(250a) Modeling the Progression of Fibrosis with Dysregulation of ACE2 in COVID19 Patients

The severity of the COVID19 pandemic has created an emerging need to investigate the long-term effect of infection in healing patients. Many individuals are at risk of suffering pulmonary fibrosis due to pathogenesis of lung injury and impairment of the healing mechanism. Fibroblasts are the central mediators of extracellular matrix deposition during tissue regeneration. In the later phase of infection, tissue damage causes the activation of latent anti-inflammatory cytokines (TGF-b), which recruits the fibroblasts [1]. The accumulation of fibroblasts in the damaged site and excess deposition of fibrillar collagen lead to fibrosis. Additionally, SARS-CoV-2 enters the host cells via binding its spike protein with the Angiotensin Converting Enzyme 2 (ACE2) receptor, which is a key component in modulating the balance of the renin-angiotensin system (RAS). The dysregulation of ACE2 by the viral infection can shift the balance of RAS towards pro-inflammation and pro-fibrosis.

We have developed an open-source, multi-scale tissue simulator that can be used to investigate the mechanisms of intracellular viral replication, infection of epithelial cells, host immune response, and tissue damage [2]. Our model simulates the dynamics of ACE2 and fibroblast-mediated collagen deposition to account for the fibrosis at the damaged site in response to immune response induced tissue injury. The severity of infection and collagen deposition depends on the anti-inflammatory cytokine secretion rate, multiplicity of infection, and contact time for a CD8+ T cell to kill an infected cell. Using the model, we predicted the dynamics of fibroblast and collagen deposition for 10 days of post-infection in virtual lung tissue. Our result shows that collagen area fraction increases from 31% to 69% with the severity of infection. We use the ACE2 dynamics as input in a separate model of RAS to predict the change in RAS signaling and collagen deposition from homeostasis for normotensive and hypertensive patients. Our model also reveals that the variation in available ACE2 due to age and gender can lead to significant change in inflammation, tissue damage, and fibrosis.

References

1. Zhang, H. et al. "Effects of transforming growth factor-beta 1 (TGF-β1) on in vitro mineralization of human osteoblasts on implant materials." Biomaterials 12 (2003): 2013-2020.
2. Wang, Y, et al. "Rapid community-driven development of a SARS-CoV-2 tissue simulator." BioRxiv (2020).

Acknowledgment

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