Abstract
Zika virus (ZIKV) has recently caused a pandemic disease, and many cases of ZIKV infection in pregnant women resulted in abortion, stillbirth, deaths and congenital defects including microcephaly, which now has been proposed as ZIKV congenital syndrome. This study aimed to investigate the in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases. Brain tissue samples were collected from 15 cases, including 10 microcephalic ZIKV-positive neonates with fatal outcome and five neonatal control flavivirus-negative neonates that died due to other causes, but with preserved central nervous system (CNS) architecture. In microcephaly cases, the histopathological features of the tissue samples were characterized in three CNS areas (meninges, perivascular space, and parenchyma). The changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells. The in situ immune response against ZIKV in the CNS of newborns is complex. Despite the predominant expression of Th2 cytokines, other cytokines such as Th1, Th17, Treg, Th9, and Th22 are involved to a lesser extent, but are still likely to participate in the immunopathogenic mechanisms of neural disease in fatal cases of microcephaly caused by ZIKV.
Highlights
Zika virus (ZIKV; genus Flavivirus, family Flaviviridae) was isolated in 1947 from Macaca mulatta in the Zika Forest of Uganda[1] and, similar to other flaviviruses, can cause lesions in the lung, kidney, heart, liver, and brain[2]
In view of the severity of presentation, many studies are currently trying to characterize the relationship of ZIKV infection with the development of Guillain-Barré syndrome and microcephaly, as well as the mechanisms underlying sexual and vertical transmission of the virus[1,3,4]
Because the central nervous system (CNS) is an immunologically privileged site and in view of the intense selectivity of the blood-brain barrier in terms of kinetics of cell and cytokine flow between blood and tissue, investigation of the in situ immune response profile and neuronal cell damage mechanism is important for understanding the pathogenesis of microcephaly by ZIKV
Summary
Zika virus (ZIKV; genus Flavivirus, family Flaviviridae) was isolated in 1947 from Macaca mulatta in the Zika Forest of Uganda[1] and, similar to other flaviviruses, can cause lesions in the lung, kidney, heart, liver, and brain[2]. Studies investigating the in situ immune response in the tissue microenvironment are lacking This tissue immune response is important for understanding of the immunopathogenesis of lesions, as this local response is intimately related to the mechanisms of immune-mediated tissue damage. Correspondence and requests for materials should be addressed to P.F.C.V. Because the CNS is an immunologically privileged site and in view of the intense selectivity of the blood-brain barrier in terms of kinetics of cell and cytokine flow between blood and tissue, investigation of the in situ immune response profile and neuronal cell damage mechanism is important for understanding the pathogenesis of microcephaly by ZIKV. By recognizing that this relationship can provide new insights into the immunopathogenesis of the disease, the present study investigated the in situ immune response profile and mechanism of neuronal cell damage in stillborn infants and newborns infected with ZIKV who died
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