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This thesis investigates the interaction between pathogens and the human host to improve understanding of airway infections at individual level (disease severity) and population level (epidemics). The COVID-19 pandemic vividly demonstrated how rapid spread of a novel pathogen can disrupt social, economic and health systems. Measures implemented to control SARS-CoV-2 also impacted other infectious diseases. After lifting these measures, an increase in severe group A streptococcal infections was observed in 2022. Re-instalment of national Streptococcus pyogenes surveillance, which included genetic analysis of the bacterium, enabled the detection of emerging variants driving the surge in the Netherlands. Next, laboratory models that mimic human infection can be used to study the characteristics of novel variants. We demonstrate that airway epithelial cultures derived from stem cells (mini-airways) can be infected with S. pyogenes and used to study the host immune responses. The second part of this thesis focuses on the immune responses to SARS-CoV-2. Absence of a virus-specific T-cell response is predictive of severe disease, underscoring the crucial role of adaptive immunity in controlling SARS-CoV-2 infection. Adaptive immunity can also be induced by vaccination. Vaccine breakthrough infections emerged shortly after the introduction of COVID-19 vaccines. We show that these breakthrough infections could not be attributed to absence of an immune response after vaccination (vaccine failure) or viral mutations (vaccine escape). Our research contributes to better understanding of infectious diseases and development of public health measures, vaccines, and treatments to combat future epidemics.