Fibroblast growth factor (FGF) signaling is cardioprotective in various models of myocardial infarction. FGF receptors (FGFRs) are expressed in multiple cell types in the adult heart, but the cell type-specific FGFR signaling that mediates different cardioprotective endpoints is not known. To determine the requirement for FGFR signaling in endothelium in cardiac ischemia-reperfusion injury, we conditionally inactivated the Fgfr1 and Fgfr2 genes in endothelial cells with Tie2-Cre ( Tie2-Cre, Fgfr1^f/f, Fgfr2^f/fDCKO mice). Tie2-Cre, Fgfr1^f/f, Fgfr2^f/fDCKO mice had normal baseline cardiac morphometry, function, and vessel density. When subjected to closed-chest, regional cardiac ischemia-reperfusion injury, Tie2-Cre, Fgfr1^f/f, Fgfr2^f/fDCKO mice showed a significantly increased hypokinetic area at 7 days, but not 1 day, after reperfusion. Tie2-Cre, Fgfr1^f/f, Fgfr2^f/fDCKO mice also showed significantly worsened cardiac function compared with controls at 7 days but not 1 day after reperfusion. Pathophysiological analysis showed significantly decreased vessel density, increased endothelial cell apoptosis, and worsened tissue hypoxia in the peri-infarct area at 7 days following reperfusion. Notably, Tie2-Cre, Fgfr1^f/f, Fgfr2^f/fDCKO mice showed no impairment in the cardiac hypertrophic response. These data demonstrate an essential role for FGFR1 and FGFR2 in endothelial cells for cardiac functional recovery and vascular remodeling following in vivo cardiac ischemia-reperfusion injury, without affecting the cardiac hypertrophic response. This study suggests the potential for therapeutic benefit from activation of endothelial FGFR pathways following ischemic injury to the heart.

Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or seasonal influenza may lead to respiratory failure requiring intubation and mechanical ventilation. The pathophysiology of this respiratory failure is attributed to local immune dysregulation, but how the immune response to viral infection in the lower airways of the human lung differs between individuals with respiratory failure and those without is not well understood. We used quantitative multiparameter flow cytometry and multiplex cytokine assays to evaluate matched blood and bronchoalveolar lavage (BAL) samples from control human subjects, subjects with symptomatic seasonal influenza who did not have respiratory failure, and subjects with severe seasonal influenza or SARS-CoV-2 infection with respiratory failure. We find that severe cases are associated with an influx of nonclassical monocytes, activated T cells, and plasmablast B cells into the lower airways. Cytokine concentrations were not elevated in the lower airways of moderate influenza patients compared with controls; however, 28 of 35 measured cytokines were significantly elevated in severe influenza, severe SARS-CoV-2 infection, or both. We noted the largest elevations in IL-6, IP-10, MCP-1, and IL-8. IL-1 family cytokines and RANTES were higher in severe influenza infection than severe SARS-CoV-2 infection. Interestingly, only the concentration of IP-10–correlated between blood and BAL during severe infection. Our results demonstrate inflammatory immune dysregulation in the lower airways during severe viral pneumonia that is distinct from lower airway responses seen in human patients with symptomatic, but not severe, illness and suggest that measurement of blood IP-10 concentration may predict this unique dysregulation.

