Trace metals are essential micronutrients required for survival across all kingdoms of life. From bacteria to animals, metals have critical roles as both structural and catalytic cofactors for an estimated third of the proteome, representing a major contributor to the maintenance of cellular homeostasis. The reactivity of metal ions engenders them with the ability to promote enzyme catalysis and stabilize reaction intermediates. However, these properties render metals toxic at high concentrations and, therefore, metal levels must be tightly regulated. Having evolved in close association with bacteria, vertebrate hosts have developed numerous strategies of metal limitation and intoxication that prevent bacterial proliferation, a process termed nutritional immunity. In turn, bacterial pathogens have evolved adaptive mechanisms to survive in conditions of metal depletion or excess. In this Review, we discuss mechanisms by which nutrient metals shape the interactions between bacterial pathogens and animal hosts. We explore the cell-specific and tissue-specific roles of distinct trace metals in shaping bacterial infections, as well as implications for future research and new therapeutic development.

The intestinal microbiota influences the development and function of myeloid lineages such as neutrophils, but the underlying molecular mechanisms are unresolved. Using gnotobiotic zebrafish, we identified the immune effector Serum amyloid A (Saa) as one of the most highly induced transcripts in digestive tissues following microbiota colonization. Saa is a conserved secreted protein produced in the intestine and liver with described effects on neutrophils in vitro , however its in vivo functions remain poorly defined. We engineered saa mutant zebrafish to test requirements for Saa on innate immunity in vivo . Zebrafish mutant for saa displayed impaired neutrophil responses to wounding but augmented clearance of pathogenic bacteria. At baseline, saa mutants exhibited moderate neutrophilia and altered neutrophil tissue distribution. Molecular and functional analyses of isolated neutrophils revealed that Saa suppresses expression of pro-inflammatory markers and bactericidal activity. Saa’s effects on neutrophils depended on microbiota colonization, suggesting this protein mediates the microbiota’s effects on host innate immunity. To test tissue-specific roles of Saa on neutrophil function, we over-expressed saa in the intestine or liver and found that sufficient to partially complement neutrophil phenotypes observed in saa mutants. These results indicate Saa produced by the intestine in response to microbiota serves as a systemic signal to neutrophils to restrict aberrant activation, decreasing inflammatory tone and bacterial killing potential while simultaneously enhancing their ability to migrate to wounds.

Microbial communities populate the mucosal surfaces of all animals. Metazoans have co-evolved with these microorganisms, forming symbioses that affect the molecular and cellular underpinnings of animal physiology. These microorganisms, collectively referred to as the microbiota, are found on many distinct body sites (including the skin, nasal cavity, and urogenital tract), however the most densely colonized host tissue is the intestinal tract. Although spatially confined within the intestinal lumen, the microbiota and associated products shape the development and function of the host immune system. Studies comparing gnotobiotic animals devoid of any microbes (germ free) with counterparts colonized with selected microbial communities have demonstrated that commensal microorganisms are required for the proper development and function of the immune system at homeostasis and following infectious challenge or injury. Animal model systems have been essential for defining microbiota-dependent shifts in innate immune cell function and intestinal physiology during infection and disease. In particular, the zebrafish has emerged as a powerful vertebrate model organism with unparalleled capacity for in vivo imaging, a full complement of genetic approaches, and facile methods to experimentally manipulate microbial communities. Here we review key insights afforded by the zebrafish into the impact of microbiota on innate immunity, including evidence that the perception of and response to the microbiota is evolutionarily conserved. We also highlight opportunities to strengthen the zebrafish model system, and to gain new insights into microbiota-innate immune interactions that would be difficult to achieve in mammalian models.

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23The intestinal microbiota influence diverse aspects of host physiology, including 24