Thesis advisor: Tim van Opijnen / Although vaccines and antibiotics have been historically successful in combating bacterial infections, limited vaccine coverage and the rise of antibiotic resistance emphasize the need to develop alternative, broadly effective, and/or targeted treatment strategies to reduce the health burden of bacterial infections. Rather than relying on therapeutics solely targeting the bacterial pathogen, such as standard antibiotics, therapies that simultaneously focus on host responses are emerging. In this thesis, we propose 'host-informed therapies' (HITs) in two categories: those that aid patients with fully functional immune systems and those that aid patients with perturbed immune processes, as promising alternative or adjunctive treatment strategies for bacterial infections. The host-pathogen interaction during infection is a highly dynamic process between diverse bacterial pathogens and hosts with varying degrees of susceptibility. Systems biology approaches have provided an understanding of host-pathogen parameters globally through the detection of putative biomarkers for diagnosis and identification of critical interactions to discover novel drug targets. However, there remains a gap in understanding bacterial pathogenesis in the context of designing novel host-informed therapies. Here, we use Streptococcus pneumoniae, the gram-positive pathogen responsible for the majority of bacterial respiratory tract infections worldwide, as a case study to: (1) Generate a genome-wide map of bacterial immune (complement) evasion targets to design novel host-informed therapies, (2) generate a dual host/pathogen transcriptome map to identify signatures of infection outcome, and (3) validate signatures of bacterial antibiotic tolerance in a mouse lung infection model. Overall, this work exemplifies how systems biology methods can elucidate the intricacies of bacterial pathogenesis but, more importantly, aid in the target identification, validation, and design of antibacterial host-informed therapies. / Thesis (PhD) — Boston College, 2023. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.