Interactions between parasites co-occurring within a single host have profound effects on infection outcomes ranging from disease severity and progression within individual hosts to patterns of disease spread across populations. Since most hosts are infected by more than one type of parasite, concurrent infection (or co-infection) has emerged as a key challenge for wildlife, veterinary, and human health. As a consequence, the study of co-infection has gained traction across a wide range of disciplines, including immunology, microbiology, disease ecology and evolution, epidemiology, and public health. Importantly, research in all of these spheres is largely focused on different aspects of the same core questions: (i) what are the causes of interactions between parasites? and (ii) what are the consequences of these interactions for patterns of infection in vulnerable hosts? Despite this increased attention to co-infection, a fundamental gap remains in our understanding of how laboratory-based insights on the mechanisms underlying interactions between co-infecting parasites and the outcomes for individual hosts translate into host and pathogen ecology and evolution in the real world. The research outlined in this proposal will help bridge this gap by investigating interactions between helminths (gastrointestinal nematodes) and bovine tuberculosis (Mycobacterium bovis, TB) in a free-ranging wildlife system. This proposal uses a combination of experimental, field, genetic, and modeling approaches to extend past work in wild African buffalo (Syncerus caffer), which has revealed that both active nematode infection and host adaptation to nematodes serve as potent drivers of variation in TB disease outcomes, to address four inter-related specific aims: (1) Identify the immunological mechanisms linking helminth resistance to variable individual outcomes of TB; (2) Quantify the strength of TB-mediated selection on helminth resistance in buffalo; (3) Investigate how selective removal of TB-infected buffalo with respect to helminth-related traits influences helminth population dynamics; (4) Examine the potential for cryptic, parasite interaction-mediated selection on TB virulence. The project integrates ideas and approaches from ecology, evolutionary biology, immunology, microbiology, genomics, and mathematical biology to address the global challenge of co-infection and its impacts on disease outcomes in host populations. The research poses novel hypotheses about how parasites interact, and the consequences for host and parasite ecology and evolution, with significant implications for understanding disease dynamics in humans, livestock, and wildlife.