ABSTRACT
Humanity has experienced four major pandemics since the twentieth century, with the 1918 Spanish flu, the 2002 severe acute respiratory syndrome (SARS), the 2009 swine flu, and the 2019 coronavirus disease (COVID)-19 pandemics having the most important impact in human health. The 1918 Spanish flu caused unprecedented catastrophes in the recorded human history, with an estimated death toll between 50 - 100 million. While the 2002 SARS and 2009 swine flu pandemics caused approximately 780 and 280,000 deaths, respectively, the current COVID-19 pandemic has resulted in > 6 million deaths globally at the time of writing. COVID-19, instigated by the SARS - coronavirus-2 (SARS-CoV-2), causes unprecedented challenges in all facets of our lives, and never before brought scientists of all fields together to focus on this singular topic. While for the past 50 years research have been heavily focused on viruses themselves, we now understand that the host immune responses are just as important in determining the pathogenesis and outcomes of infection. Research in innate immune mechanisms is crucial in understanding all aspects of host antiviral programmes and the mechanisms underpinning virus-host interactions, which can be translated to the development of effective therapeutic avenues. This review summarizes what is known and what remains to be explored in the innate immune responses to influenza viruses and SARS-CoVs, and virus-host interactions in driving disease pathogenesis. This hopefully will encourage discussions and research on the unanswered questions, new paradigms, and antiviral strategies against these emerging infectious pathogens before the next pandemic occurs.