Tissue architecture, feedback regulation, and resilience to viral infection

• Tissue homeostasis is required for multi-cellular organisms.
• Tissue homeostasis is maintained by feedback regulation.
• Feedback regulation can be influenced by viral infections.
• We investigate the effect of viral infections on tissue homeostasis.
• Protection against tissue pathology is found to increase vulnerability to cancer.

Tissue homeostasis is one of the central requirements for the existence of multicellular organisms, and is maintained by complex feedback regulatory processes. Homeostasis can be disturbed by diseases such as viruses and tumors. Here, we use mathematical models to investigate how tissue architecture influences the ability to maintain tissue homeostasis during viral infections. In particular, two different tissue designs are considered. In the first scenario, stem cells secrete negative feedback factors that influence the balance between stem cell self-renewal and differentiation. In the second scenario, those feedback factors are not produced by stem cells but by differentiated cells. The model shows a tradeoff. If feedback factors are produced by stem cells, then a viral infection will lead to a significant reduction in the number of differentiated cells leading to tissue pathology, but the number of stem cells is not affected at equilibrium. In contrast, if the feedback factors are produced by differentiated cells, a viral infection never reduces the number of tissue cells at equilibrium because the feedback mechanism compensates for virus-induced cells death. The number of stem cells, however, becomes elevated, which could increase the chance of these stem cells to accumulate mutations that can drive cancer. Interestingly, if the virus interferes with feedback factor production by cells, uncontrolled growth can occur in the presence of the virus even in the absence of genetic lesions in cells. Hence, the optimal design would be to produce feedback factors by both stem and differentiated cells in quantities that strike a balance between protecting against tissue destruction and stem cell elevation during infection.