Bovine respiratory disease (BRD) is a multifactorial condition where different genera of bacteria, such as Mannheimia haemolytica, Histophilus somni, Pasteurella multocida, and Mycoplasma bovis, and viruses, like bovine respiratory syncytial virus, bovine viral diarrhea virus, and bovine herpes virus-1, infect the lower respiratory tract of cattle. These pathogens can co-infect cells in the respiratory system, thereby making specific treatment very difficult. Currently, the most common models for studying BRD include a submerged tissue culture (STC), where monolayers of epithelial cells are typically covered either in cellular or spent biofilm culture medium. Another model is an air−liquid interface (ALI), where epithelial cells are exposed on their apical side and allowed to differentiate. However, limited work has been reported on the study of three-dimensional (3D) bovine models that incorporate multiple cell types to represent the architecture of the respiratory tract. The roles of different defense mechanisms in an infected bovine respiratory system, such as mucin production, tight junction barriers, and the production of antimicrobial peptides in in vitro cultures require further investigation in order to provide a comprehensive understanding of the disease pathogenesis. In this report, we describe the different aspects of BRD, including the most implicated pathogens and the respiratory tract, which are important to incorporate in disease models assembled in vitro. Although current advancements of bovine respiratory cultures have led to knowledge of the disease, 3D multicellular organoids that better recapitulate the in vivo environment exhibit potential for future investigations.

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