Drugs to cure avian influenza infection – multiple ways to prevent cell death

Yuan, S

The SARS mortality statistics published by World Health Organization in 2003 showed that the overall average mortality rate was about 15%, but the mortality rate of young people with strong immunity was much higher than that of old people with weak immunity. 3 For H5N1, the overall mortality rate was about 56%. However, the youth group (10-19 years old individuals) got the highest mortality rate of 73% and the mortality rate for people over 50 years was only 18%. 4 Moreover, H1N1 deaths mostly occur in middle-aged adults and the severity of the H1N1 cases was by far higher in the 18-50 years age group, contrary to seasonal influenza where fatal disease occurs most often in the elderly people (465 years old), with an overall mortality rate being o1%. 5 Some researchers believe that the infection of avian influenza causes multiple complications in the patient, resulting in multiorgan failure, and may be related to the hyperimmune response to the virus, which may have adverse effects on vital organs and result in high pathogenicity and mortality. [6] [7] [8] [9] The H5N1 virus may set off a cytokine storm, for example, interferon (IFN)-inducible protein IP-10, IFN-b, chemokines, interleukin-6 (IL-6) and so on. This cytokine outbreak is likely to lead to cell death. [6] [7] [8] [9] These data may suggest that healthy young people would become the main target of H5N1 attack. In other words, the stronger the immune system, the more severe the inflammatory response after the infection and, thus, the higher risk of death. AIV does not kill us, but we may be killed by ourselves. For the newborn virus H7N9, no such full-scale statistics is available now. Nevertheless, from its high mortality rate and rapid disease progression, 1,2 a similar cytokine burst with an excessive immune response can be expected (cytokine burst in the H7N9 patient has been proved recently). 10, 11 Antioxidant Reactive oxygen species (ROS) have a crucial role in inflammatory response. 12 Aggregation of neutrophils at pulmonary alveoli activate and release the oxygen-free radicals, proteases and lipid peroxide, resulting in injuries to the pulmonary microvascular membrane and alveolar epithelial membrane, and the subsequent pulmonary edema and ARDS. The activated neutrophils generate ROS exponentially (over 10 times the rate in the resting cell). The oxidative injuries include the following: (i) lipid peroxidation and detriments to structures and functions of the cell membrane and the organelle membrane; (ii) enzyme inactivation; (iii) inactivation of protease inhibitors and release of lysosomal proteases; and (iv) working on blood plasma to induce strong chemoattractants, causing more neutrophil aggregation, more ROS production and subsequently more severe lung injury. 12 Thus, ROS form a positive feedback loop (they could be self-amplified).