The Enigma of COVID-19

Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, play a central role in severity and lethality in COVID-19. Recognition by innate Pattern-recognition receptors (PPRs) and activation of central cellular signal transduction pathways were shown to play a central role in the pathophysiology of COVID-19. The impact and interplay of different additional factors, such as age, comorbidities, endemic infections with the underlying immune pathological mechanisms for COVID-19 are discussed and provide a better understanding of the disease and the development of new targets for more efficient treatment strategies. Importantly, different SARS-CoV-2 variants were found to differ in their engagement of various signalling pathways correlating with differences in their cellular tropism and pathologies. Finally, by using selected parts of the virus for immunization various very rare vaccination-associated side effects can imitate the picture of a limited COVID-19 pathological pattern. The present collection provides an excellent integrated overview on central cellular and molecular mechanisms involved in COVID-19 as well as in rare vaccination-associated side effects.