Interferon-λ cures persistent murine norovirus infection in the absence of adaptive immunity

Area of Science:

• Immunology
• Virology
• Gastroenterology

Background:

• Norovirus gastroenteritis poses a significant global public health challenge.
• Understanding immune factors limiting persistent enteric viral infections is crucial for public health.
• The role of interferons in controlling enteric norovirus infection remains largely unexplored.

Purpose of the Study:

• To investigate the distinct roles of different interferon cytokines in controlling murine norovirus (MNoV) infection.
• To elucidate the mechanisms by which interferon-lambda (IFN-λ) restricts persistent enteric MNoV infection.
• To assess the therapeutic potential of IFN-λ in established gastrointestinal viral infections.

Main Methods:

• Mice were infected with MNoV, and the effects of systemic administration of IFN-α, IFN-β, and IFN-λ on viral spread and persistence were evaluated.
• The role of the MNoV capsid protein in regulating infection-dependent IFN-λ induction was assessed.
• The requirement for nonhematopoietic cell expression of the IFN-λ receptor (Ifnlr1) and the involvement of adaptive immunity in IFN-λ-mediated clearance were investigated.

Main Results:

• While IFN-α and IFN-β inhibited systemic MNoV spread, only IFN-λ effectively controlled persistent enteric infection.
• IFN-λ induction was dependent on the MNoV capsid protein and correlated with reduced enteric viral persistence.
• Therapeutic administration of IFN-λ resolved established MNoV infection in mice, independent of adaptive immunity but dependent on Ifnlr1 expression in nonhematopoietic cells.

Conclusions:

• Interferon-lambda is a key cytokine for controlling persistent norovirus infection within the gastrointestinal tract.
• The MNoV capsid protein regulates IFN-λ production, impacting viral persistence.
• IFN-λ demonstrates significant therapeutic potential for treating established gastrointestinal viral infections, acting through nonhematopoietic cells.