Secondary lung infection by inhaled Staphylococcus aureus (SA) is a common and lethal event for individuals infected with influenza A virus (IAV). How IAV disrupts host defense to promote SA ...infection in lung alveoli, where fatal lung injury occurs, is not known. We addressed this issue using real-time determinations of alveolar responses to IAV in live, intact, perfused lungs. Our findings show that IAV infection blocked defensive alveolar wall liquid (AWL) secretion and induced airspace liquid absorption, thereby reversing normal alveolar liquid dynamics and inhibiting alveolar clearance of inhaled SA. Loss of AWL secretion resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in the alveolar epithelium, and airspace liquid absorption was caused by stimulation of the alveolar epithelial Na+ channel (ENaC). Loss of AWL secretion promoted alveolar stabilization of inhaled SA, but rescue of AWL secretion protected against alveolar SA stabilization and fatal SA-induced lung injury in IAV-infected mice. These findings reveal a central role for AWL secretion in alveolar defense against inhaled SA and identify AWL inhibition as a critical mechanism of IAV lung pathogenesis. AWL rescue may represent a new therapeutic approach for IAV-SA coinfection.
Alveolar wall liquid (AWL) secretion prevents acute lung injury (ALI), a disease of lung alveoli, by generating liquid flow on the apical surface of the alveolar epithelium and transporting injurious ...particles and bacteria from alveoli. This physiological process is mediated by the alveolar epithelial cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Although both alveolar type 1 (AT1) and 2 (AT2) epithelial cells express CFTR, the cell type that drives AWL secretion is unclear. In vitro studies of cultured cells suggest AT2 cells are the source of AWL secretion. However, AT1 cells may be the driver in vivo on account of their extensive lung surface area. To study the role of live AT1 cell CFTR in AWL secretion, we employ live lung imaging of mouse lungs from a novel cell-specific fluorescent CFTR knockout mouse model.
In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast-derived mAbs from individuals who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in ...vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to spikes of seasonal human coronaviruses OC43 and HKU1. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine-induced RBD binding antibodies may provide substantial protection against viral variants carrying single E484K RBD mutations.
Display omitted
•Antibody responses after SARS-CoV-2 mRNA vaccination target RBD, NTD, and S2•SARS-CoV-2 mRNA vaccination induces a high rate of non-neutralizing antibodies•Crossreactive antibodies to seasonal β-coronaviruses are induced by vaccination•Variant mutation N501Y enhances affinity to human ACE2 while E484K reduces it
An analysis of mRNA vaccine-induced polyclonal antibodies and plasmablast-derived monoclonal antibodies from individuals vaccinated against SARS-CoV-2 identifies a high proportion of non-neutralizing antibodies and the induction of cross-reactive antibodies to seasonal coronaviruses and also maps the regions in the spike protein that are targeted, even among viral variants.
INTRODUCTION:
3D surgical navigation has revolutionized spinal surgery. However, information on the overall usability of these tools is limited and inconsistent, especially with regard to operative ...time and radiation exposure. Complication rates across institutions and platforms have not been systematically examined, leading to a lack of quantitative understanding on surgical success rates.
METHODS:
This study used PRISMA guidelines and a PROSPERO-registered protocol to identify studies on FDA-approved 3D navigation systems in spinal procedures from Ovid MEDLINE(R), Embase, and Cochrane CENTRAL. Results were assessed by two independent reviewers using inclusion/exclusion criteria and risk of bias tools.
RESULTS:
70 studies, totaling 3500 patients, were included. Complication and surgical success rates have remained constant since 2004, with overall rates of 5.18% and 93.74%, respectively. When segmented by spinal region, complication rates may be moderately positively correlated with frequency of cervical and thoracic procedures (r = 0.49, p = 0.40). 23 studies, totaling 1723 patients, compared the performance of 3D navigation to 2D fluoroscopy or freehand navigation. There was a significant difference of 6.47% between surgical success rates of the interventional and control groups (p = 0.01). However, there was no significant difference in radiation exposure or operative time between 3D navigated procedures and their controls.
CONCLUSIONS:
This study concludes that 3D navigation may have higher surgical success rates than 2D fluoroscopy and freehand navigation; increased surgeon comfort with riskier procedures on more complex segments of the spine may explain the slight increase in complication rates observed since 2004; and there is a need for improvement in 3D navigation tools to decrease operative time and radiation exposure.
One‐third of patients with severe lung infection by influenza A virus (IAV) develop secondary lung infection by inhaled S. aureus(SA), leading to mortality in 30% of cases. It is unclear how IAV ...promotes secondary SA infection in lung alveoli, where fluid barrier dysfunction causes fatal acute lung injury (ALI). Our objective is to define alveolar responses to IAV that promote SA infection, leading to SA‐induced alveolar damage and mortality. Our hypothesis is IAV lung infection blocks alveolar wall liquid (AWL) secretion, a homeostatic alveolar function that defends against alveolar stabilization of inhaled particles. AWL secretion depends on function of the alveolar epithelial cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Our methods include optical imaging of live, intact mouse lungs and mouse survival determinations. Mice were untreated or intranasally instilled with IAV (2000 PFU, A/PR/8/34). We excised, inflated, and blood‐perfused the lungs at 24h, then viewed live alveoli by confocal microscopy. Alveolar airspaces were microinstilled separately with: (A) the fluorescent cytosolic dye, calcein‐AM; (B) the fluorescent AWL tracer, tetramethylrhodamine‐conjugated dextran (70 kD); (C) the CFTR potentiator, ivacaftor; and (D) the SA toxin, alpha hemolysin (Hla). For survival studies, IAV‐infected mice were intranasally instilled with SA (USA300, 1x10^8 CFU) at 24h, then observed for 72h. Mice were given intraperitoneal injections of ivacaftor or vehicle at 4, 24, and 48h after SA instillation. Analysis was by t test (n=3) and log rank. Our results follow. Calcein fluorescence indicated the alveolar epithelium of IAV‐infected lungs was viable. In alveoli of untreated lungs, airspace dextran fluorescence decreased over 1h, indicating dextran was progressively diluted by AWL secretion. However, in IAV‐infected lungs, dextran fluorescence was steady (P<0.05), indicating IAV blocked AWL secretion. Since alveolar ivacaftor pretreatment restored dextran loss (P=NS versus untreated), we interpret IAV blocked AWL secretion in a CFTR‐dependent manner, and CFTR potentiation rescued AWL secretion. Hla microinstillation into alveoli of IAV‐infected lungs caused loss of epithelial calcein fluorescence, but alveolar pretreatment with ivacaftor blocked the loss (P<0.05). We interpret that rescue of AWL secretion protected against Hla‐induced alveolar damage, probably by promoting Hla clearance and disrupting Hla‐epithelial interactions. IAV‐infected mice treated with ivacaftor were protected from SA‐induced mortality (60% and 0% in vehicle‐ versus ivacaftor‐treated mice, respectively; P<0.05; N=10 each). We conclude that IAV disrupted AWL secretion, causing retention of airspace contents and augmenting Hla‐induced alveolar damage. Rescue of AWL secretion blocked Hla‐induced alveolar damage and increased survival in IAV‐SA coinfected mice. We propose strategies that rescue AWL secretion may represent a new therapeutic approach for ALI caused by IAV‐SA coinfection.
PDF
