The genus Neisseria provides an especially informative model for understanding how evolution reshapes bacterial “lifestyles”. Within the same genus, some species are primarily commensal, whereas others are pathogens capable of causing infection. The project starts from a simple idea: before a bacterium can become pathogenic, it must first pass through key steps such as adapting to a new environmental niche. Moving from one environment to another (for example, from the oral cavity to the nasopharynx, or from one colonization site to another) exposes bacteria to new chemical constraints and immune pressures.
At the core of the study are two selective pressures. The first is copper homeostasis: copper is essential at low levels but becomes toxic when in excess. The second is redox stress (oxidative and nitrosative), often linked to host defense mechanisms, which can damage proteins and disrupt metabolism. The project investigates the hypothesis that, over the course of Neisseria evolution, these two responses have been “rewired”. Instead of being controlled by the canonical copper regulator CueR, the expression of key copper-export genes may have shifted under the control of NmlR, a regulator associated with the redox stress response. Such a reorganization would more tightly couple copper detoxification with resistance to oxidative stress potentially providing an advantage during niche transitions and, indirectly, affecting the ability to cause disease.
To test this hypothesis, we will compare many Neisseria species, experimentally characterize how CueR and NmlR function, and then swap regulatory modules between species to assess causally the impact on copper tolerance, redox-stress resistance, and survival in the presence of immune cells. The ultimate goal is to determine whether certain traits associated with pathogenesis primarily reflect ecological adaptation to new niches, rather than an intrinsic link to virulence.