During SIRS and MODS, the brain appears to be a main target organ, with activation of glial cells, upregulation of NOS2, apoptosis and loss of neurons [7, 42] . The proximal inducers of this encephalopathy include TNF-α, type I IFNs, IL-1β and IL-6 [17, [43] [44] [45] , all of which were highly up-regulated in animals with H5N1 virus infection throughout the 7-day observation period [23] . Neurological symptoms, other than 'depression', are difficult to monitor in macaques, and this, for logistic reasons, could not be done in this study. However, the finding of microglial activation, as evidenced by increased cell size and Iba-1 expression [30] and upregulation of VEGF-A expression in the neuropil and of HIF-1α expression in intravascular leukocytes and leukocytes in the interstitium of the choroid plexus of H5N1 infected animals, suggests that these animals might have experienced an encephalopathy, albeit relatively mild, that could have contributed to their constitutional symptoms and consequent high clinical scores [23] .