Intranasal interferon-λ treatment protects mice against SARS-CoV-2 Beta and Omicron variants

As of January 27, 2021, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)  has infected over 363 million individuals around the world and caused the deaths of almost 5.7 million. The SARS-CoV-2 infection causes a variety of influenza-like symptoms; however, in a minority of cases, it can quickly progress to pneumonia, acute respiratory distress syndrome (ARDS), and death.

COVID-19 and IFN

The role of interferon-λ (IFN-λ) in SARS-CoV-2 infection and pathogenesis is unknown. Although patients with severe coronavirus disease 2019 (COVID-19) have higher amounts of pro-inflammatory cytokines and chemokines in their blood, they have lower levels of type I and III IFN, thereby suggesting virus-induced antagonism or skewing of antiviral responses.

Study: Nasally-delivered interferon-λ protects mice against upper and lower respiratory tract infection of SARS-CoV-2 variants including Omicron. Image Credit: Kateryna Kon / Shutterstock.com

Despite this, higher serum IFN-λ levels were linked to reduced viral infection in the respiratory tract and faster viral clearance in one human trial. Furthermore, a higher IFN-λ to type I IFN ratio was linked to a better outcome. IFN-λ expression in the respiratory tract varies with location, viral burden, and illness severity and may have opposing functions at different anatomical sites in COVID-19 patients.

In a recent study published on the preprint server bioRxiv*, researchers investigate the possible efficacy of IFN-λ in the context of SARS-CoV-2 infection in mice. To this end, Ifnlr1-/- (also known as IL28R-/-) C57BL/6 mice infected with SARS-CoV-2 Beta (B.1.351) or Omicron (B.1.1.529) variants had greater viral loads in the respiratory tract, thereby demonstrating that IFN-λ plays a protective role against SARS-CoV-2 infection.

Study findings

In the current study, the authors inoculated six-week-old wild-type (WT) and congenic Ifnlr1-/- C57BL/6 mice with 10⁵ focus-forming units (FFU) of SARS-CoV-2 B.1.351 virus, which contains K417Y, E484K, and N501Y substitutions in the spike receptor-binding domain (RBD) to assess the importance of IFN-λ signaling in protecting against SARS-CoV-2 infection.

As compared to WT mice, Ifnlr1-/- mice had greater viral ribonucleic acid (RNA) levels in nasal washes and lung homogenates at seven days post-infection (dpi). According to these findings, the researchers found significantly larger quantities of infectious virus in the lungs of Ifnlr1-/- mice at seven dpi using a plaque assay.

The authors then determined whether IFN-λ had any protective benefits against the new SARS-CoV-2 B.1.1.529 Omicron strain, which possesses mutations that are associated with the ability of this variant to evade vaccines and therapeutic antibodies. The scientists infected three-month-old WT and Ifnlr1-/- mice with 105 FFU of B.1.1.529 and found that at five dpi, Ifnlr1-/- animals had greater levels of viral RNA in nasal turbinates, nasal washes, and lungs.

The authors then tested exogenous IFN-λ2 for its ability to protect mice against SARS-CoV-2 infection. K18-human angiotensin-converting enzyme 2 (hACE2) transgenic mice express hACE2 under the control of the epithelial cell cytokeratin-18 promoter and are extremely susceptible to SARS-CoV-2-induced pneumonia and brain infection. As a result, these mice were used for this set of experiments.

K18 mice that were intranasally administered IFN-λ2 showed significantly decreased amounts of viral RNA and infectious virus in the nasal turbinates, nasal washes, lungs, and brain at three dpi, whereas mice that were intraperitoneally administered IFN-λ2 did not exhibit this response. Based on these findings, the authors decided to adopt intranasal IFN-λ2 delivery for the rest of the research.

The authors used a single intranasal dosage of IFN-λ2 at day two or three before inoculation with WA1/2020 D614G to extend the window of prophylaxis in K18-hACE2 mice. At three dpi, IFN-λ2 treatment resulted in decreased viral RNA levels in the nasal turbinates, nasal washes, and lungs, but not in the brain.

To test the therapeutic efficacy of IFN-λ2, the researchers gave K18-hACE2 mice a single dosage of IFN-2 through nasal route eight hours after infection, and mice were euthanized 3 days later. In the nasal turbinates, lungs, and brains of IFN-λ2 treated mice, viral RNA levels were lower, as were infectious virus titers in the nasal turbinates and lungs.

When compared to PBS-treated mice, therapeutic treatment of IFN-λ2 did not diminish the viral burden in nasal washes. The researchers also used IFN-λ2 as a two-dose therapy at one and two dpi, which reduced viral RNA loads in the nasal turbinates and lungs but not in nasal washes or the brain. This IFN-λ2 treatment scheme also resulted in lower amounts of infectious virus in the lungs.

Implications

The authors of the current study demonstrate that the nasal injection of IFN-λ provides pre-and post-exposure protection against infection by multiple SARS-CoV-2 strains, including key variants of concern, without generating significant inflammation. IFN-λ controls infection in the lungs by acting on radio-resistant cells.

Additional treatment studies are needed to assess the potential of IFN-λ as a widely acting antiviral drug against SARS-CoV-2 and its numerous variants.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Colin Lightfoot

Colin graduated from the University of Chester with a B.Sc. in Biomedical Science in 2020. Since completing his undergraduate degree, he worked for NHS England as an Associate Practitioner, responsible for testing inpatients for COVID-19 on admission.