Host Susceptibility to Severe Influenza A Virus Infection

Most people exposed to a new flu virus do not notice any symptoms. A small minority develop critical illness.Some of this extremely broad variation in susceptibility is explained by the size of the initial inoculum, or the influenza exposure history; some is explained by generic host factors, such as frailty, that decrease resilience following any systemic insult. Some demographic factors (pregnancy, obesity, and advanced age) appear to confer a more specific suceptibility to severe illness following infection with influenza viruses. As with other infectious diseases, a substantial component of susceptibility is determined by host genetics. Several genetic susceptbility variants have now been reported with varying levels of evidence. Susceptible hosts may have impaired intracellular controls of viral replication (e.g.IFITM3, TMPRS22variants), defective interferon responses (e.g.GLDC, IRF7/9 variants), or defects in cell-mediated immunity with increased baseline levels of systemic inflammation (obesity, pregnancy, advanced age). These mechanisms may explain the prolonged viral replication reported in critically ill patients with influenza: patients with life-threatening disease are, by definition, abnormal hosts. Understanding these molecular mechanisms of susceptibility may in future enable the design of host-directed therapies