Effective Interferon Lambda Treatment Regimen To Control Lethal MERS-CoV Infection in Mice.

Dijkman, Ronald; Verma, Abhishek Kumar; Selvaraj, Muneeswaran; Ghimire, Roshan; Gad, Hans Henrik; Hartmann, Rune; More, Sunil; Perlman, Stanley; Thiel, Volker Earl; Channappanavar, Rudragouda (2022). Effective Interferon Lambda Treatment Regimen To Control Lethal MERS-CoV Infection in Mice. Journal of virology, 96(11), e0036422. American Society for Microbiology 10.1128/jvi.00364-22

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Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made toward identifying and evaluating several synthetic broad-spectrum antivirals against hCoV infections, a narrow therapeutic window has limited their success. Enhancing the endogenous interferon (IFN) and IFN-stimulated gene (ISG) response is another antiviral strategy that has been known for decades. However, the side effects of pegylated type-I IFNs (IFN-Is) and the proinflammatory response detected after delayed IFN-I therapy have discouraged their clinical use. In contrast to IFN-Is, IFN-λ, a dominant IFN at the epithelial surface, has been shown to be less proinflammatory. Consequently, we evaluated the prophylactic and therapeutic efficacy of IFN-λ in hCoV-infected airway epithelial cells and mice. Human primary airway epithelial cells treated with a single dose of IFN-I (IFN-α) and IFN-λ showed similar ISG expression, whereas cells treated with two doses of IFN-λ expressed elevated levels of ISG compared to that of IFN-α-treated cells. Similarly, mice treated with two doses of IFN-λ were better protected than mice that received a single dose, and a combination of prophylactic and delayed therapeutic regimens completely protected mice from a lethal Middle East respiratory syndrome CoV (MERS-CoV) infection. A two-dose IFN-λ regimen significantly reduced lung viral titers and inflammatory cytokine levels with marked improvement in lung inflammation. Collectively, we identified an effective regimen for IFN-λ use and demonstrated the protective efficacy of IFN-λ in MERS-CoV-infected mice. IMPORTANCE Effective antiviral agents are urgently required to prevent and treat individuals infected with SARS-CoV-2 and other emerging viral infections. The COVID-19 pandemic has catapulted our efforts to identify, develop, and evaluate several antiviral agents. However, a narrow therapeutic window has limited the protective efficacy of several broad-spectrum and CoV-specific antivirals. IFN-λ is an antiviral agent of interest due to its ability to induce a robust endogenous antiviral state and low levels of inflammation. Here, we evaluated the protective efficacy and effective treatment regimen of IFN-λ in mice infected with a lethal dose of MERS-CoV. We show that while prophylactic and early therapeutic IFN-λ administration is protective, delayed treatment is detrimental. Notably, a combination of prophylactic and delayed therapeutic administration of IFN-λ protected mice from severe MERS. Our results highlight the prophylactic and therapeutic use of IFN-λ against lethal hCoV and likely other viral lung infections.

Item Type:	Journal Article (Original Article)
Division/Institute:	05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
UniBE Contributor:	Dijkman, Ronald, Thiel, Volker Earl
Subjects:	600 Technology > 630 Agriculture
ISSN:	0022-538X
Publisher:	American Society for Microbiology
Language:	English
Submitter:	Pubmed Import
Date Deposited:	20 May 2022 14:44
Last Modified:	05 Dec 2022 16:19
Publisher DOI:	10.1128/jvi.00364-22
PubMed ID:	35588276
Uncontrolled Keywords:	IFN lambda MERS-CoV hCoV-229E human coronavirus inflammation interferon lambda mouse model murine model
URI:	https://boris.unibe.ch/id/eprint/170131