TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs

JCI Insight. 2021 Mar 8;6(5):e140267. doi: 10.1172/jci.insight.140267.


The impact of respiratory virus infections on global health is felt not just during a pandemic, but endemic seasonal infections pose an equal and ongoing risk of severe disease. Moreover, vaccines and antiviral drugs are not always effective or available for many respiratory viruses. We investigated how induction of effective and appropriate antigen-independent innate immunity in the upper airways can prevent the spread of respiratory virus infection to the vulnerable lower airways. Activation of TLR2, when restricted to the nasal turbinates, resulted in prompt induction of innate immune-driven antiviral responses through action of cytokines, chemokines, and cellular activity in the upper but not the lower airways. We have defined how nasal epithelial cells and recruitment of macrophages work in concert and play pivotal roles to limit progression of influenza virus to the lungs and sustain protection for up to 7 days. These results reveal underlying mechanisms of how control of viral infection in the upper airways can occur and support the implementation of strategies that can activate TLR2 in nasal passages to provide rapid protection, especially for at-risk populations, against severe respiratory infection when vaccines and antiviral drugs are not always effective or available.

Keywords: Infectious disease; Influenza; Innate immunity; Therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • Disease Models, Animal
  • Female
  • Humans
  • Immunity, Innate / drug effects*
  • Immunologic Factors / pharmacology*
  • Immunologic Factors / therapeutic use
  • Influenza A virus
  • Influenza, Human* / drug therapy
  • Influenza, Human* / immunology
  • Influenza, Human* / metabolism
  • Influenza, Human* / virology
  • Lipopeptides / pharmacology*
  • Lipopeptides / therapeutic use
  • Lung* / drug effects
  • Lung* / immunology
  • Lung* / metabolism
  • Lung* / virology
  • Male
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections / drug therapy
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / virology
  • Respiratory System / drug effects
  • Respiratory System / immunology
  • Respiratory System / metabolism
  • Respiratory System / virology
  • Respiratory Tract Infections* / drug therapy
  • Respiratory Tract Infections* / immunology
  • Respiratory Tract Infections* / metabolism
  • Respiratory Tract Infections* / virology
  • Toll-Like Receptor 2 / agonists
  • Toll-Like Receptor 2 / metabolism*


  • Antiviral Agents
  • Immunologic Factors
  • Lipopeptides
  • S-(2,3-bis(palmitoyloxy)propyl)cysteine
  • Toll-Like Receptor 2