Abstract: The devastating outbreak of the ongoing coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected not only the lives of almost everyone around the world but also the governments and societies as well turning into a global catastrophe. Pneumonia of unknown cause was reported in December 2019 in Wuhan, China (Zhu et al., 2020), it rapidly spread to all parts of the globe prompting World Health Organization to declare a pandemic on March 11, 2020 (Cucinotta and Vanelli, 2020). As of October 11th, 2021, 223 countries and territories have reported COVID-19 cases with a total of more than 237 million confirmed cases and more than 4.8 million confirmed deaths (World Health Organization), with the United States leading the world by the highest number of cases thus far (over 43 million infected and 703,599 deaths). Although COVID-19 results mainly in acute lung injury leading to high mortality in the elderly and people with underlying comorbidities, significant nervous system-associated morbidities including meningoencephalitis with elevated lymphocytes and cytokines in the cerebrospinal fluid frequently with viral presence are reported (Lv et al., 2021). Neurons may be more vulnerable to SARS-CoV-2 than SARS-CoV because the virus has been confirmed to replicate in neuronal cell lines (Bar-On et al., 2020) and COVID-19 patients show signs of confusion and dizziness which were rarely reported for SARS-CoV. The most troubling outcome of the pandemic is the practice of critical care triage to ration the scarce resources of intensive care units. Therefore, it is very critical to identify how the virus elicits the massive cytokine storm and the failure of homeostatic and defense mechanisms so that mechanism-based novel therapeutics may be identified quickly and lives saved.  Here, I propose that cytokine storm which is the major cause of death in COVID-19 patients may indeed be triggered by undigested viral proteins and genomic materials due to viral-induced dysfunction of the autophagy-lysosome pathway (ALP).