Of the three viruses, SARS-1 is bes

Of the three viruses, SARS-1 is best understood withregard to pathogenesis. Following viral entry, ACE2 isdownregulated, which paradoxically enhances pathology, because the presence of ACE2 has been shown to beprotective against acute lung injury (Imai et al. 2005).Specifically, downregulation of ACE2 leads to compensatory overproduction of angiotensin II by ACE. Angiotensin II in turn stimulates its type 1a receptor, whichincreases lung vascular permeability and potentiateslung pathology (rev. in (de Wit et al. 2016)) . Therefore,both the initial and most serious prolonged injury occursto the lungs. While the immune response is critical forthe resolution of SARS-1 infection, it can also potentiate, if not drive, pathogenesis in the second phase of thedisease (de Wit et al. 2016), with a paradoxical observation that viral loads often decline when the severity ofthe disease increases. It is not clear whether MERSfollows the same course. Progression to the acute respiratory distress syndrome (ARDS) in SARS-1 has beenindeed marked by upregulation of proinflammatory cytokines and chemokines, particularly interleukin-1β(IL-1β), IL-8, IL-6, CXC-chemokine ligand 10(CXCL10) and CC-chemokine ligand 2 (CCL2). In fact,retrospective analysis of survivors versus non-survivorsrevealed an early and sustained pattern of innate immune activation and soluble mediator elevation in nonsurvivors, most notably IFN-α and γ, CXCL10 andCCL2, and the downstream interferon-stimulated genes(SIG), without ever progressing to production of significant amounts of antibodies. Survivors, by contrast,exhibited the expected switch to antibody production