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Abstract
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.
Highlights
The onslaught of respiratory pathogens is felt during the emergence of novel viruses, such as the pandemic H1N1 influenza virus of 2009, SARS coronavirus, Middle East respiratory syndrome coronavirus, and SARS coronavirus 2, but endemic seasonal virus infections pose an equal and ongoing risk of severe disease and death for many individuals
To model as closely as possible physiological infection of mice with influenza virus and to anatomically restrict treatment with INNA-X, we examined the distribution of i.n. delivered inocula throughout the respiratory tract
We have demonstrated that administration of INNA-X, when restricted to the upper airways, resulted in a reduction of viral loads in the nasal epithelia and a decline in viral progression to the lungs
Summary
The onslaught of respiratory pathogens is felt during the emergence of novel viruses, such as the pandemic H1N1 influenza virus of 2009, SARS coronavirus, Middle East respiratory syndrome coronavirus, and SARS coronavirus 2 (the causative agent of COVID-19), but endemic seasonal virus infections pose an equal and ongoing risk of severe disease and death for many individuals. Nonspecific in the sense that they lack the specificity of adaptive immune responses, innate immune responses can be initiated by activation of TLRs, which exhibit a comprehensive range of recognition capabilities, from signatures of bacterial cell wall components to the RNA and DNA of viruses [4]. These pathogenic signatures can alert the host cell to immediately mobilize innate effector mechanisms to combat infection processes, making them prime targets for inducing antiviral responses [5]
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