An aberrant inflammatory response in severe COVID-19

Mérad, Miriam; Subramanian, Aruna; Wang, Taia T.

doi:10.1016/j.chom.2021.06.018

Cited by 28 publications

(21 citation statements)

References 17 publications

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“…Thus, the biggest hurdle to obtaining definitive answers with various intervention trials in severe COVID-19 has been to select the right timing and the right patient who might benefit from the intervention, on the basis of either clinical or biochemically easy to measure (point of care) biomarkers. It is very likely that the hyperinflammation that characterizes severe disease is driven by several molecular and cellular pathways that tend to self-amplify 111 , so in advanced disease, targeting only one pathway and hoping for improvement is likely to be futile. Early intervention without causing immunosuppression is probably key.…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

The state of complement in COVID-19

et al. 2021

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Hyperactivation of the complement and coagulation systems is recognized as part of the clinical syndrome of COVID-19. Here we review systemic complement activation and local complement activation in response to the causative virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their currently known relationships to hyperinflammation and thrombosis. We also provide an update on early clinical findings and emerging clinical trial evidence that suggest potential therapeutic benefit of complement inhibition in severe COVID-19.

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Section: Therapeutic Perspectivesmentioning

confidence: 99%

The state of complement in COVID-19

et al. 2021

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“…As such, IFN released by T cells drives the emergence of pathologically activated, hyperinflammatory monocytes and macrophages that produce large amounts of interleukin (IL)-6, TNF and IL-1 (Grant et al, 2021). Although numerous studies investigated immune responses upon SARS-CoV-2 infection in humans, these studies are largely correlations in hospitalized patients with moderate to severe disease (Merad et al, 2021).…”

mentioning

confidence: 99%

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

Gawish

Starkl

Pimenov

et al. 2022

eLife

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In silico modelling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNg and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

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“…The ideal therapy should correct the dysfunction of the innate immune response to SARS-CoV-2 which leads to excess inflammation and over-expression of IL-6, as well as enhancing adaptive immune responses to resolve the infection and prevent re-infection [ 10 , 11 ]. Ezrin peptides have been tested in human volunteers for the treatment of mild-to-moderate COVID, and seem to have the potential to achieve these clinical endpoints [ 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Ezrin Peptide Therapy from HIV to COVID: Inhibition of Inflammation and Amplification of Adaptive Anti-Viral Immunity

Holms¹,

Ataullakhanov

2021

IJMS

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Human Ezrin Peptides (HEPs) are inhibitors of expression of IL-6 and other inflammatory cytokines, amplifiers of adaptive B cell and T cell immunity and enhancers of tissue repair. The mutation stable C-terminus of HIV gp120, mimics 69% of the “Hep-receptor”, a zipped α-helical structure in the middle of the α domain of human ezrin protein. Synthetic peptides homologous to the Hep-receptor of ezrin of five to fourteen amino acids, activate anti-viral immunity against a wide range of viruses (HIV, HCV, herpes, HPV, influenza and other human respiratory viruses). Human Ezrin Peptide One (HEP1) TEKKRRETVEREKE (brand name Gepon, registered for human use in Russia from 2001) is a successful treatment for opportunistic infections in HIV-infected patients. That treats HEP1and prevents mucosal candidiasis, herpes zoster outbreaks and infection-induced chronic diarrhea. There are clinical publications in Russian on the successful treatments of chronic recurrent vaginal candidiasis, acute and chronic enterocolitis and dysbacteriosis, which are accompanied by normalization of the mucosal microbiome, and the decline or disappearance of inflammation. HEP1 is also an effective treatment and prevention for recurrent inflammation and ulceration in the stomach, duodenum and colon. HEP1 and RepG3 GEKKRRETVEREGG (a derivative of HEP1) have been used successfully as an inhaled spray peptide solution to treat a small number of human volunteers with mild-to-moderate COVID, resulting from SARS-CoV-2 infection, based on earlier successes in treating acute viral respiratory disease with inflammatory complications. Ezrin peptides seem to correct a dysregulation of innate immune responses to SARS-CoV-2. They are also adjuvants of B cell adaptive immunity and increase antibody titres, resulting in protection from lethal virus infection of mice. In a clinical study in Moscow, orally administered HEP1 was shown to enhance antibody-titres produced in response to hepatitis-B vaccination. These very preliminary but promising results with ezrin peptide treatment of COVID must be replicated in large-scale randomised placebo controlled clinical studies, to be verified.

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An aberrant inflammatory response in severe COVID-19

Cited by 28 publications

References 17 publications

The state of complement in COVID-19

The state of complement in COVID-19

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

Ezrin Peptide Therapy from HIV to COVID: Inhibition of Inflammation and Amplification of Adaptive Anti-Viral Immunity

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