Abstract
Zika virus (ZIKV) is associated with brain development abnormalities such as primary microcephaly, a severe reduction in brain growth. Here we demonstrated in vivo the impact of congenital ZIKV infection in blood vessel development, a crucial step in organogenesis. ZIKV was injected intravenously in the pregnant type 2 interferon (IFN)-deficient mouse at embryonic day (E) 12.5. The embryos were collected at E15.5 and postnatal day (P)2. Immunohistochemistry for cortical progenitors and neuronal markers at E15.5 showed the reduction of both populations as a result of ZIKV infection. Using confocal 3D imaging, we found that ZIKV infected brain sections displayed a reduction in the vasculature density and vessel branching compared to mocks at E15.5; altogether, cortical vessels presented a comparatively immature pattern in the infected tissue. These impaired vascular patterns were also apparent in the placenta and retina. Moreover, proteomic analysis has shown that angiogenesis proteins are deregulated in the infected brains compared to controls. At P2, the cortical size and brain weight were reduced in comparison to mock-infected animals. In sum, our results indicate that ZIKV impairs angiogenesis in addition to neurogenesis during development. The vasculature defects represent a limitation for general brain growth but also could regulate neurogenesis directly.
Highlights
Primary microcephaly is a severe brain malformation characterized by the reduction of the cephalic perimeter at birth
There was a significant decrease in the weight of Zika virus (ZIKV) infected brains (71.1 μg ± 3.7 μg, n = 9) compared to MOCK brains (100.5 μg ± 9.3 μg, n = 3) at P2 (p = 0.005; Fig. 1E)
We demonstrated that ZIKV infection at E12.5 in Ifng−/− mice causes a reduction in brain size at P2
Summary
Primary microcephaly is a severe brain malformation characterized by the reduction of the cephalic perimeter at birth. ZIKV infects human neural progenitors and impairs the growth of 3D differentiating cultures, such as neurospheres and brain organoids[3,4,5]. Studies using mouse models showed brain growth impairment as a result of ZIKV congenital infection[7,8,9]. Length (D); (E) ZIKV infected brains show a significant decrease in brain weight compared to MOCK brains at P2. (K) ZIKV brains show a significant decrease in cortical thickness compared to MOCK brains; Scale bars A, B = 1 mm; C, D = 500 μm. (L) ZIKV infected P2 brains show a significant decrease in thickness compared to MOCK brains in the cortical progenitor layers, infragranular layers (M) and supragranular layers (N). Disruption of the vascular network has previously been shown to alter neurogenesis and cortical patterning[12]
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