Correlation between Apoptosis and in Situ Immune Response in Fatal Cases of Microcephaly Caused by Zika Virus

Abstract

Zika virus (ZIKV) is a single-stranded positive-sense RNA flavivirus that possesses a genome approximately 10.7 Kb in length. Although pro-inflammatory and anti-inflammatory cytokines and apoptotic markers belonging to the extrinsic and intrinsic pathways are suggested to be involved in fatal cases of ZIKV-induced microcephaly, their exact roles and associations are unclear. To address this, brain tissue samples were collected from 10 individuals, five of whom were diagnosed as ZIKV positive with microcephaly and a further five were flavivirus-negative controls that died because of other causes. Examination of material from the fatal cases of microcephaly revealed lesions in the cerebral cortex, edema, vascular proliferation, neuronal necrosis, gliosis, neuronophagy, calcifications, apoptosis, and neuron loss. The expression of various apoptosis markers in the neural parenchyma, including FasL, FAS, BAX, BCL2, and caspase 3 differed between ZIKV-positive cases and controls. Further investigation of type 1 and 2 helper T-cell cytokines confirmed a greater anti-inflammatory response in fatal ZIKV-associated microcephaly cases. Finally, an analysis of the linear correlation between tumor necrosis factor-α, IL-1β, IL-4, IL-10, transforming growth factor-β, and IL-33 expression and various apoptotic markers suggested that the immune response may be associated with the apoptotic phenomenon observed in ZIKV-induced microcephaly.

RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

“…ZIKV infection causes apoptosis [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. We therefore asked whether reduced innate immune recognition of ZIKV in RIG-I KO cells impacts virus-induced cell death.…”

Tumor Necrosis Factor-Alpha Signaling May Contribute to Chronic West Nile Virus Post-infectious Proinflammatory State

“…First, the clinical data provide evidence that WNV infection in humans induces a significant upregulation of TNF-α. This is not surprising since previous studies in mice and cell cultures have demonstrated essential protective roles for TNF-α and other proinflammatory cytokines against acute WNV infection (10,(12)(13)(14) Moreover, high TNF-α levels have been reported in other flavivirus human infections, including dengue (21,22), Zika virus (23,24), and Japanese encephalitis virus (JEV) (25). Children infected with dengue virus showed significantly higher serum levels of TNF-α, with the highest levels in those with severe dengue disease (21), formerly "dengue shock syndrome" and "dengue hemorrhagic fever."…”

“…In fact, the potentially critical causative role of TNF-α and the associated "cytokine storm" in severe dengue disease and other viral diseases has long been recognized (26). In fatal cases of Zika fetal syndrome, a significantly increased expression of TNF-α, IFNγ, and other proinflammatory cytokines has been found in the meninges, perivascular region, and parenchyma of microcephalic brains (23,24). Japanese encephalitis virus (JEV) infection also significantly elevates expression of TNF-α and other proinflammatory cytokines in animals and cell cultures, leading to neuroinflammation and neuronal death (25).…”

Betulinic Acid Exerts Cytoprotective Activity on Zika Virus-Infected Neural Progenitor Cells

“…Indeed, it has been demonstrated that ZIKV infection is capable of triggering the production of proinflammatory cytokines, such as TNF and IL-β, and glutamate, mediators shown to induce neuronal cell death in ZIKV ( Olmo et al., 2017 ). Moreover, apoptosis-induced microcephaly alterations have been linked to high proinflammatory cytokines production, for instance TNFα and IL-1β ( de Sousa et al., 2018 ). In our study, when ZIKV-infected NPCs were treated BA after infection, the lower concentration of BA had a milder antiviral activity but caused less toxicity to the NPCs, protecting these cells from ZIKV-induced death.…”