In the last decade, the potential of β-glucan, a fungal cell wall component, to induce epigenetic and functional modification of innate immune cells, signified as trained innate immunity (TII) has been demonstrated in several pre-clinical and clinical studies. Parenteral administration of β-glucan has resulted in centrally induced TII in the bone marrow/circulating monocytes. Such trained innate immune cells play a critical role in protection against secondary infections. However, there are now indications that inducing local long-lasting immunity at mucosal barrier tissues such as the lung is warranted for protective immunity against respiratory pathogens. Currently, it remains unclear whether respiratory mucosal administration of β-glucan will induce long-lasting resident-memory macrophages and TII and if so, what are the underlying mechanisms of development and maintenance of memory macrophages at respiratory mucosa. To address this, and kinetics of immune responses in the lung were studied. Profound changes in airway macrophage (AM) pools were observed starting from 3 days post-exposure, which was associated with monocyte recruitment, and this was followed by a series of phenotypic shifts in AMs. The altered AM phenotype profile persisted for up to 8 weeks post-exposure. Importantly, β-glucan-trained AMs demonstrated heightened MHC II expression, enhanced responses to secondary stimulation and improved capacity to perform bacterial phagocytosis. Furthermore, mice with, β-glucan-trained AMs displayed higher rates of survival and improved bacterial control, in the lung and periphery, following a lethal S. pneumoniae infection. Our findings together indicate that a single intranasal delivery of β-glucan is able to train AMs. Further work into epigenetics, metabolism, and the contribution of AMs in protection is needed. / Thesis / Master of Health Sciences (MSc) / The immune system has been classically divided into two major compartments known as the innate and adaptive immune system. For decades, the predominant consensus amongst the field was that only the adaptive immune system can form memory against any pathogens encountered. It has been well established that plants and invertebrates only possess an innate immune system and still show boosted responses and enhanced protection against previously encountered as well as new pathogens. Recently, such capacity for innate immune memory has also been demonstrated in humans and pre-clinical animal models. Innate immune memory provides non-specific, broad- spectrum protection whereas adaptive memory is specific to a singular pathogen. Inducing broad-spectrum protection can be crucial for the future of human medicine. Activation of both adaptive and innate immune arms could prove to be extremely beneficial in vaccination strategies. Through the use of a pre-clinical model, we have found that administering β-glucan, a component of fungal cell wall, directly into the lung significantly alters the phenotype and functionality of lung immune cells, and also provides enhanced protection against a heterologous infection.