Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation
Cell Stem Cell Aug 18, 2016 link
Hongda Li5, Laura Saucedo-Cuevas5, Jose A. Regla-Nava, Guoliang Chai, Nicholas Sheets, William Tang, Alexey V. Terskikh, Sujan Shresta, Joseph G. Gleeson 6, 5Co-first author
In Press Corrected Proof, DOI: http://dx.doi.org/10.1016/j.stem.2016.08.005
I had wondered for months why Zika only affected infant brains.
Is appears that Zika also affects adult (mouse) brain cells in 6 days
The study documented huge changes in brain cells
The study did not attempt to measure differences in memory/learning
Since 30 mouse days = 14 human years, it might take 5 years to notice any adult human brain problems
No indication of how often this might occur or if would result in permanent damage
Cannot seem to find out how the mice had compromized immune systems
This is another reason to increase immune system functioning - with vitamin D
Wall St Journal
- “But the findings clearly suggest that Zika may not be as benign an infection for adults—or even children—as currently thought, particularly for those with weakened immune systems, they said.”
- ‘“Zika has the potential to cause damage in the adult brain,” said Joseph Gleeson, adjunct professor and head of the laboratory of pediatric brain disease at New York’s Rockefeller University, and an author on the study.”
Joseph Gleeson is adjunct professor at Rockefeller, head of the Laboratory of Pediatric Brain Disease, and Howard Hughes Medical Institute investigator.
Zika infection may affect adult brain cells, suggesting risk may not be limited to pregnant women Rockefeller University Press Release
- “The mature brain retains niches of these neural progenitor cells that appear to be especially impacted by Zika. These niches—in mice they exist primarily in two regions, the subventricular zone of the anterior forebrain and the subgranular zone of the hippocampus—are vital for learning and memory.”
- “Gleeson and colleagues recognize that healthy humans may be able to mount an effective immune response and prevent the virus from attacking. However, they suggest that some people, such as those with weakened immune systems, may be vulnerable to the virus in a way that has not yet been recognized.”
- . . “raise questions such as: Does the damage inflicted on progenitor cells by the virus have lasting biological consequences, and can this in turn affect learning and memory? Or, do these cells have the capability to recover? Nonetheless, these findings raise the possibility that Zika is not simply a transient infection in adult humans, and that exposure in the adult brain could have long-term effects.”
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No abstract, here is the start of the text
Recent world attention has been drawn to a global Zika virus (ZIKV) outbreak and its link with devastating cases of microcephaly and Guillain-Barre syndrome. ZIKV infection is spreading rapidly within the Americas after originating from an outbreak in Brazil (Campos et al., 2015). Mounting evidence suggests that ZIKV infection in pregnant women can cause congenital abnormalities as well as fetal demise (Calvet et al., 2016, Cugola et al., 2016, Miner et al., 2016, Wu et al., 2016). Initial case descriptions of microcephaly and spontaneous abortions have been supported by evidence of viral RNA and antigen in the brains of congenitally infected fetuses and newborns (Martines et al., 2016, Mlakar et al., 2016).
The radial-glial-derived cortical neural stem cells (NSCs) in the fetal brain appear to be especially impacted by ZIKV infection, either through greater susceptibility to the viral infection or virus-induced cytotoxicity. This same population is affected by inherited forms of microcephaly, suggesting that loss of these cells is responsible for the microcephaly after ZIKV infection. Indeed recent work demonstrated that ZIKV can infect human cortical NSCs and attenuate their growth and survival, when applied directly to either monolayer culture (Tang et al., 2016) or cerebral organoids or neurospheres (Dang et al., 2016, Garcez et al., 2016, Nowakowski et al., 2016, Qian et al., 2016). Vertical transmission from ZIKV-infected murine dams to fetuses yielded virus in brain and histopathological evidence of cytotoxicity, supporting direct infection of NSCs. Effects of ZIKV on the placenta and secondary effects on brain may have also contributed (Miner et al., 2016).
