In situ inflammasome activation results in severe damage to the central nervous system in fatal Zika virus microcephaly cases

Abstract

Zika virus (ZIKV) has caused substantial concern worldwide owing to its association with severe birth defects, such as microcephaly and other congenital malformations. Inflammasomes, i.e., multi-protein complexes that induce inflammation and pyroptosis, are predicted to contribute to the immune response to this flavivirus. Accordingly, in this study, the in situ inflammasome response was evaluated in fatal cases of ZIKV-linked microcephaly. Brain tissue samples were collected from eight babies, including four ZIKV-positive microcephalic neonates who died after birth and four flavivirus-negative neonatal controls who died of other causes and whose central nervous system (CNS) architecture was preserved. In the ZIKV-positive newborn/stillbirth babies, the major histopathological alterations included atrophy of the cortical layer, a predominance of mononuclear cell infiltration in the Virchow-Robin space, neuronal necrosis, vacuolization and neuronal degeneration, neuronophagy, and gliosis. An immunohistochemical analysis of tissues in the neural parenchyma showed significantly higher expression of the receptors NLRP1, NLRP3, and AIM2, cytokines IL-1β, IL-18, and IL-33, and enzymes caspase 1, iNOS, and arginase 1 in ZIKV-positive microcephaly cases than in flavivirus-negative controls. These results suggest that inflammasome activation can aggravate the neuroinflammatory response and consequently increase CNS damage in neonates with fetal neural ZIKV infection and microcephaly.

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

“…DENV infection in macrophages induces pyroptosis together with the release of IL-1β ( 30 , 31 ). ZIKV infection elicits pyroptosis in the brains of fatal microcephaly cases and increases IL-1β expression ( 32 ). In addition, WNV infection in the brain also provokes the expression of pyroptosis markers (caspase-1, IL-1β, and IL-18) ( 33 ).…”

The involvement of regulated cell death forms in modulating the bacterial and viral pathogenesis

“…Zika virus (ZIKV), an RNA virus, has gained increased attention over the last years due to its association with severe birth defects, including microcephaly. Infection with this flavivirus triggers higher expression levels of NLRP1, 3, AIM2 and caspase-1 in brain tissues collected from fatal human cases (de Sousa et al, 2018). It is, however, not clear whether the accompanied brain tissue damage is the direct consequence of the GSDMD driven pyroptosis or the detected higher inflammasome expression levels represent a completely unrelated phenomenon.…”

Cell death signalling in virus infection

“…AIM2 in the cytosol binds DNA fragments and recruits the adaptor ASC leading to ASC polymerization and assembly of the ASC specks. Interestingly, the upregulation of AIM2 has been observed in brain tissues after Zika virus infection, collected from fatal human cases [ 100 ]. This is therefore possible that the associated neuronal damage is linked to the over activation of AIM-2-dependent pyroptosis in neurons.…”