Host-encoded antivirulence defenses: host physiologies teach pathogens to play nice

Successful treatment of infectious diseases requires a multiprong approach involving strategies that limit pathogen burdens and that limit disease. Traditionally, disease defense is thought to be a direct function of pathogen killing, and thus, our current methods for treating infections have largely relied on pathogen eradication, leading to drug resistance. Strategies that target the virulence of the pathogen, called antivirulence, have been proposed to be a necessary strategy to integrate into our infectious disease toolbox to promote disease defense and alleviate the burden of drug resistance. Traditional antivirulence strategies have largely focused on developing compounds that directly target microbial virulence factors or products to impair their ability to initiate and sustain infection. As virulence is linked to pathogen fitness, simply targeting a virulence factor may not be sufficient to overcome the ability of pathogens evolving resistance. In this review, I discuss co-operative defenses that hosts have evolved to promote antivirulence mechanisms that suppress pathogen virulence without having a negative impact on pathogen fitness. I also discuss the different definitions antivirulence has been assigned over the years and suggest a more holistic one. Co-operative defenses remain an underexplored resource in medicine, and by learning from how hosts have evolved to promote antivirulence, we have the potential to develop disease defense interventions without the risk of pathogens developing drug resistance.