Ficolin A exacerbates severe H1N1 influenza virus infection-induced acute lung immunopathological injury via excessive complement activation.
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ABSTRACT:
SUBMITTER: Wu X
PROVIDER: S-EPMC8298942 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The influenza A (H1N1) pdm09 virus remains a critical global health concern and causes high levels of morbidity and mortality. Severe acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the major outcomes among severely infected patients. Our previous study found that interleukin (IL)-17A production by humans or mice infected with influenza A (H1N1) pdm09 substantially contributes to ALI and subsequent morbidity and mortality. However, the cell types responsible for IL-17A production during the early stage of severe influenza A (H1N1) pdm09 infection remained unknown. In this study, a mouse model of severe influenza A (H1N1) pdm09 infection was established. Our results show that, in the lungs of infected mice, the percentage of ??T cells, but not the percentages of CD4+Th and CD8+Tc cells, gradually increased and peaked at 3?days post-infection (dpi). Further analysis revealed that the V?4+??T subset, but not the V?1+??T subset, was significantly increased among the ??T cells. At 3?dpi, the virus induced significant increases in IL-17A in the bronchoalveolar lavage fluid (BALF) and serum. IL-17A was predominantly secreted by ??T cells (especially the V?4+??T subset), but not CD4+Th and CD8+Tc cells at the early stage of infection, and IL-1? and/or IL-23 were sufficient to induce IL-17A production by ??T cells. In addition to secreting IL-17A, ??T cells secreted interferon (IFN)-? and expressed both an activation-associated molecule, natural killer group 2, member D (NKG2D), and an apoptosis-associated molecule, FasL. Depletion of ??T cells or the V?4+??T subset significantly rescued the virus-induced weight loss and improved the survival rate by decreasing IL-17A secretion and reducing immunopathological injury. This study demonstrated that, by secreting IL-17A, lung V?4+??T cells, at least, in part mediated influenza A (H1N1) pdm09-induced immunopathological injury. This mechanism might serve as a promising new target for the prevention and treatment of ALI induced by influenza A (H1N1) pdm09.
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2021-06-08 | GSE175450 | GEO
Project description:Influenza A virus (IAV) infection alters lung epithelial cell metabolism in vitro by promoting a glycolytic shift. We hypothesized that this shift benefits the virus rather than the host and that inhibition of glycolysis would improve infection outcomes. A/WSN/33 IAV-inoculated C57BL/6 mice were treated daily from 1 day post-inoculation (d.p.i.) with 2-deoxy-d-glucose (2-DG) to inhibit glycolysis and with the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) to promote flux through the TCA cycle. To block OXPHOS, mice were treated every other day from 1 d.p.i. with the Complex I inhibitor rotenone (ROT). 2-DG significantly decreased nocturnal activity, reduced respiratory exchange ratios, worsened hypoxemia, exacerbated lung dysfunction, and increased humoral inflammation at 6 d.p.i. DCA and ROT treatment normalized oxygenation and airway resistance and attenuated IAV-induced pulmonary edema, histopathology, and nitrotyrosine formation. None of the treatments altered viral replication. These data suggest that a shift to glycolysis is host-protective in influenza.
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Project description:Historically, the membrane attack complex, composed of complement components C5b-9, has been connected to lytic cell death and implicated in secondary injury after a CNS insult. However, studies to date have utilized either non-littermate control rat models, or mouse models that lack significant C5b-9 activity. To investigate what role C5b-9 plays in spinal cord injury and recovery, we generated littermate PVG C6 wildtype and deficient rats and tested functional and histological recovery after moderate contusion injury using the Infinite Horizon Impactor. We compare the effect of C6 deficiency on recovery of locomotor function and histological injury parameters in PVG rats under two conditions: (1) animals maintained as separate C6 WT and C6-D homozygous colonies; and (2) establishment of a heterozygous colony to generate C6 WT and C6-D littermate controls. The results suggest that maintenance of separate homozygous colonies is inadequate for testing the effect of C6 deficiency on locomotor and histological recovery after SCI, and highlight the importance of using littermate controls in studies involving genetic manipulation of the complement cascade.
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Project description:Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.
