezo1 transcription and channel activity, which elevates TFEB-driven lysosome biogenesis and stiffness-dependent phagolysosome maturation to enhance bacterial clearance. This establishes a mechanotransduction pathway linking injured lung matrix stiffness to macrophage antimicrobial function.
Impact: Identifies a previously uncharted NF-κB→Piezo1→TFEB axis that mechanistically links lung stiffness to macrophage bacterial killing, opening a therapeutic avenue for pneumonia-induced lung injury.
Clinical Implications: Modulating Piezo1 or its upstream NF-κB signaling may augment host defense during pneumonia, particularly in stiff, injured lung matrices; this could complement antibiotics and reduce progression to severe lung injury.
Key Findings
- NF-κB (p65)-MyD88 signaling increases macrophage Piezo1 transcription and Ca2+ channel activity during pneumonia-relevant stimulation.
- Piezo1 upregulation enhances TFEB abundance, driving lysosome biogenesis and stiffness-dependent phagolysosome maturation.
- Enhanced Piezo1 mechanotransduction improves macrophage bacterial clearance on pathophysiologic lung stiffness.
- Chromatin at the Piezo1 promoter becomes more open, supporting increased transcription.
Methodological Strengths
- Mechanistically integrated approach linking transcriptional control, chromatin state, ion channel activity, and functional bacterial clearance.
- Use of pathophysiologic stiffness models to mimic injured lung matrix microenvironment.
Limitations
- Primarily preclinical in vitro macrophage systems without in vivo therapeutic modulation of Piezo1.
- Pathogen spectrum limited to P. aeruginosa virulence context; generalizability to other bacteria needs testing.
Future Directions: Test pharmacologic or genetic modulation of Piezo1/NF-κB in vivo across pneumonia models and evaluate synergy with antibiotics; map tissue stiffness–immune response coupling in human pneumonia.
RATIONALE: Respiratory pathogens, such as Pseudomonas aeruginosa damage the alveolar-capillary barrier leading to lung injury and stiffness. Lung stiffness is a key macrophage signal for bacterial clearance, but it remains unknown how stiffness-sensing mechanosensitive ion channels in macrophages are regulated during pneumonia. Macrophage Piezo1 is critical to bacterial clearance in experimental pneumonia in vivo; however, identification of putative matrix-derived signals and the mechanism of their effects remain to be determined. OBJECTIVES: We investigated the role of P. aeruginosa virulence factors on Piezo1 activity in macrophages on infected lung matrix stiffness. METHODS: Using bone-marrow derived macrophages, we measured Piezo1 abundance and function and bacterial clearance in response to P. aeruginosa virulence factors on pathophysiologic range lung stiffnesses and standard tissue culture conditions. MEASUREMENTS AND MAIN RESULTS: To our knowledge, our work is the first to show that during pneumonia, transcription of the mechanosensitive ion channel Piezo1 is increased in macrophages by the NF-κB transcription factor, p65, through its signaling adaptor protein, MyD88, leading to increased Piezo1 Ca2 + channel activity. Piezo1 mRNA abundance is increased in association with open chromatin at the Piezo1 promoter in macrophages. The enhanced level of Piezo1 increases the abundance of transcription factor EB (Tfeb) resulting in lysosome biogenesis and stiffness-dependent phagolysosome maturation, a critical step for macrophage bacterial clearance. CONCLUSIONS: Our data support the mechanism whereby transcription of macrophage Piezo1 is enhanced by p65 to augment bacterial clearance on an injured, stiffened lung matrix during pneumonia. Therefore, Piezo1 is a future therapeutic target against pneumonia-induced lung injury.
3. RSV can infect the human nasal epithelium via the basolateral route and shows distinct subgroup infectivity and basal cell tropism.
In human nose organoid ALI cultures, RSV established infection from the basolateral side by targeting Krt23+ activated basal cells before spreading apically, with RSV/B showing higher basolateral infectivity than RSV/A. This reveals an alternative entry route and expands RSV cellular tropism beyond apical ciliated cells.
