Downregulation of Defensin genes in SARS-CoV-2 infection

Idris, Mohammed M.; Banu, Sarena; Siva, Archana Bharadwaj; Nagaraj, Ramakrishnan

doi:10.1101/2020.09.21.20195537

Cited by 16 publications

(22 citation statements)

References 26 publications

(38 reference statements)

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“…The most significant outcome of our repurposing study is the prediction that several members of the alarmin family such as defensins, HMBG1, IL1α, IL25, IL33, TSLP, S100A4, S100A7, S100A8, S100A9, S100A12, S100B, S100P likely contribute to lung inflammation during COVID-19 (Fig 4) [68][69][70]. The role of each individual alarmin in this regard remains to be investigated, with presumably some of them (e.g.…”

Section: Discussionmentioning

confidence: 98%

Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19

et al. 2021

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While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1β, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19.

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Section: Discussionmentioning

confidence: 98%

Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19

et al. 2021

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“…The so-called “silent spreaders” may involuntarily contribute to the exponential growth of disease, as nasal secretions contain spreadable virus ( Higgins et al, 2020 ) but lack endogenous expression of some of the AMPs [e.g., hBD-2 ( Guaní-Guerra et al, 2011 ; Bouloukaki et al, 2011 )]. Additionally, nasopharyngeal swab samples have revealed that CoV-2–infected patients have lower mRNA levels of several defensins when compared to uninfected subjects ( Idris et al, 2020 ). To “ramp up” AMP levels, AMPs and/or their derivatives could be administered intranasally and/or intraorally as prophylactic aerosols, in early stages of infection when telltale symptoms begin to appear and in combinatorial therapeutic approaches for more severe situations.…”

Section: Discussionmentioning

confidence: 99%

Ramping Up Antimicrobial Peptides Against Severe Acute Respiratory Syndrome Coronavirus-2

Ghosh

Weinberg

2021

Front. Mol. Biosci.

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Human-derived antimicrobial peptides (AMPs), such as defensins and cathelicidin LL-37, are members of the innate immune system and play a crucial role in early pulmonary defense against viruses. These AMPs achieve viral inhibition through a variety of mechanisms including, but not limited to, direct binding to virions, binding to and modulating host cell-surface receptors, blocking viral replication, and aggregation of viral particles and indirectly by functioning as chemokines to enhance or curb adaptive immune responses. Given the fact that we are in a pandemic of unprecedented severity and the urgent need for therapeutic options to combat severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), naturally expressed AMPs and their derivatives have the potential to combat coronavirus disease 2019 (COVID-19) and impede viral infectivity in various ways. Provided the fact that development of effective treatments is an urgent public health priority, AMPs and their derivatives are being explored as potential prophylactic and therapeutic candidates. Additionally, cell-based platforms such as human mesenchymal stem cell (hMSC) therapy are showing success in saving the lives of severely ill patients infected with SARS-CoV-2. This could be partially due to AMPs released from hMSCs that also act as immunological rheostats to modulate the host inflammatory response. This review highlights the utilization of AMPs in strategies that could be implemented as novel therapeutics, either alone or in combination with other platforms, to treat CoV-2–infected individuals.

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“…SARS-CoV-2 infection has been shown to suppress defensins, a type of HDP, suggesting that the innate immunity provided by defensins may be compromised [ 41 ]. Suppression of LL37, a human cathelicidin (another type of HDP) shown to possess immunomodulatory and antiviral properties [ 42 ], has also been observed in COVID-19 patients [ 43 ].…”

Section: Introductionmentioning

confidence: 99%

Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell Culture

Bakovic

Risner

Bhalla

et al. 2021

Viruses

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the newly emergent causative agent of coronavirus disease-19 (COVID-19), has resulted in more than two million deaths worldwide since it was first detected in 2019. There is a critical global need for therapeutic intervention strategies that can be deployed to safely treat COVID-19 disease and reduce associated morbidity and mortality. Increasing evidence shows that both natural and synthetic antimicrobial peptides (AMPs), also referred to as Host Defense Proteins/Peptides (HDPs), can inhibit SARS-CoV-2, paving the way for the potential clinical use of these molecules as therapeutic options. In this manuscript, we describe the potent antiviral activity exerted by brilacidin—a de novo designed synthetic small molecule that captures the biological properties of HDPs—on SARS-CoV-2 in a human lung cell line (Calu-3) and a monkey cell line (Vero). These data suggest that SARS-CoV-2 inhibition in these cell culture models is likely to be a result of the impact of brilacidin on viral entry and its disruption of viral integrity. Brilacidin demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that brilacidin exerts potent inhibition of SARS-CoV-2 against different strains of the virus in cell culture.

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Downregulation of Defensin genes in SARS-CoV-2 infection

Cited by 16 publications

References 26 publications

Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19

Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19

Ramping Up Antimicrobial Peptides Against Severe Acute Respiratory Syndrome Coronavirus-2

Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell Culture

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