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Project description:The vitamin E family includes both tocopherols and tocotrienols, where ?-tocopherol (?TOC) is the most bioavailable form. Clinical trials testing the therapeutic efficacy of high-dose ?TOC against stroke have largely failed or reported negative outcomes when a "more is better" approach to supplementation (>400 IU/d) was used. This work addresses mechanisms by which supraphysiologic ?TOC may contribute to stroke-induced brain injury. Ischemic stroke injury and the neuroinflammatory response were studied in tocopherol transfer protein-deficient mice maintained on a diet containing ?TOC vitamin E at the equivalent human dose of 1680 IU/d. Ischemic stroke-induced brain injury was exacerbated in the presence of supraphysiologic brain ?TOC levels. At 48 h after stroke, S100B and RAGE expression was increased in stroke-affected cortex of mice with elevated brain ?TOC levels. Such increases were concomitant with aggravated microglial activation and neuroinflammatory signaling. A poststroke increase in markers of oxidative injury and neurodegeneration in the presence of elevated brain ?TOC establish that at supraphysiologic levels, ?TOC potentiates neuroinflammatory responses to acute ischemic stroke. Exacerbation of microglial activation by excessive ?TOC likely depends on its unique cell signaling regulatory properties independent of antioxidant function. Against the background of clinical failure for high-dose ?TOC, outcomes of this work identify risk for exacerbating stroke-induced brain injury as a result of supplementing diet with excessive levels of ?TOC.
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Project description:Severe influenza diseases with high mortality have been frequently reported, especially in those patients infected with avian influenza A (H5N1, H7N9 or H10N8) or during a pandemic. Respiratory distress, which is attributed to alveolar damage associated with immunopathological lesions, is the most common cause of death. There is a wealth of information on pathogenesis or treatment options. In this study, we showed that high levels of C-reactive protein (CRP) were induced and correlated with complement activation in patients infected with severe influenza A (H5N1, H7N9 or H10N8), and higher levels were induced in fatal patients than in survivors. CRP treatment enhanced the phagocytosis of monocytes THP-1 to H5N1 virus as well as the expression of proinflammatory cytokines or apoptosis-associated genes in THP-1 cells or pneumocytes A-549 respectively. CRP may link to proinflammatory mediators contributing to activation of complement and boosting inflammatory response in severe influenza infections. Compound 1,6-bis(phosphocholine)-hexane improved the severity and mortality of mice infected with lethal influenza virus significantly. These observations showed that CRP is involved in deterioration of severe influenza diseases, and indicated a substantial candidate molecule for immunotherapy of severe influenza diseases.
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Project description:Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition--a marker of complement activation mediated by immune complexes--was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.
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Project description:Brain death (BD) can immunologically prime the donor organ and is thought to lead to exacerbated ischemia/reperfusion injury after transplantation. Using a newly developed mouse model of BD, we investigated the effect of donor BD on posttransplantation cardiac ischemia/reperfusion injury. We further investigated the therapeutic effect of a targeted complement inhibitor in recipients of BD donor hearts and addressed the clinical relevance of these studies by analyzing human heart biopsies from BD and domino (living) donors.Hearts from living or BD donor C57BL/6 mice were transplanted into C57BL/6 or BALB/c recipients. Recipient mice were treated with the complement inhibitor CR2-Crry or vehicle control (n=6). Isografts were analyzed 48 hours after transplantation for injury, inflammation, and complement deposition, and allografts were monitored for graft survival. Human cardiac biopsies were analyzed for complement deposition and inflammatory cell infiltration. In the murine model, donor BD exacerbated ischemia/reperfusion injury and graft rejection, as demonstrated by increased myocardial injury, serum cardiac troponin, cellular infiltration, complement deposition, inflammatory chemokine and cytokine levels, and by decreased graft survival. CR2-Crry treatment of recipients significantly reduced all measured outcomes in grafts from both BD and living donors compared with controls. Analysis of human samples documented the relevance of our experimental findings and revealed exacerbated complement deposition and inflammation in grafts from BD donors compared with grafts from living donors.BD exacerbates posttransplantation cardiac ischemia/reperfusion injury in mice and humans and decreases survival of mouse allografts. Furthermore, targeted complement inhibition in recipient mice ameliorates BD-exacerbated ischemia/reperfusion injury.
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