Background Discovery of the origin of SARS-CoV-2 become an urgent international need due to the current health and economic implications. Recently, pangolins were reported to have a diminished immunity and vulnerable to several infections. By the end of 2019; recent studies reported the pangolins infection with SARS like virus that showed a 99% genetic homology with SARS-CoV-2. In 2020; a genetic mutation was reported in pangolins that increases their vulnerability to infection with flagellated bacteria such as Mycobacterium species. Moreover, the introduced food formula containing yeast at several zoos, considered as a source of opportunistic Saccharomyces infection in such immunocompromised pangolins. Methods The coexistence of multiple infections in an immunocompromised pangolin is the concept of SARS-CoV-2 evolution hypothesis. The structures of the three proposed microorganisms; SARS-CoV-1, Saccharomyces cerevisiae and Mycobacterium avium as well as their glycobiology and host cell interactions were studied. The α -mannoses and phosphates present in the spike protein of SARS-CoV-2 is supposed to be introduced through fermentation of the spike protein of SARS-CoV-1 by Saccharomyces cerevisiae while the PRRAR furin putative sequence as well as the LDPLSE motif are supposed to be introduced through microbial interaction with Mycobacterium avium strain 104 . Moreover, the interaction with pangolins cells resulted in the presence of the reserved O-glycosylation sites in the spike protein of SARS-CoV-2. Results and discussion SARS-CoV-2 was naturally developed in an immunocompromised pangolin through microbial interaction that resulted in a hybrid microorganism containing viral RNA encapsulated within a glycan shield (Spike glycoprotein) manipulated by both Saccharomyces cerevisiae and Mycobacterium avium. The proposed origin of the novel virus; SARS-CoV-2, explained the abnormal clinical findings such as disseminated infection, blood clotting, hyperpigmentation in some cases and Kawasaki like syndrome in kids. Lactose intolerance is also suggested as a new genetic risk factor that increases the vulnerability to infection with SARS-CoV-2. Moreover, the likelihood biofilm formation by SARS-CoV-2 is discussed. Furthermore, this hypothesis discussed the potential evolution of MERS through microbial interaction between Mycobacterium tuberculosis and SARS-CoV-1 virus. Conclusions Trials using triple therapy treatment strategy consisting of Remdesivir, Aithromycin and fluorocytosine as well as a yeast-based vaccine are suggested.