The solution on enigmas in COVID-19: the protein-homeostasis-system hypothesis

Abstract

Infectious diseases, including coronavirus disease 2019 (COVID-19), are representative, of which etiology is known in all human diseases. However, many enigmas persist in relation to COVID-19, including different clinical phenotypes and incubation periods across individuals, species-specificity, appearance of cytokine storm and lymphopenia, and the mechanism of damage to organ cells. Current immunological concepts have limitations to explain these unsolved issues. Meanwhile, results of clinical, pathological, and animal studies have suggested that the virus itself is not a direct cause of acute injury to the lung or other organ cells. For better understanding of COVID-19, a presumed immunopathogenesis of COVID-19 is presented under the protein-homeostasis-system hypothesis; every disease, including COVID-19, has associated etiological substances, and the host immune system controls these diverse substances according to the size and biochemical property. These etiological substances, inducing inflammation and subsequent tissue injury, are smaller substances derived from virus-infected cells. Initially acting nonspecific adaptive immune reaction with cytokine imbalance may be responsible for target cell injury. Furthermore, substances from initial target cell injury and secondary bacterial invasion can induce further inflammation if released from local or systemic circulation. COVID-19 patients with pneumonia show hypercytokinemia with lymphocytopenia corresponding to the severity of pneumonia at early stages. Thus, early immune-modulator treatment, including corticosteroids and intravenous immunoglobulin, has an immunological rationale. It could help reduce the morbidity and possibly mortality of older patients with underlying conditions.