From Plato to Pareto: Defining the shape of infection’s disease space

If the immune system is an interconnected network, then the evolution of an archetype that is ideal for fighting one pathogen should result in trade-offs decreasing its ability to fight others. How many archetypes are there in an immune system? We infected diverse mice with <i>Plasmodium chabaudi</i> and identified five distinct archetypes of responses on the basis of the host's position in microbial load, immune activity, and host damage space. To better understand the nature of these archetypes, we developed a mathematical model of a generalized host-pathogen system. This model explains the number and distribution of archetypes across a population of diverse hosts. Mice resilient to <i>P. chabaudi</i> exhibited poor outcomes when challenged with influenza, SARS-CoV-1, or <i>Mycobacterium tuberculosis</i>, and vice versa, supporting our trade-off hypothesis.