RESUMEN
Despite surviving a SARS-CoV-2 infection, some individuals experience an intense post-infectious Multisystem Inflammatory Syndrome (MIS) of uncertain etiology. Children with this syndrome (MIS-C) can experience a Kawasaki-like disease, but mechanisms in adults (MIS-A) are not clearly defined. Here we utilize a deep phenotyping approach to examine immunologic responses in an individual with MIS-A. Results are contextualized to healthy, convalescent, and acute COVID-19 patients. The findings reveal systemic inflammatory changes involving novel neutrophil and B-cell subsets, autoantibodies, complement, and hypercoagulability that are linked to systemic vascular dysfunction. This deep patient profiling generates new mechanistic insight into this rare clinical entity and provides potential insight into other post-infectious syndromes.
RESUMEN
Despite surviving a SARS-CoV-2 infection, some individuals experience an intense post-infectious Multisystem Inflammatory Syndrome (MIS) of uncertain etiology. Children with this syndrome (MIS-C) can experience a Kawasaki-like disease, but mechanisms in adults (MIS-A) are not clearly defined. Here we utilize a deep phenotyping approach to examine immunologic responses in an individual with MIS-A. Results are contextualized to healthy, convalescent, and acute COVID-19 patients. The findings reveal systemic inflammatory changes involving novel neutrophil and B-cell subsets, autoantibodies, complement, and hypercoagulability that are linked to systemic vascular dysfunction. This deep patient profiling generates new mechanistic insight into this rare clinical entity and provides potential insight into other post-infectious syndromes.
Asunto(s)
COVID-19 , Enfermedades del Tejido Conjuntivo , Niño , Humanos , Adulto , Neutrófilos , SARS-CoV-2RESUMEN
Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.
Asunto(s)
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico , Autorrenovación de las Células , Macrófagos Alveolares , Neutrófilos , Animales , Ratones , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Lesión Pulmonar Aguda , Animales Recién Nacidos , Araquidonato 12-Lipooxigenasa/deficiencia , Araquidonato 15-Lipooxigenasa/deficiencia , COVID-19 , Virus de la Influenza A , Lipopolisacáridos , Pulmón/citología , Pulmón/virología , Macrófagos Alveolares/citología , Macrófagos Alveolares/metabolismo , Neutrófilos/metabolismo , Infecciones por Orthomyxoviridae , Prostaglandinas E , SARS-CoV-2 , Susceptibilidad a EnfermedadesRESUMEN
The lung naturally resists Aspergillus fumigatus (Af) in healthy individuals, but multiple conditions can disrupt this resistance, leading to lethal invasive infections. Core processes of natural resistance and its breakdown are undefined. We investigated three distinct conditions predisposing to lethal aspergillosis-severe SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, influenza A viral pneumonia, and systemic corticosteroid use-in human patients and murine models. We found a conserved and essential coupling of innate B1a lymphocytes, Af-binding natural immunoglobulin G antibodies, and lung neutrophils. Failure of this axis concealed Af from neutrophils, allowing rapid fungal invasion and disease. Reconstituting the axis with immunoglobulin therapy reestablished resistance, thus representing a realistic pathway to repurpose currently available therapies. Together, we report a vital host resistance pathway that is responsible for protecting against life-threatening aspergillosis in the context of distinct susceptibilities.
Asunto(s)
COVID-19 , Neutrófilos , Humanos , Animales , Ratones , SARS-CoV-2 , Esteroides/uso terapéuticoRESUMEN
Objectives. To identify key effects of the pandemic and its economic consequences on menstrual product insecurity with implications for public health practice and policy. Methods. Study participants (n = 1496) were a subset of individuals enrolled in a national (US) prospective cohort study. Three survey waves were included (MarchâOctober 2020). Menstrual product insecurity outcomes were explored with bivariate associations and logistic regression models to examine the associations between outcomes and income loss. Results. Income loss was associated with most aspects of menstrual product insecurity (adjusted odds ratios from 1.34 to 3.64). The odds of not being able to afford products for those who experienced income loss was 3.64 times (95% confidence interval [CI] = 2.14, 6.19) that of those who had no income loss and 3.95 times (95% CI = 1.78, 8.79) the odds for lower-income participants compared with higher-income participants. Conclusions. Pandemic-related income loss was a strong predictor of menstrual product insecurity, particularly for populations with lower income and educational attainment. Public Health Implications. Provision of free or subsidized menstrual products is needed by vulnerable populations and those most impacted by pandemic-related income loss.(Am J Public Health. 2022;112(4):675-684. (https://doi.org/10.2105/AJPH.2021.306674).
Asunto(s)
COVID-19 , Productos para la Higiene Menstrual , COVID-19/epidemiología , Estudios Transversales , Abastecimiento de Alimentos , Humanos , Estudios Prospectivos , Estados Unidos/epidemiologíaRESUMEN
Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated genes and activated IL-1R2+ neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see 'Data availability' section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.