Respiratory infectious diseases such as tuberculosis and COVID-19 are the leading cause of morbidity and mortality worldwide. It is known that immunopathological changes among the patients are complex and may associate with disease severity. We performed genome-wide epigenomic approaches, Histone acetylation (HWAS) and DNA methylation (WGBS), to investigate the heterogeneous epigenetic networks in longitudinal blood samples from TB and COVID-19 patients. In this talk I will discuss the data from these investigations which has resulted in the identification of novel immune factors of host defense, those can be targeted to design host-directed therapies.