Citations

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S–specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19–vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

AbstractPurposeImage guidance is used to improve the accuracy of radiation therapy delivery but results in increased dose to patients. This is of particular concern in children who need be treated per Pediatric Image Gently Protocols due to long‐term risks from radiation exposure. The purpose of this study is to design a deep neural network architecture and loss function for improving soft‐tissue contrast and preserving small anatomical features in ultra‐low‐dose cone‐beam CTs (CBCT) of head and neck cancer (HNC) imaging.MethodsA 2D compound U‐Net architecture (modified U‐Net++) with different depths was proposed to enhance the network capability of capturing small‐volume structures. A mask weighted loss function (Mask‐Loss) was applied to enhance soft‐tissue contrast. Fifty‐five paired CBCT and CT images of HNC patients were retrospectively collected for network training and testing. The output enhanced CBCT images from the present study were evaluated with quantitative metrics including mean absolute error (MAE), signal‐to‐noise ratio (SNR), and structural similarity (SSIM), and compared with those from the previously proposed network architectures (U‐Net and wide U‐Net) using MAE loss functions. A visual assessment of ten selected structures in the enhanced CBCT images of each patient was performed to evaluate image quality improvement, blindly scored by an experienced radiation oncologist specialized in HN cancer.ResultsAll the enhanced CBCT images showed reduced artifactual distortion and image noise. U‐Net++ outperformed the U‐Net and wide U‐Net in terms of MAE, contrast near structure boundaries, and small structures. The proposed Mask‐Loss improved image contrast and accuracy of the soft‐tissue regions. The enhanced CBCT images predicted by U‐Net++ and Mask‐Loss demonstrated improvement compared to the U‐Net in terms of average MAE (52.41 vs 42.85 HU), SNR (14.14 vs 15.07 dB), and SSIM (0.84 vs 0.87), respectively (, in all paired t‐tests). The visual assessment showed that the proposed U‐Net++ and Mask‐Loss significantly improved original CBCTs (), compared to the U‐Net and MAE loss.ConclusionsThe proposed network architecture and loss function effectively improved image quality in soft‐tissue contrast, organ boundary, and small structure preservation for ultra‐low‐dose CBCT following Image Gently Protocol. This method has potential to provide sufficient anatomical representation on the enhanced CBCT images for accurate treatment delivery and potentially fast online‐adaptive re‐planning for HN cancer patients.

Abstract Alveolar macrophages (AMs) are major lung tissue-resident macrophages capable of proliferating and self-renewal in situ. AMs are vital in pulmonary antimicrobial immunity and surfactant clearance. The mechanisms regulating AM compartment formation and maintenance remain to be fully elucidated currently. In this study, we have explored the roles of mitochondrial transcription factor A (TFAM)–mediated mitochondrial fitness and metabolism in regulating AM formation and function. We found that TFAM deficiency in mice resulted in significantly reduced AM numbers and impaired AM maturation in vivo. TFAM deficiency was not required for the generation of AM precursors nor the differentiation of AM precursors into AMs, but was critical for the maintenance of AM compartment. Mechanistically, TFAM deficiency diminished gene programs associated with AM proliferation and self-renewal and promoted the expression of inflammatory genes in AMs. We further showed that TFAM-mediated AM compartment impairment resulted in defective clearance of cellular debris and surfactant in the lung and increased the host susceptibility to severe influenza virus infection. Finally, we found that influenza virus infection in AMs led to impaired TFAM expression and diminished mitochondrial fitness and metabolism. Thus, our data have established the critical function of TFAM-mediated mitochondrial metabolism in AM maintenance and function.

Respiratory tissue resident–like CD8 + T cells are associated with chronic lung sequelae post-acute COVID-19.

Objective To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods A genome‐wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta‐analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function. Results Among the genome‐wide significant associations identified, the largest effect on risk of AAV came from the single‐nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3 , in which the top‐scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3‐ANCAs and those with myeloperoxidase‐ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%. Conclusion This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.