Resistance is futile? Mucosal immune mechanisms in the context of microbial ecology and evolution

In the beginning it was simple: we injected a protein antigen and studied the immune responses against the purified protein. This elegant toolbox uncovered thousands of mechanisms via which immune cells are activated. However, when we consider immune responses against real infectious threats, this elegant simplification misses half of the story: the infectious agents are typically evolving orders-of-magnitude faster than we are. Nowhere is this more pronounced than in the mammalian large intestine. A bacterium representing only 0.1% of the human gut microbiota will have a population size of 10(9) clones, each actively replicating. Moreover, the evolutionary pressure from other microbes is at least as profound as direct effects of the immune system. Therefore, to really understand intestinal immune mechanisms, we need to understand both the host response and how rapid microbial evolution alters the apparent outcome of the response. In this review we use the examples of intestinal inflammation and secretory immunoglobulin A (SIgA) to highlight what is already known (Fig. 1). Further, we will explore how these interactions can inform immunotherapy and prophylaxis. This has major implications for how we design effective mucosal vaccines against increasingly drug-resistant bacterial pathogens