Many vector-borne flaviviruses have to overcome host type I IFN responses to replicate and cause disease in vertebrates. Wild-type mice are resistant to parenteral infection with dengue virus (DENV), and unlike in human cells where the virus is able to block type I and type II IFN receptor signaling, murine cells do not show the same block (Aguirre et al., 2012, Ashour et al., 2010, Yu et al., 2012). Therefore, similar to DENV mouse models, current ZIKV models utilize mice lacking one or more components of the IFN signaling. These models include the use of the IFN regulatory factor (IRF) transcription factors IRF-3, -5, and -7 triple knockout strain (aka IRF-TKO) (Zellweger and Shresta, 2014), which lacks type I IFN production. These mouse models appear to reproduce key features of human ZIKV infection, including viremia and neuronal tissue tropism, and are proving to be valuable for answering fundamental questions about ZIKV pathogenesis.
In the adult brain, neurogenesis contracts after birth to just the anterior subventricular zone (SVZ) of the forebrain and the subgranular zone (SGZ) of the hippocampal dentate gyrus. These restricted niches contain progenitor cells that divide to produce neurons or glia, depending upon intrinsic and environmental cues. Neurogenic niches are characterized by a comparatively high vascular density and proximity to cerebrospinal fluid (CSF) (Stolp and Molnar, 2015), allowing not just communication through signaling molecules but also proximity to circulating viruses.
To identify direct target cells of ZIKV in the adult CNS, we infected 5- to 6-week-old Irf3?/? Irf5?/? Irf7?/? TKO mice with an Asian lineage ZIKV strain (FSS13025, 2010 Cambodian isolate) via retro-orbital injection (see Supplemental Experimental Procedures for section of strain rationale). Retro-orbital injection was selected as a method to introduce virus into the peripheral circulation, rather than direct introduction into the brain, to model the blood-borne route of arbovirus transmission. In results similar to those of a previous report, TKO mice were vulnerable to ZIKV infection (Lazear et al., 2016) and began to exhibit ruffled fur and lethargy as evidence for viral illness by 3–4 days post-infection (DPI) and developed evidence of hindlimb weakness by 6 DPI.
To examine the potential for virus infection in the brain, we screened serial coronal sections of whole brain from infected and mock-treated mice with the monoclonal 4G2 antibody that reacts with the flavivirus-specific family envelope protein. We observed dramatic immunoreactivity in proximity to the SVZ of the anterior forebrain, as well as the SGZ of the hippocampus (Figures 1A–1C), the two regions in mouse that maintain stem cell populations throughout adulthood, in infected (but not mock-infected) mice. In contrast there was less immunoreactivity in other regions of the brain under these conditions (Figures S1A–S1C), suggesting a particular tropism of the virus for proliferative regions of the brain. Quantification across major brain regions showed statistically significant selective vulnerability to these proliferative zones (Figure S1D).
In adult SVZ and SGZ, radial-glia-like NSCs give rise to intermediate progenitor cells (IPCs), which then migrate to final destinations, where they express developmental-dependent markers and integrate into neuronal circuitry (Figure 1D, see Supplemental Information). For the remainder of this paper, neural progenitor cell (NPC) is used to refer to both NSCs and IPCs. To identify which cells were positive for 4G2, we co-stained them with different cell type markers. We detected the presence of ZIKV in GFAP- and Nestin-expressing NSCs, SOX2-expressing IPCs, and DCX-expressing immature neurons (Figures 1E–1J). 4G2 reactivity in sagittal sections confirmed ZIKV-infected DCX+ cells along the rostral migratory stream (Figure S1E). Consistent with previous reports where ZIKV was introduced directly into newborn and juvenile brain (Bell et al., 1971), we detected 4G2 reactivity in NeuN-expressing neurons and S100β-expressing astrocytes (Figures S2A–S2D), but much less than that in SOX2+ or DCX+ cells (Figures S2F and S2G). We rarely observed 4G2 reactivity in NG2-expressing oligodendrocytes (Figures S2E). We conclude that ZIKV has tropism for proliferative NPCs and immature neurons over terminal-differentiated cell population in the adult brain.