Figure 8.

Contributions of the NiV P gene products to pathogenesis in the ferret model. (a) After i.n. challenge of ferrets with NiV, early targets include lung endothelial cells. The V protein prevents induction of an “innate cytokine cloud” that would inhibit spread of NiV through the endothelium. The W protein prevents induction of an “inflammatory chemokine cloud” that would recruit leukocytes to control NiV-mediated pulmonary lesions. After spreading through lung endothelium, NiV rapidly spreads to multiple organ systems. (b) Spread to the spleen leads to germinal center necrosis and a subsequent lack of neutralizing antibody production. This ability of NiV to prevent neutralizing antibody production is mediated by multiple factors: NiV must efficiently spread to the spleen, for which the V protein is essential; additionally, both the ability of P/V/W to inhibit STAT1 and expression of either the W or C protein must be functional to allow for germinal center destruction and prevention of a neutralizing antibody response. (c) Endothelial and parenchymal cells of multiple other organ systems, including liver, kidney, adrenal gland, pancreas, and urinary bladder also become infected. This often leads to blood chemistry abnormalities including increases in BUN and glucose levels. (d) Eventually NiV spreads to the CNS with infection of the endothelium with mild neurological signs, although the ferrets succumb before many neurons become infected, more extensive infection of neurons, together with more extensive neurological clinical signs, can be observed when either the W and/or C proteins are not expressed, or when NiV is unable to inhibit STAT1. This may be due to increased time to death and/or to altered cytokine expression by infected cells allowing penetration of the blood brain barrier.