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bioRxiv · 10.64898/2026.03.10.710826

Guarding versus self-guarding in innate immunity

Ashby, B.·Anderson, A.
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Abstract

Hosts have evolved a variety of innate immune responses to pathogens. In many cases, hosts directly detect pathogen-associated molecular patterns (PAMPs) or pathogen effectors to trigger an immune response. However, hosts may also detect pathogens indirectly through guarding, whereby immune receptors ( guards) monitor the effects of pathogens (e.g., modification of target cells) rather than the pathogens themselves. Guarding poses a different evolutionary challenge for pathogens than direct recognition of PAMPs, as replication may necessitate the modification or disruption of guarded host proteins ( guardees). Recently, self-guarding has been discovered, in which the host target functions as both guard and guardee. Self-guarding appears to present an intractable problem for pathogens: modification of the host target may benefit replication, but also triggers an immune response. If self-guarding creates an apparently inescapable detection mechanism, why has self-guarding only recently been discovered? Here, we use mathematical models of within-host pathogen and immune dynamics to compare guarding and self-guarding architectures. We show that self-guarding leads to a more rapid immune response and faster pathogen suppression, but is also more prone to false-positive immune responses, likely imposing greater costs through autoimmunity. We therefore hypothesise that the greater potential for false-positive immune responses may limit the conditions under which self-guarding evolves.

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Ashby, B., Anderson, A.. 2026-03-12. Guarding versus self-guarding in innate immunity. https://doi.org/10.64898/2026.03.10.710826

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