Short Title: Virulence and Immunopathology

Word Count (Main text) ~4700 Abstract The trade-off hypothesis of virulence evolution rests on the assumption that infection-induced mortality is a consequence of host exploitation by parasites. This hypothesis lies at the heart of many empirical and theoretical studies of virulence evolution, despite growing evidence that infection-induced mortality is very often a by-product of host immune responses. We extend the theoretical framework of the trade-off hypothesis to incorporate such immunopathology, and explore how this detrimental aspect of host defense mechanisms affects the evolution of pathogen exploitation and hence infection-induced mortality. We argue that there are qualitatively different ways in which immunopathology can arise, and suggest ways in which empirical studies can tease apart these effects. We show that immunopathology can cause infection-induced mortality to increase or decrease as a result of pathogen evolution, depending how it covaries with pathogen exploitation strategies, and with parasite killing by hosts. Immunopathology is thus an important determinant of whether public and animal health programmes will drive evolution in a clinically beneficial or detrimental direction. Immunopathology complicates our understanding of disease evolution, but can nevertheless be readily accounted for within the framework of the trade-off hypothesis.