Disturbed respiratory viral ecology by COVID-19 pandemic reveals the pivotal role of Influenza in virus-virus interaction network.

Concurrent epidemics of respiratory viruses provide avenues for intricate virus-virus interactions, yet how molecular-level viral interactions patterns shape viral ecology and epidemic dynamics remain enigmatic. Here, we present real-world virus crosstalk by comprehensively analyzing diagnostic data from a large cohort (37,415 respiratory illness cases pre-COVID-19 pandemic, 22,239 cases thereafter), mainly infants/toddlers, sourced from the same local hospital. Such high-risk group cohort allowed us to examine consistent coinfections among 7 respiratory viruses, despite under an overall reduced infection rates due to COVID-19 disruption. We explored drivers of stable ecosystem and identified a directional virus-virus interaction network between influenza and other respiratory viruses. Monthly prevalence patterns analysis of individual virus revealed IAV positively interacted with RSV, characterized by synchronous seasonality ({rho}= 0.67). Conversely, IAV negatively interacted with HPIV3, marked by asynchronous seasonality ({rho}= -0.56). Sequential/simultaneous coinfection experiments further confirmed two viruses could contact in the same cell but show distinct coinfection outcomes, such as IAV significantly augmented RSV infection but inhibited HPIV3. We further demonstrated coinfection with IAV and RSV led to exacerbated lung damage in mice, while were associated with aggravated disease outcomes among children. Post-COVID-19, we observed a notable suppression in the spread of respiratory viruses, with a particularly sharp decline in influenza. This reduced influenza activity disrupted virus interactions between influenza and other respiratory viruses, driving the concurrent resurgence of other respiratory viruses. When influenza gradually returns to circulation, the interactions could be reinstated, shaping respiratory virus circulations in a predictable and typical pattern. These findings underscore the pivotal role of influenza in directional interplays among respiratory viruses that shape viral ecology. Striking image O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/24319626v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@6176fdorg.highwire.dtl.DTLVardef@cb0859org.highwire.dtl.DTLVardef@19117c6org.highwire.dtl.DTLVardef@afe5b0_HPS_FORMAT_FIGEXP M_FIG C_FIG The respiratory viral ecology with directional virus-virus interactions.A substantial cohort of infants and toddlers, comprising 37,415 cases of acute respiratory infection (ARI) pre-COVID-19 pandemic and 22,239 cases thereafter, underwent testing for seven human respiratory viruses: ADV, RSV, IAV, IBV, HPIV1, 2, and 3. The prevalence of coinfection with at least two viruses was 11.18% (pre-) and 9.70% (post-) respectively, showcasing a stable and intricate ecosystem of multiple respiratory viruses even amidst the global disruption caused by COVID-19. Findings from experimental coinfections are consistent with viral seasonal dynamics, where positive interactions (red arrows), such as Flu promoting RSV, exhibit synchronous seasonal patterns, whereas negative interactions (blue arrows), like Flu inhibiting HPIV, display asynchronous seasonal trends. Viruses that demonstrate no interactions with each other (gray arrows), like ADV and RSV, can coexist harmoniously within the host environment (accommodate).