TLRs in COVID-19: How they drive immunopathology and the rationale for modulation.
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ABSTRACT:
SUBMITTER: Mabrey FL
PROVIDER: S-EPMC8762091 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As the outbreak of the new coronavirus (SARS-CoV-2) infection is spreading globally, great effort is being made to understand the disease pathogenesis and host factors that predispose to disease progression in an attempt to find a window of opportunity for intervention. In addition to the direct cytopathic effect of the virus, the host hyper-inflammatory response has emerged as a key factor in determining disease severity and mortality. Accumulating clinical observations raised hypotheses to explain why some patients develop more severe disease while others only manifest mild or no symptoms. So far, Covid-19 management remains mainly supportive. However, many researches are underway to clarify the role of antiviral and immunomodulating drugs in changing morbidity and mortality in patients who become severely ill. This review summarizes the current state of knowledge on the interaction between SARS-CoV-2 and the host immune system and discusses recent findings on proposed pharmacologic treatments.
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Project description:The rapid spread of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), has resulted in an unprecedented public health crisis worldwide. Recent studies indicate that a hyperinflammatory syndrome induced by SARS-CoV-2 contributes to disease severity and mortality in COVID-19. In this review, an overview of the pathophysiology underlying the hyperinflammatory syndrome in severe COVID-19 is provided. The current evidence suggests that the hyperinflammatory syndrome results from a dysregulated host innate immune response. The gross and microscopic pathologic findings as well as the alterations in the cytokine milieu, macrophages/monocytes, natural killer cells, T cells, and neutrophils in severe COVID-19 are summarized. The data highlighted include the potential therapeutic approaches undergoing investigation to modulate the immune response and abrogate lung injury in severe COVID-19.
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Project description:we profiled the inflammatory transcriptome of ten COVID-19 skin manifestations from patients with moderate-to-severe disease and compared the resultant signatures with those obtained from skin lesions of patients with cutaneous lupus erythematosus.
2022-01-07 | GSE193068 | GEO
Project description:Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.
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Project description:Syndrome Coronavirus 2 (SARS-CoV-2), is characterized by significant lung pathology and extrapulmonary complications. Type I interferons (IFNs) play an essential role in the pathogenesis of COVID-19. While rapid induction of type I IFNs limits virus propagation, sustained elevation of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome. Using proteomic data from a lung-on-chip model revealed that, in addition to macrophages, SARS-CoV-2 infection activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, leading to cell death and type I IFN production.
2022-04-04 | PXD030753 | Pride
Project description:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organ-specific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
| S-EPMC8013908 | biostudies-literature
Project description:The clinical manifestation of coronavirus disease 2019 (COVID-19) mainly targets the lung as a primary affected organ, which is also a critical site of immune cell activation by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, recent reports also suggest the involvement of extrapulmonary tissues in COVID-19 pathology. The interplay of both innate and adaptive immune responses is key to COVID-19 management. As a result, a robust innate immune response provides the first line of defense, concomitantly, adaptive immunity neutralizes the infection and builds memory for long-term protection. However, dysregulated immunity, both innate and adaptive, can skew towards immunopathology both in acute and chronic cases. Here we have summarized some of the recent findings that provide critical insight into the immunopathology caused by SARS-CoV-2, in acute and post-acute cases. Finally, we further discuss some of the immunomodulatory drugs in preclinical and clinical trials for dampening the immunopathology caused by COVID-19.
| S-EPMC9537925 | biostudies-literature
Project description:Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.
| S-EPMC7262347 | biostudies-literature
Project description:BackgroundSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain-containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy.MethodsUsing a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19.ResultsTwenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8+ T cells, CD4+ T cells, and CD56+ natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis.ConclusionsOur data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.
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Project description:A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document excessive FcγRIIIA/CD16A activation in patients developing severe or critical COVID-19 but not in those with mild disease. We identify two independent ligands mediating extreme FcγRIIIA/CD16A activation. Soluble circulating IgG immune complexes (sICs) are detected in about 80% of patients with severe and critical COVID-19 at levels comparable to active systemic lupus erythematosus (SLE) disease. FcγRIIIA/CD16A activation is further enhanced by afucosylation of SARS-CoV-2 specific IgG. Utilizing cell-based reporter systems we provide evidence that sICs can be formed prior to a specific humoral response against SARS-CoV-2. Our data suggest a cycle of immunopathology driven by an early formation of sICs in predisposed patients. These findings suggest a reason for the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19. The involvement of circulating sICs in the promotion of immunopathology in predisposed patients opens new possibilities for intervention strategies to mitigate critical COVID-19 progression.
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