Curiouser and curiouser: understanding the intersection of inter- and intra-specific diversity during the Borrelia burgdorferi enzootic cycle and Lyme disease.

A consequence of the Borrelia (Borreliella) burgdorferi lifecycle is that a "standard" host-pathogen interaction involving the spirochete is challenging to define. The bacteria continuously cycle between vertebrate and invertebrate hosts, each inflicting substantially different selective pressures on the spirochete. Focusing solely on vertebrate infections, the spirochete can be found in numerous hosts in nature, including deermice, shrews, birds, and lizards. The immune pressures that the bacteria face in each of these hosts are variable and are thought to drive broad intraspecific variation across B. burgdorferi strains-with different strains appearing to be avian adapted, mammalian adapted, or generalist. In addition to its natural zoonotic hosts, B. burgdorferi can infect humans and cause Lyme disease. Here, natural human genetic variation can drive dramatically different disease outcomes, as some individuals seem capable of killing the bacteria before it can successfully colonize, while others are predisposed to continue reacting to the pathogen even long after it is killed by antibiotics. In this review, we describe studies investigating how host and bacterial diversity affect B. burgdorferi infection outcomes, with an emphasis on how this variability impacts the bacteria's spread in nature and Lyme disease severity during human infection.