Coronavirus disease 2019 (COVID-19) is characterized by a high incidence of acute respiratory failure. The underlying immunopathology of that failure and how it compares to other causes of severe respiratory distress, such as influenza virus infection, are not fully understood. Here we addressed this by developing a prospective observational cohort of COVID-19 and influenza subjects with varying degrees of disease severity and assessing the quality and magnitude of their immune responses at the cellular and protein level. Additionally, we performed single-cell RNA transcriptional profiling of peripheral blood mononuclear cells from select subjects. The cohort consists of 79 COVID-19 subjects, 26 influenza subjects, and 15 control subjects, including 35 COVID-19 and 7 influenza subjects with acute respiratory failure. While COVID-19 subjects exhibited largely equivalent or greater activated lymphocyte counts compared to influenza subjects, they had fewer monocytes and lower surface HLA-class II expression on monocytes compared to influenza subjects and controls. At least two distinct immune profiles were observed by cytokine levels in severe COVID-19 patients: 3 of 71 patients were characterized by extreme inflammation, with greater than or equal to ~50% of the 35 cytokines measured greater than 2 standard deviations from the mean level of other severe patients (both influenza and COVID-19); the other immune profile, which characterized 68 of 71 subjects, had a mixed inflammatory signature, where 28 of 35 cytokines in COVID-19 patients had lower mean cytokine levels, though not all were statistically significant. Only 2 cytokines were higher in COVID-19 subjects compared to influenza subjects (IL-6 and IL-8). Influenza and COVID-19 patients could be distinguished statistically based on cytokine module expression, particularly after controlling for the significant effects of age on cytokine expression, but again with lower levels of most cytokines in COVID-19 subjects. Further, high circulating levels of IL-1RA and IL-6 were associated with increased odds of intubation in the combined influenza and COVID-19 cohort [OR = 3.93 and 4.30, respectively] as well as among only COVID-19 patients. Single cell transcriptional profiling of COVID-19 and influenza subjects with respiratory failure identified profound suppression in type I and type II interferon signaling in COVID-19 patients across multiple clusters. In contrast, COVID-19 cell clusters were enriched for alterations in metabolic, stress, and apoptotic pathways. These alterations were consistent with an increased glucocorticoid response in COVID-19 patients compared to influenza. When considered across the spectrum of innate and adaptive immune profiles, the immune pathologies underlying severe influenza and COVID-19 are substantially distinct. The majority of COVID-19 patients with acute respiratory failure do not have a cytokine storm phenotype but instead exhibit profound type I and type II IFN immunosuppression when compared to patients with acute influenza. Upregulation of a small number of inflammatory mediators, including IL-6, predicts acute respiratory failure in both COVID-19 and influenza patients.

Background: The 2022–23 US influenza season peaked early in fall 2022.Methods: Late‐season influenza vaccine effectiveness (VE) against outpatient, laboratory‐confirmed influenza was calculated among participants of the US Influenza VE Network using a test‐negative design.Results: Of 2561 participants enrolled from December 12, 2022 to April 30, 2023, 91 laboratory‐confirmed influenza cases primarily had A(H1N1)pdm09 (6B.1A.5a.2a.1) or A(H3N2) (3C.2a1b.2a.2b). Overall, VE was 30% (95% confidence interval −9%, 54%); low late‐season activity precluded estimation for most subgroups.Conclusions: 2022–23 late‐season outpatient influenza VE was not statistically significant. Genomic characterization may improve the identification of influenza viruses that circulate postinfluenza peak.

Traumatic stress exposures (TSEs) are common in life. Although most individuals recover after a TSE, a substantial subset develop adverse post-traumatic neuropsychiatric sequelae such as chronic post-traumatic musculoskeletal pain (CPMP). Vulnerability factors for CPMP are poorly understood, which hinders identification of high-risk individuals for targeted interventions. One known vulnerability factor for many pain types is exposure to early life adversity (ELA), but few studies have assessed whether ELA increases risk for CPMP. This study used data from the Advancing Understanding of RecOvery afteR traumA study, a prospective human cohort study of TSE survivors, to test the hypothesis that ELA increases risk for CPMP. In addition, in secondary analyses, we assessed which subtypes of ELA (including childhood bullying) were most predictive of CPMP and whether a rat ELA model consisting of neonatal limited bedding, combined with single prolonged stress (SPS) in adulthood, would accurately model human findings. In Advancing Understanding of RecOvery afteR traumA study participants (n = 2480), using multinomial logistic regression modeling of 4 identified latent pain classes, we found that ELA increased vulnerability to the high unremitting pain class (odds ratio [OR] = 1.047, P < 0.001), the moderate pain class (OR = 1.031, P < 0.001), and the moderate recovery pain class (OR = 1.018, P = 0.004), with physical abuse, emotional abuse, and bullying being the strongest predictors of high pain class assignment. Similarly, in male and female Sprague Dawley rats, in comparison with SPS alone, neonatal limited bedding combined with SPS caused increased baseline sensitivity and prolonged mechanical hypersensitivity (F(11,197) = 3.22, P < 0.001). Further studies in animals and humans are needed to understand mechanisms by which ELA confers vulnerability to CPMP.