It has been over 100 years since the 1918 influenza pandemic, one of the most infamous examples of viral immunopathology. Since that time, there has been an inevitable repetition of influenza pandemics every few decades and yearly influenza seasons, which have a significant impact on human health. Recently, noteworthy progress has been made in defining the cellular and molecular mechanisms underlying pathology induced by an exuberant host response to influenza virus infection. Infection with influenza viruses is associated with a wide spectrum of disease, from mild symptoms to severe complications including respiratory failure, and the severity of influenza disease is driven by a complex interplay of viral and host factors. This chapter will discuss mechanisms of infection severity using concepts of disease resistance and tolerance as a framework for understanding the balance between viral clearance and immunopathology. We review mechanistic studies in animal models of infection and correlational studies in humans that have begun to define these factors and discuss promising host therapeutic targets to improve outcomes from severe influenza disease.
Keywords: Adaptive immunity; Disease resistance; Disease tolerance; Immunopathology; Influenza; Innate immunity.
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