TNF controls a speed-accuracy tradeoff in the cell death decision to restrict viral spread

• Published in: Nature communications 2021-05, Vol.12 (1), p.2992-11, Article 2992
• Main Authors: Oyler-Yaniv, Jennifer, Oyler-Yaniv, Alon, Maltz, Evan, Wollman, Roy
• Format: Article
• Language: English
• Subjects: 631/250/127/1220; 631/250/2504/342; 631/326/596; 631/80/82/23; 96/106; 96/35; 96/63; Accuracy; Animals; Antiviral agents; Apoptosis; Apoptosis - immunology; Cell culture; Cell death; Cognitive ability; Cornea - immunology; Cornea - virology; Damage tolerance; Decision making; Disease Models, Animal; Exposure; Female; Herpes Simplex - immunology; Herpes Simplex - virology; Herpesvirus 1, Human - immunology; Host-Pathogen Interactions - immunology; Humanities and Social Sciences; Humans; Immunological tolerance; Immunoregulation; Infections; Intravital Microscopy; Macrophages; Macrophages - immunology; Macrophages - metabolism; Male; Mathematical analysis; Mathematical models; Mice; Mice, Knockout; Models, Immunological; Mortality; multidisciplinary; NIH 3T3 Cells; Organ culture; Organ Culture Techniques; Primary Cell Culture; Science; Science (multidisciplinary); Time-Lapse Imaging; Tissues; Tumor necrosis factor; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Viral infections
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23195-9

Rapid death of infected cells is an important antiviral strategy. However, fast decisions that are based on limited evidence can be erroneous and cause unnecessary cell death and subsequent tissue damage. How cells optimize their death decision making strategy to maximize both speed and accuracy is unclear. Here, we show that exposure to TNF, which is secreted by macrophages during viral infection, causes cells to change their decision strategy from “slow and accurate” to “fast and error-prone”. Mathematical modeling combined with experiments in cell culture and whole organ culture show that the regulation of the cell death decision strategy is critical to prevent HSV-1 spread. These findings demonstrate that immune regulation of cellular cognitive processes dynamically changes a tissues’ tolerance for self-damage, which is required to protect against viral spread. Controlled cell death can be an efficient anti-viral strategy, but also leads to tissue damage and needs to be balanced. Oyler-Yaniv et al. combine mathematical modelling and microscopy to show that exposure to TNF in response to viral infection causes cells to tune their speed-vs-accuracy trade-off in cell death decision to limit HSV-1 spread.