Drosophila study contributes to understanding molecular mechanisms related to Zika virus-associated microcephaly

Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly

Nichole Link, Hyunglok Chung, Angad Jolly, Ghayda M. Mirzaa, James R. Lupski, Hugo J. Bellen
Published:November 14, 2019
DOI:https://doi.org/10.1016/j.devcel.2019.10.009

Summary: "The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division."

Drosophila used in study of receptor for entry into cells of disease-causing viruses

Zhang R, Earnest JT, Kim AS, Winkler ES, Desai P, Adams LJ, Hu G, Bullock C, Gold B, Cherry S, Diamond MS. Expression of the Mxra8 Receptor Promotes Alphavirus Infection and Pathogenesis in Mice and Drosophila. Cell Rep. 2019 Sep 3;28(10):2647-2658.e5. doi: 10.1016/j.celrep.2019.07.105. PubMed PMID: 31484075; PubMed Central PMCID: PMC6745702.

From the abstract: "Mxra8 is a recently described receptor for multiple alphaviruses, including Chikungunya (CHIKV), Mayaro (MAYV), Ross River (RRV), and O'nyong nyong (ONNV) viruses. ... Ectopic Mxra8 expression is sufficient to enhance CHIKV infection and lethality in transgenic flies. ... targeting this protein may mitigate disease in humans."

Studies in Drosophila help reveal how Dengue and Zika virus cause disease

Shah, et al. (2018) Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis. Cell 175(7):1931-1945.e18

Graphical abstract for this report in Cell
from the Bellen, Andino, & Krogan labs

Summary: "Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms."

Note: when available from PubMed, the full author list and PubMed ID will be added.

Fly cell study identifies conserved host cell factors related to West Nile Virus infection

Yasunaga A, Hanna SL, Li J, Cho H, Rose PP, Spiridigliozzi A, Gold B, Diamond MS, Cherry S. Genome-Wide RNAi Screen Identifies Broadly-Acting Host Factors That Inhibit Arbovirus Infection. PLoS Pathog. 2014 Feb 13;10(2):e1003914. PMID: 24550726; PMCID: PMC3923753.


From the abstract:  "Investigation of two newly identified factors that restrict diverse viruses, dXPO1 and dRUVBL1, in the Tip60 complex, demonstrated they contributed to antiviral defense at the organismal level in adult flies, in mosquito cells, and in mammalian cells. These data suggest the existence of broadly acting and functionally conserved antiviral genes and pathways that restrict virus infections in evolutionarily divergent hosts."