Abstract
The advent of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has shaken the dynamic nature of the human respiratory virome and caused robust interactions among pathogens either through viral interference or co-pathogenesis. SARS-CoV-2 can suppress host innate immunity in a process known as viral interference, namely, the use of viral proteins to suppress interferons via viral protein NSP1 to establish dominance over the cellular setting. On the other hand, synergistic co-pathogenesis consists of initial infection causing immune exhaustion, hyper inflammation, and necroptosis of respiratory epithelium, which creates a very susceptible microenvironment that allows secondary viral and bacterial invaders to bypass the immune mechanism. Epidemiologically, the de-escalation of COVID-19 non-pharmaceutical interventions (NPIs) has left the population-wide with an immunity debt that has seen, off-season increases with endemic viruses, such as Respiratory Syncytial Virus (RSV) and Influenza, to create a post-pandemic tripledemic. Also, the extreme immune dysregulation and lymphopenia of the severe cases of COVID-19 have been found to stimulate the opportunistic reactivation of latent pathogens, such as the Epstein - Barr virus. To address the issue of these molecular mechanisms and epidemiological changes, this review highlights the urgency of using the holistic approach to molecular surveillance and the development of new dual-target pharmacologic interventions, including probenecid, in the future to cope with the complex pathology.