Impact: Demonstrates a non-canonical basolateral entry route and identifies a rare basal cell subset as an initial target, reshaping concepts of RSV spread and potentially informing vaccine/antiviral strategies.
Clinical Implications: Preventive or therapeutic strategies may need to consider protecting basal cell compartments and epithelial integrity, and subgroup-specific differences (A vs B) could influence prophylaxis effectiveness.
Key Findings
- RSV can initiate infection basolaterally in human nasal epithelium with delayed apical release compared to apical inoculation.
- RSV/B (Buenos Aires strain) showed a higher basolateral infection frequency than RSV/A (Ontario strain) (81.3% vs 25%).
- Krt23+ activated basal cells are uniquely susceptible to RSV and serve as initial targets in basolateral infection.
- Basolateral infection preserves epithelial integrity initially before apical spread to ciliated cells.
Methodological Strengths
- Use of adult- and infant-derived human nose organoid ALI models to dissect apical vs basolateral infection.
- Strain- and subgroup-comparative design revealing differential basolateral infectivity.
Limitations
- In vitro organoid/ALI systems may not fully capture in vivo immune and microenvironmental factors.
- Limited number of strains; generalization across broader RSV diversity needs confirmation.
Future Directions: Validate basolateral infection and basal cell targeting in vivo; assess how subgroup differences impact transmission, lower airway spread, and vaccine-induced protection.
Respiratory syncytial virus (RSV) causes millions of lower respiratory tract infections (LRTIs) in young children, older adults, and immunocompromised populations every year. RSV infection initiates in the upper respiratory tract and can progress to the lower airways, resulting in bronchiolitis, pneumonia, and even death. RSV primarily infects epithelial cells apically, but we hypothesized that basolateral exposure of the respiratory epithelium could provide an alternative mechanism of infection that contributes to LRTI development. Using a human nose organoid-air-liquid interface (HNO-ALI) model, we performed apical and basolateral inoculations with contemporaneous RSV strains (RSV/A/Ontario [RSV/A/ON] and RSV/B/Buenos Aires [RSV/B/BA]) representing the two RSV subgroups (A and B) in both adult- and infant-derived HNO-ALIs. Basolateral RSV exposure resulted in delayed viral replication and apical release compared to apical infection. A statistically significant difference in basolateral infection frequency was observed between RSV/B/BA and RSV/A/ON (81.3% versus 25%). Basolateral infection selectively targeted a rare basal cell population, while preserving epithelial integrity. Using undifferentiated HNO-ALIs, we determined for the first time that Krt23+ activated basal cells are uniquely susceptible to RSV infection, a finding we confirmed in fully differentiated HNO-ALIs. Together, our findings show that RSV can infect the respiratory epithelium from the basolateral side by initially targeting a rare subset of basal cells before spreading apically to ciliated cells. Moreover, RSV/B/BA may have an advantage over RSV/A/ON in utilizing the basolateral infection route. These findings highlight an alternative RSV infection pathway and could be a potential mechanism for RSV spread to the lower airways.IMPORTANCEUnderstanding the pathogenesis of respiratory syncytial virus (RSV) is essential to understanding and preventing acute and long-term sequelae from infection. The canonical understanding of RSV infection is that the virus infects and is restricted to the apical ciliated cells upon inhalation or fomite exposure. We demonstrate that an alternative route of infection-the basolateral route-can be utilized by RSV to infect the apical ciliated cells of the respiratory epithelium. We also show for the first time a novel difference in infectivity between the two contemporaneous RSV strains (RSV/A/Ontario and RSV/B/Buenos Aires). In addition, we describe a rare basal subset-the Krt23+ activated basal cells-that are uniquely susceptible to RSV, expanding the known cellular tropism of RSV. Infection of basal cells can impact airway differentiation, homeostasis, and remodeling. Overall, our findings expand on RSV pathogenesis and indicate there are alternative mechanisms of infection and cell populations that are susceptible to RSV.