Deciphering the Swine-Flu Pandemics of 1918 and 2009

Abstract

The devastating "Spanish flu" of 1918 killed an estimated 50 million people worldwide, ranking it as the deadliest pandemic in recorded human history. It is generally believed that the virus transferred from birds directly to humans shortly before the start of the pandemic, subsequently jumping from humans to swine. By developing 'non-homogeneous' substitution models that consider that substitution patterns may be different in human, avian, and swine hosts, we can determine the timing of the host shift to mammals. We find it likely that the Spanish flu of 1918, like the current 2009 pandemic, was a 'swine-origin' influenza virus. Now that we are faced with a new pandemic, can we understand how influenza is able to change hosts? Again by modelling the evolutionary process, considering the different selective constraints for viruses in the different hosts, we can identify locations that seem to be under different selective constraints in humans and avian hosts. This allows us to identify changes that may have facilitated the establishment of the 2009 swine-origin flu in humans. The swine-origin pandemic flu pandemic of 2009 highlighted the importance of understanding the process of host shifts in zoonotic pathogens. Understanding past host shifts can provide important information about where current threats may originate. Analysing past host shifts using molecular evolutionary analysis has been limited by models of sequence change that consider the substitution process to be the same for all locations at all time (at most modulated by a site-specific scaling factor). By considering non-homogeneous non-stationary models, we can model how the substitution process in viruses such as influenza differs at different locations in the proteins and in different hosts. This allows us to determine the timing and trajectory of host shift events, as well as identify locations where changes in amino acid may assist or be required for the host shift event to occur. We apply these methods to the 1918 'Spanish Flu' pandemic, determining that, contrary to what is widely believed, this pandemic also was likely from a swine-origin virus. We then apply these techniques to the 2009 influenza pandemic, determining locations where changes in amino acid may have facilitated the ability of these viruses to sift from swine to human hosts. These models have wide applicability where changes in selective constraints might have occurred, including understanding other pathogen host shifts, deciphering how HIV responds to drug treatment, and how to understand and predict changes in functionality or physiological context of proteins.