Animal models of post-acute COVID-19 syndrome: a call for longitudinal animal studies

Abstract

Animal models are indispensable for unraveling the mechanisms underlying post-acute sequelae of COVID-19 (PASC). This review evaluates recent research on PASC-related perturbations in animal models, drawing comparisons with clinical findings. Despite the limited number of studies on post-COVID conditions, particularly those extending beyond three months, these studies provide valuable insights. Three hallmark features of PASC-lung fibrosis, hyperglycemia, and neurological sequelae-have been successfully replicated in animal models, paving the way for mechanistic discoveries and future medical interventions. Although most studies have reported post-COVID conditions within 14-60 days post-infection, they still offer critical reference for future long-term research. This review also explores potential mechanisms of persisting immune misfiring, a key factor in the chronicity of PASC symptoms. Moreover, challenges in modeling PASC are also discussed, including the limited genetic diversity in inbred animal strains and difficulties in accurately identifying PASC-affected individuals. To address these issues, we propose methodological improvements, such as comparing individual animal parameters with control averages and incorporating genetically diverse populations like collaborative cross models. These strategies will enhance the identification and characterization of PASC endotypes in animal studies. By integrating findings from animal models with clinical manifestations of PASC, future research can provide more valuable insights into its mechanisms and support the development of effective therapeutic strategies. Finally, we emphasize the urgent need for longitudinal studies in animal models to fully uncover the mechanisms driving PASC and guide interventions to mitigate its public health impact.

Keywords: animal models; immune tolerance; long-term perturbations post coronavirus infection; organ manifestations; post-acute COVID-19 syndrome.

Figure 1

(A) Three pillars underlie long-COVID: acute phase damage, persistent inflammation or perturbations and maladaptive repair. Persistent inflammation can be caused by perturbations in immune tolerance (acquired immunity) and persisting activation of innate immunity by unknown reasons. In Figure (A), four classes are represented by distinct colors. These colors correspond to the same classes depicted in (B). (B) Timeframes for long-COVID animal models. In addition to only recording organ manifestations in long-COVID models, viral clearance and inflammation resolution can provide valuable insights into the underlying mechanisms. We put only one study with a duration of less than 2 weeks’ here to address the importance of acute damage. Dpi, wpi, mpi and ypi represent days, weeks, months and years post infection respectively. .