Age related loss of immune resilience during response to severe respiratory viral infections

Abstract. The clinical responses to respiratory viruses are very heterogenous as recently demonstrated by the COVID-19 pandemic with most aggressive clinical courses among elders, suffering the highest mortality. The pathophysiological mechanisms leading to poor outcome among elders people are not well understood. Beyond the increased mortality seen in advanced age group, older critically ill COVID-19 patients (>65yo) had higher viral loads in their lower airways and blunted anti-SARS-CoV-2 immune responses. Using host transcriptomic approaches described in our preliminary data we are identifying a pattern suggestive of maladaptive immune responses, more prominently present among elders, that leads to poor outcomes in patients with respiratory viruses. In addition, through a collaboration between Drs. Segal, Zhang and Forst, we have identified age-related signatures that are distinct from the lower airway and systemic transcriptome. Interestingly, some of these signals are also seen in a cohort of patients with influenza virus infections, suggesting a novel profiling that may uncover important mechanisms of immunoaging. Thus, using samples and data collected from patients with SARS-CoV- 2 or influenza infection, we will test the hypothesis that among older patients with respiratory virus infections, poor prognosis is characterize by maladaptive host immune responses characterized by downregulation of type 1 interferon (IFN) responses and increased inflammatory injury, thereby suppressing immune mechanisms designed to limit viral load. Here, in Aim 1 we will focus on lower airway and blood samples from critically ill COVID-19 patients. In these, we will use RNA sequencing and single cell RNA sequencing to evaluate for longitudinal host immune signatures associated with poor outcome among different age groups. Then in Aim 2 we will establish multiscale gene network models associated with poor outcome among different age groups of critically ill COVID-19 patients. Then, in Aim 3 we will perform a comparative study of age-dependent host immune response signatures and network models in COVID-19 and influenza virus infection. Therefore, this is an unprecedented opportunity to conduct investigations on paired lower airway and systemic samples from patients suffering infections with respiratory viruses across different age segments in order to identify novel mechanisms that lead to poor viral control and clinical outcomes.