The microbiome includes both ‘mutualist’ and ‘pathogen’ microbes, regulated by the same innate immune architecture. A major question has therefore been: how do hosts prevent pathogenic infections while maintaining beneficial microbes? One idea suggests hosts can selectively activate innate immunity upon pathogenic infection, but not mutualist colonization. Another idea posits that hosts can selectively attack pathogens, but not mutualists. Here I review evolutionary principles of microbe recognition and immune activation, and reflect on newly observed immune effector–microbe specificity perhaps supporting the latter idea. Recent work in
Drosophila
has found a surprising importance for single antimicrobial peptides in combatting specific ecologically relevant microbes. The developing picture suggests these effectors have evolved for this purpose. Other defence responses like reactive oxygen species bursts can also be uniquely effective against specific microbes. Signals in other model systems including nematodes,
Hydra
, oysters, and mammals, suggest that effector–microbe specificity may be a fundamental principle of host–pathogen interactions. I propose this effector–microbe specificity stems from weaknesses of the microbes themselves: if microbes have intrinsic weaknesses, hosts can evolve effectors that exploit those weaknesses. I define this host–microbe relationship as ‘the Achilles principle of immune evolution’. Incorporating this view helps interpret why some host–microbe interactions develop in a coevolutionary framework (e.g. Red Queen dynamics), or as a one-sided evolutionary response. This clarification should be valuable to better understand the principles behind host susceptibilities to infectious diseases.
This article is part of the theme issue ‘Sculpting the microbiome: how host factors determine and respond to microbial colonization’.