Nasally delivered interferon-λ protects mice against infection by SARS-CoV-2 variants including Omicron

Chong, Zhenlu; Karl, Courtney E; Halfmann, Peter; Kawaoka, Yoshihiro; Winkler, Emma S.; Keeler, Shamus P.; Holtzman, Michael J.; Yu, Jinsheng; Diamond, Michael S.

doi:10.1016/j.celrep.2022.110799

Cited by 64 publications

(48 citation statements)

References 66 publications

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“…The host factor IFN-lambda is thought to play a particularly important role in these early defenses, as infection of mice defective in IFN-lambda with influenza results in an inability to control infection in the upper airway and dissemination to the lower airway (Klinkhammer et al ., 2018). The protective role of IFN-lambda has just begun to be studied during HCoV infection (Chong et al ., 2022). A recent study investigated potential mechanisms for the relative protection against developing severe COVID-19 seen in children compared to adults and revealed that pediatric airways showed higher basal expression levels of relevant immune sensors such as MDA5, which detects CoV double-stranded RNA (Loske et al ., 2022).…”

Section: Discussionmentioning

confidence: 99%

Infection of primary nasal epithelial cells differentiates among lethal and seasonal human coronaviruses

Otter

Fausto

Tan

et al. 2022

Preprint

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The nasal epithelium is the initial entry portal and primary barrier to infection by all human coronaviruses (HCoVs). We utilize primary nasal epithelial cells grown at air-liquid interface, which recapitulate the heterogeneous cellular population as well as mucociliary clearance functions of the in vivo nasal epithelium, to compare lethal (SARS-CoV-2 and MERS-CoV) and seasonal (HCoV-NL63 and HCoV-229E) HCoVs. All four HCoVs replicate productively in nasal cultures but diverge significantly in terms of cytotoxicity induced following infection, as the seasonal HCoVs as well as SARS-CoV-2 cause cellular cytotoxicity as well as epithelial barrier disruption, while MERS-CoV does not. Treatment of nasal cultures with type 2 cytokine IL-13 to mimic asthmatic airways differentially impacts HCoV replication, enhancing MERS-CoV replication but reducing that of SARS-CoV-2 and HCoV-NL63. This study highlights diversity among HCoVs during infection of the nasal epithelium, which is likely to influence downstream infection outcomes such as disease severity and transmissibility.

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Section: Discussionmentioning

confidence: 99%

Infection of primary nasal epithelial cells differentiates among lethal and seasonal human coronaviruses

Otter

Fausto

Tan

et al. 2022

Preprint

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“…Hence, an augmented mucosal innate immune response to Omicron could capture the virus at the upper respiratory tract and limit viral replication and consequent pathology in the lungs. In addition to the upregulated ISG, the observed induction of IFNλ by Omicron in the nasal and lung tissues ( Figure 2 and Figure S3 ) is noteworthy, given the reported key role of mucosal IFNλ in the protection against infection and excessive inflammation caused by SARS-CoV-2 variants (including Omicron) in animal models, and in the protection against life-threatening COVID-19 in humans [ 16 , 20 ]. A similar effect in antiviral protection, as well as in the prevention of excessive inflammatory damage, was reported for IFNλ in experimental influenza infection [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Omicron Induces Enhanced Mucosal Interferon Response Compared to other Variants of Concern, Associated with Restricted Replication in Human Lung Tissues

Alfi

Hamdan

Wald

et al. 2022

Viruses

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SARS-CoV-2 Omicron variant has been characterized by decreased clinical severity, raising the question of whether early variant-specific interactions within the mucosal surfaces of the respiratory tract could mediate its attenuated pathogenicity. Here, we employed ex vivo infection of native human nasal and lung tissues to investigate the local-mucosal susceptibility and innate immune response to Omicron compared to Delta and earlier SARS-CoV-2 variants of concern (VOC). We show that the replication of Omicron in lung tissues is highly restricted compared to other VOC, whereas it remains relatively unchanged in nasal tissues. Mechanistically, Omicron induced a much stronger antiviral interferon response in infected tissues compared to Delta and earlier VOC-a difference, which was most striking in the lung tissues, where the innate immune response to all other SARS-CoV-2 VOC was blunted. Notably, blocking the innate immune signaling restored Omicron replication in the lung tissues. Our data provide new insights to the reduced lung involvement and clinical severity of Omicron.

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“…This phenomenon represents a major impediment to realizing the full potential of mRNA vectors. For example, the development of vaccines for COVID-19 has highlighted the key functional gains that accrue mucosal immunization [8,[31][32][33][34][35]. In this context, there are not currently available liposomes or LNP vectors capable of efficient delivery of mRNA via the mucosal route.…”

Section: Discussionmentioning

confidence: 99%

A Novel Piggyback Strategy for mRNA Delivery Exploiting Adenovirus Entry Biology

Lee¹,

Rice-Boucher²,

Collins³

et al. 2022

Preprint

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Molecular therapies exploiting mRNA vectors embody enormous potential, as evidenced by the utility of this technology for the context of the COVID-19 pandemic. None-the-less, broad implementation of these promising strategies has been restricted by the limited repertoires of delivery vehicles capable of mRNA transport. On this basis, we explored a strategy based on exploiting the well characterized entry biology of adenovirus. To this end, we studied an adenovirus-polylysine (AdpL) that embodied “piggyback” transport of the mRNA on the capsid exterior of adenovirus. We hypothesized that the efficient steps of Ad binding, receptor-mediated entry, and capsid-mediated endosome escape could provide an effective pathway for transport of mRNA to the cellular cytosol for transgene expression. Our studies confirmed that AdpL could mediate effective gene transfer of mRNA vectors in vitro and in vivo. Facets of this method may offer key utilities to feasibilize the promise of mRNA-based therapeutics.

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Nasally delivered interferon-λ protects mice against infection by SARS-CoV-2 variants including Omicron

Cited by 64 publications

References 66 publications

Infection of primary nasal epithelial cells differentiates among lethal and seasonal human coronaviruses

Infection of primary nasal epithelial cells differentiates among lethal and seasonal human coronaviruses

SARS-CoV-2 Omicron Induces Enhanced Mucosal Interferon Response Compared to other Variants of Concern, Associated with Restricted Replication in Human Lung Tissues

A Novel Piggyback Strategy for mRNA Delivery Exploiting Adenovirus Entry Biology

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