Daily Respiratory Research Analysis

Current COVID-19 vaccines have saved countless lives but primarily aim to induce immunity to the spike or its RBD protein and often fail to confer broad or durable protection against rapidly evolving variants and prevent transmission. Here, we invented a live-attenuated broad-spectrum coronavirus vaccine (cb1) by changing the codon usage bias of SARS-CoV-2 genome, which maintained amino acid conservation but reduced virulence. A single intranasal dose of cb1 vaccine elicits remarkably broad and potent immunity that overcomes existing parenteral vaccine's limitations. cb1 induced robust neutralizing antibody and T cell responses that translated into complete protection in animal models, including prevention of viral transmission to unvaccinated contacts. Notably, cb1 provided cross-protection not only against diverse SARS-CoV-2 variants of concern but also against more divergent SARS-CoV-1 and hCoV-OC43, a breadth of immunity unparalleled by current vaccines. These findings highlight the potential of cb1 to address urgent needs for next-generation COVID-19 vaccines that elicit mucosal immunity with broad, long-lasting efficacy, eliminating the necessity for frequent updates.

Virus-induced inflammation and programmed cell death (PCD) are critical antiviral defenses, prompting viruses like respiratory syncytial virus (RSV) to develop PCD regulation mechanisms. Here, we demonstrate that RSV orchestrates the temporal and sequential regulation of distinct PCD pathways in human macrophages to optimize replication and dissemination. During early stages of infection, RSV activates the PI3K-Akt pathway to induce cFLIP expression, effectively suppressing TNF-driven extrinsic apoptosis. Simultaneously, viral degradation of ZDHHC9 prevents GSDMD-mediated pyroptosis downstream of NLRP3 activation, thereby sustaining an intracellular environment permissive to viral propagation. In contrast, following the completion of replication, RSV subverts caspase-1 signaling to trigger the intrinsic apoptotic cascade via the Casp-1-BID-APAF1-Casp-9 axis, and subsequently promotes GSDME-mediated secondary pyroptosis. This late-stage PCD reprogramming enables synchronized release of virions and pro-inflammatory cytokines, exacerbating pulmonary pathology. These findings delineate a temporally resolved strategy by which RSV balances early immune evasion with subsequent viral dissemination and immunopathology, and identify discrete stage-specific molecular targets for therapeutic intervention in RSV-induced lung disease.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) is a promising tool for pathogen detection. However, its clinical utility in detecting opportunistic pulmonary infections of immunocompromised patients remains controversial. METHODS: This multicenter retrospective study involving 162 immunocompromised patients with opportunistic pulmonary infections was conducted across four respiratory centers. The enrolled patients were divided into the conventional microbiological tests (CMT) group and the mNGS group based on whether mNGS of BALF was performed after admission. Propensity score-matching (PSM) was adopted to minimize selection bias, and sensitivity analysis confirmed the robustness. The primary outcomes were >30% improvement in oxygenation index (OI) at 7 days post-admission and clinical improvement by day 14 as assessed with the WHO 7-category ordinal scale. Secondary outcomes included 21-day mortality, incidence of septic shock during hospitalization, and pathogen detection rate. RESULTS: Among the 110 patients who underwent mNGS, the results prompted modifications to the antibiotic therapy in 89 patients (80.9%), encompassing both escalation and de-escalation of therapy. The remaining 52 patients received only CMT. After the PSM, 41 matched pairs were further analyzed. Compared to the CMT group, OI improvement >30% on day 7 was more frequent in the mNGS group (41.5% vs. 9.8%, P = 0.001). Clinical improvement on day 14 in the mNGS group was higher than in the CMT group (36.6% vs. 9.8%, P = 0.004). Additionally, BALF mNGS was associated with decreased 21-day mortality (7.3% vs. 34.1%; P = 0.003) in patients with opportunistic pulmonary infections, while showing no significant association with reduced incidence of septic shock during hospitalization. Moreover, the causative pathogen detection rate was significantly higher in the mNGS group compared to the CMT group (97.6% vs. 22.0%, P<0.001), demonstrating the superior diagnostic yield of mNGS. CONCLUSION: Our study indicated that early BALF mNGS testing upon admission was associated with improved OI up to day 7, clinical improvement on day 14, and decreased 21-day mortality. These benefits are likely facilitated by the higher diagnostic yield of mNGS and its direct impact on guiding targeted antibiotic therapy.