Autocrine and paracrine interferon signaling as ‘ring vaccination’ and ‘contact tracing’ strategies to suppress virus infection in a host

Abstract

The innate immune response, particularly the interferon response, represents a first line of defense against viral infections. The interferon molecules produced from infected cells act through autocrine and paracrine signaling to turn host cells into an antiviral state. Although the molecular mechanisms of IFN signaling have been well characterized, how the interferon response collectively contribute to the regulation of host cells to stop or suppress viral infection during early infection remain unclear. Here, we use mathematical models to delineate the roles of the autocrine and the paracrine signaling, and show that their impacts on viral spread are dependent on how infection proceeds. In particular, we found that when infection is well-mixed, the paracrine signaling is not as effective; in contrast, when infection spreads in a spatial manner, a likely scenario during initial infection in tissue, the paracrine signaling can impede the spread of infection by decreasing the number of susceptible cells close to the site of infection. Furthermore, we argue that the interferon response can be seen as a parallel to population-level epidemic prevention strategies such as contact tracing or ring vaccination. Thus, our results here may have implications for the outbreak control at the population scale more broadly.

Mechanistic Modeling of SARS‐CoV‐2 and Other Infectious Diseases and the Effects of Therapeutics

“…24,40 In contrast, recent works of ours pointed out when target cells are spatially segregated, e.g., in epithelium, the combined impact of autocrine and paracrine signaling can strongly suppress viral spread during early infection before the viral peak. 68,69 These types of models may be important in understanding how early interferon-alpha response or treatment determines long-term infection outcome as suggested recently by experimental studies of SARS-CoV-2 and MERS coronavirus. 64,70,71 The quantitative impact of the interferon-alpha response on SARS-CoV-2 dynamics and which aspect of the response plays a more important role still need to be resolved.…”

“…One study shows that in 10% of severe COVID-19 cases, interferon-alpha was largely absent due to the presence of autoantibodies targeting interferon-alpha, 109 whereas another study 110 showed that 3.5% of patients with life-threatening COVID-19 had inborn errors in genes associated with the interferon-alpha response. Therefore, modeling that aims to better understand the role of interferon-alpha responses 68,69 and the responses to proinflammatory cytokines will be useful for designing and understanding the impact of therapeutics to mitigate severe disease.…”