(694a) Mathematical Modeling of Dysregulation of ACE2 Depending on Age-Sex and Blood Pressure and Progression of Fibrosis in COVID19 Survivors

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cells via binding its spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor, which is a crucial component in modulating the balance of the renin-angiotensin system (RAS). RAS is composed of distinct angiotensin peptides and receptors responsible for maintaining the local and systemic inflammation. The dysregulation of ACE2 by the viral infection can shift the balance of RAS towards pro-inflammation and pro-fibrosis. Experimental studies showed downregulation of ACE2 increases collagen deposition in lung tissue, leading to fibrosis [1]. ACE2 receptors maintain the balance between pro-fibrotic ANGII and anti-fibrotic ANG1-7 by converting ANGII to ANG1-7. The downregulation in ACE2 causes higher ANGII resulting in activation and production of anti-inflammatory cytokine TGF-beta in the local tissue. Fibroblasts are recruited by TGF-beta and deposit collagen to repair the damage. But excess deposition of collagen can initiate long-term fibrosis. The fibrotic outcome in COVID19 survivors also depends on age-sex and pre-existing comorbidities.

Methods: We developed a multiscale tissue simulator to investigate the mechanisms of SARS-CoV-2 infection in lung epithelial cells. The overall model contains intracellular viral replication kinetics, ACE2 receptor trafficking, immune response, and tissue damage models [2]. We infect the tissue by placing SARS-CoV-2 viruses in the extracellular space using uniform random and gaussian distribution. Viral particles diffuse through tissue, bind with unoccupied ACE2 receptors on the epithelial cell surface, internalize via endocytosis, replicate through intracellular viral replication kinetics, and export back to the extracellular domain by exocytosis. The viral bound ACE2 is also recycled back to the cell surface after releasing the virus inside the cell. We varied the initial unoccupied ACE2 receptors concentration on the cell surface based on the availability of ACE2 receptors for different age-sex groups [3]. Then, the simulated dynamics of ACE2 receptors for the different age-sex groups are used as input in a separate model of RAS to predict the change in ANGII from homeostasis for normotensive and hypertensive patients. We also consider the effect of feedback signaling of the ANGII-Angiotensin receptor 1 (ANGII-AT1) complex to renin and how the absence of feedback signaling can affect the dynamics of ANGII. The increase of ANGII also increases TGF-beta, which recruits fibroblasts. Fibroblasts are responsible for the excess deposition of collagen. We also consider the effect of negative regulator MMP, produced from macrophages, and can degrade collagen.

Results: Our model reveals that the variation in available ACE2 due to age and sex can significantly change inflammation, tissue damage, and fibrosis. Old males, old females, and mid males are most susceptible to viral infection due to the lower availability of ACE2 receptors, and a higher amount of ANGII and collagen deposition is observed from model simulation. We observed epithelial cell death as the main source of reduction of ACE2 compared to the internalization of ACE2 receptors by viral particles. Since the concentration of ACE2 receptors is high compared to the number of viral bound ACE2 receptors, the downregulation of ACE2 by viral bound ACE2 receptors doesn’t significantly affect the RAS. But the change in initial unoccupied ACE2 receptors can affect the viral infectivity of epithelial cells and result in cell death. The death of a large number of epithelial cells can significantly reduce the number of available ACE2 for the RAS network. Our model also identifies that impairment in the feedback signaling of ANGII-AT1 to renin and hypertension can increase the concentration of ANGII and collagen deposition.

Conclusions: Our model quantifies age-sex and blood pressure as major factors for fibrotic outcomes in COVID19 survivors. The predicted results can be used to develop personalized therapeutic strategies for different patients groups and patients with pre-existing comorbidities.

Acknowledgment: This work was supported by the National Institutes of Health grant R35GM133763 and the University at Buffalo.

References

1. Kuba, et al., A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury, Nature medicine8 (2005): 875-879

2. Getz, et al., Iterative community-driven development of a SARS-CoV-2 tissue simulator, BioRxiv (2021)

3. Xudong, et al., Age-and gender-related difference of ACE2 expression in rat lung, Life sciences19 (2006): 2166-2171