Intranasal type I interferon treatment is beneficial only when administered before clinical signs onset in the SARS-CoV-2 hamster model

Bessière, Pierre; Wasniewski, Marine; Picard-Meyer, Evelyne; Servat, Alexandre; Figueroa, Thomas; Foret‐Lucas, Charlotte; Coggon, Amelia; Lesellier, Sandrine; Boué, Frank; Cebron, Nathan; Gausserès, Blandine; Trumel, Catherine; Foucras, Gilles; Salguero, Francisco J.; Monchâtre-Leroy, Élodie; Volmer, Romain

doi:10.1371/journal.ppat.1009427

Cited by 43 publications

(24 citation statements)

References 37 publications

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“…In 3,000 medical staff administered intranasal IFN-α as a prophylactic during a COVID-19 outbreak, no new infections were seen during a 28-day observation period compared with 100 new infections in untreated staff at neighboring Wuhan hospitals ( 47 ). Prophylactic IFN-α has also been confirmed in Syrian hamster models to restrict COVID-19 disease progression but showed little effect after the onset of symptoms ( 48 , 49 ). The sex differences regarding late IFN levels are unknown.…”

Section: Discussionmentioning

confidence: 97%

Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2

et al. 2021

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Coronavirus disease 2019 (COVID-19) exhibits a sex bias with males showing signs of more severe disease and hospitalizations compared with females. The mechanisms are not clear but differential immune responses, particularly the initial innate immune response, between sexes may be playing a role. The early innate immune responses to SARS-CoV-2 have not been studied because of the gap in timing between the patient becoming infected, showing symptoms, and getting the treatment. The primary objective of the present study was to compare the response of dendritic cells (DCs) and monocytes from males and females to SARS-CoV-2, 24 h after infection. To investigate this, peripheral blood mononuclear cells (PBMCs) from healthy young individuals were stimulated in vitro with the virus. Our results indicate that PBMCs from females upregulated the expression of HLA-DR and CD86 on pDCs and mDCs after stimulation with the virus, while the activation of these cells was not significant in males. Monocytes from females also displayed increased activation than males. In addition, females secreted significantly higher levels of IFN-α and IL-29 compared with males at 24 h. However, the situation was reversed at 1 week post stimulation and males displayed high levels of IFN-α production compared with females. Further investigations revealed that the secretion of CXCL-10, a chemokine associated with lung complications, was higher in males than females at 24 h. The PBMCs from females also displayed increased induction of CTLs. Altogether, our results suggest that decreased activation of pDCs, mDCs, and monocytes and the delayed and prolonged IFN-α secretion along with increased CXCL-10 secretion may be responsible for the increased morbidity and mortality of males to COVID-19.

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Section: Discussionmentioning

confidence: 97%

Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2

et al. 2021

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“…Moreover, as global efforts are underway to identify and develop new antiviral and immunomodulatory therapeutics that reduce COVID-19 related hospitalization and deaths, the need arises for the right timing [39]. Indeed, early type I IFN treatment seemed to be critical for therapeutic success [40]. However, prophylactic im-munomodulation might not be feasible for most COVID-19 patients due to high costs and potential adverse events.…”

Section: Discussionmentioning

confidence: 99%

Distinguishing Incubation and Acute Disease Stages of Mild-to-Moderate COVID-19

Müller

Volzke

Subin

et al. 2022

Viruses

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While numerous studies have already compared the immune responses against SARS-CoV-2 in severely and mild-to-moderately ill COVID-19 patients, longitudinal trajectories are still scarce. We therefore set out to analyze serial blood samples from mild-to-moderately ill patients in order to define the immune landscapes for differently progressed disease stages. Twenty-two COVID-19 patients were subjected to consecutive venipuncture within seven days after diagnosis or admittance to hospital. Flow cytometry was performed to analyze peripheral blood immune cell compositions and their activation as were plasma levels of cytokines and SARS-CoV-2 specific immunoglobulins. Healthy donors served as controls. Integrating the kinetics of plasmablasts and SARS-CoV-2 specific antibodies allowed for the definition of three disease stages of early COVID-19. The incubation phase was characterized by a sharp increase in pro-inflammatory monocytes and terminally differentiated cytotoxic T cells. The latter correlated significantly with elevated concentrations of IP-10. Early acute infection featured a peak in PD-1+ cytotoxic T cells, plasmablasts and increasing titers of virus specific antibodies. During late acute infection, immature neutrophils were enriched, whereas all other parameters returned to baseline. Our findings will help to define landmarks that are indispensable for the refinement of new anti-viral and anti-inflammatory therapeutics, and may also inform clinicians to optimize treatment and prevent fatal outcomes.

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“…It is important to note that for further in vivo studies, it will be necessary to consider the time and route of administration, as well as the metabolism of IFNα-containing drug combinations. In particular, intranasal IFNα treatment is beneficial only when administered before the onset of clinical signs in the SARS-CoV-2 hamster model [70]. In addition, earlier intramuscular administration of IFN-α was suggested to be beneficial for COVID-19 patients (10.2217/fvl-2020-0404).…”

Section: Discussionmentioning

confidence: 99%

“…The following are available online at www.mdpi.com/xxx/s1, Table S1: Compounds, their suppliers, and catalogue numbers, Table S2: Statistical analysis of data presented in Figure 1 using pairwise Wilcoxon Rank Sum Test with continuity correction, Table S3: Statistical analysis of data presented in Figure 2 using pairwise Wilcoxon Rank Sum Test, Figure S1: Three It is important to note that for further in vivo studies, it will be necessary to consider the time and route of administration, as well as the metabolism of IFNα-containing drug combinations. In particular, intranasal IFNα treatment is beneficial only when administered before the onset of clinical signs in the SARS-CoV-2 hamster model [70]. In addition, earlier intramuscular administration of IFN-α was suggested to be beneficial for COVID-19 patients (10.2217/fvl-2020-0404).…”

Section: Supplementary Materialsmentioning

confidence: 99%

Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections

Ianevski

Yao

Žusinaite

et al. 2021

Viruses

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Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα–remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Conclusions: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.

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Intranasal type I interferon treatment is beneficial only when administered before clinical signs onset in the SARS-CoV-2 hamster model

Cited by 43 publications

References 37 publications

Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2

Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2

Distinguishing Incubation and Acute Disease Stages of Mild-to-Moderate COVID-19

Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections

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