Immune System Suppression Essay Example

normal immune system function, and NSC and NPC proliferation in fetal brains through gene regulation will be outlined, specifically looking at viral protein disruption of neural cell proliferation pathways and the downstream effects of dysregulated genes.

ZIKV is able to proliferate in fetal brains due to gene regulation that acts to suppress the immune system response and change processes of neural growth to actively depress neurogenesis (Shashi et al., 2017). In viral genes expressed after ZIKV infection, changes occurred post-infection in the adaptive immune system enabling sustained viral production (Shashi et al., 2017). In human NSCs, microglia in infected cells expressed fewer antiviral and viral response genes than did uninfected NSCs, increasing the ability for the virus to multiply uninhibited (Shashi et al., 2017). A receptor, Axl, expressed in microglial cells in a developing fetal brain, was found to be important in promoting ZIKV survival against the immune response (Meertens et al., 2017). ZIKV can bind with Axl, and once bound, ZIKV is internalized by endocytosis, enabling ZIKV production. Binding to Axl also activates Axl kinase, which further facilitates ZIKV infection by downregulation of the immune response (Meertens et al., 2017). The deregulation of the immune response establishes high proliferation of the virus, and once at a high viral level, ZIKV then alters neurogenesis processes.

ZIKV infection of the fetal brain leads to inhibition of normal neural development, a process reliant on successful mitotic proliferation of NPCs. Proliferation of NPCs through mitosis is perturbed by ZIKV. The induced abnormalities in mitosis lead to defective cell cycle progression. In fetal mice brains infected with ZIKV, NPC proliferation rates were lower than in uninfected cells due to a decrease

in the number of mitotic cells in growing neural tissue (Cui Li et al., 2016). Infected NPCs entered cell cycle arrest at S-phase, G1 phase, and G2 phase, generating less than normal amounts of NPCs in the M phase of mitosis. This indicates decreased differentiation and development of NPCs (Cui Li et al., 2016). Human induced pluripotent stem cells that underwent neuronal differentiation infected with ZIKV had more than the normal number of centrosomes when compared with uninfected cells, and were unable to complete mitosis successfully (Bruno et al. 2016). The infected cells displaying abnormal centrosome levels displayed defects such as polyploidy, trisomy, and monosomy. These cells had increased rates of cell death (Bruno et al. 2016). This deviation from normal mitotic processes is similar to other growth pathways that ZIKV dysregulates to cause microcephaly.

Zika virus may be able to decrease growth and migration of NSCs during critical periods of fetal brain development through dysregulation of development pathways by ZIKV viral proteins. Two specific viral proteins identified as belonging to ZIKV impair NSC and NPC proliferation pathways important for neurogenesis: NS4A and NS4B (Xuan et al., 2018). The cell-signaling pathway PI3K-Akt-mTOR to induces brain overdevelopment if mutated, but if inhibited, causes underdevelopment of the brain and lead to fetal microcephaly (Xuan et al., 2018). In NSCs from second trimester human fetuses, NS4A and NS4B worked together to suppress the mTOR pathway, thereby inhibiting NSC growth (Xuan et al., 2018). Fetal mouse brains injected with ZIKV containing these viral proteins also demonstrated the downregulation of the expression of the protein doublecortin, a protein important for proliferation of NPCs (Liang Q et al., 2016). The downregulation of

neural cell proliferation through inhibition of important cellular pathways decreases neural tissue growth, and is correlated with increased cell apoptosis pathways.

Cell death is a large contributor to ZIKV-induced microcephaly, and there are several modalities by which apoptosis is increased in developing neural cells. TLR3, a gene highly expressed in early brain development pruning but which decreases as the NPC population differentiates and the brain matures, is increased by ZIKV, instead of decreasing (Dang et al., 2016). This induces a pro-apoptotic pathway in which genes and their associated proteins involved in downregulating NPC proliferation, growth, and migration are allowed to increase abnormal levels in the fetal brain. NTN1 is a gene severely downregulated by the upregulation of TLR3 (Dang et al., 2016). Without this gene, proteins responsible for neural cell death are upregulated, perhaps increasing the degeneration of NPCs in ZIKV infected fetal brains (Dang et al., 2016). In human stem cells differentiated into NPCs, ZIKV increases caspase-3 activation (Tang et al., 2016). Caspase-3 upregulation is attributed to higher levels of apoptosis and lower NPC populations (Tang et al., 2016). These processes of cell apoptosis promotion are another means by which ZIKV causes microcephaly.

ZIKV causes microcephaly in infants born to mothers infected with the virus. ZIKV is transmitted vertically to newborns and suppresses the fetal immune system response, allowing the virus to proliferate. Once at high viral levels, ZIKV changes processes of neural growth to actively depress neurogenesis. Through gene regulation and mitotic inhibition, ZIKV increases NPC apoptosis and decreases NPC migration, resulting in an overall inhibition of neurogenesis and fetal brain development. Together with immune system suppression and depressed brain development, ZIKV produces microcephaly in

infants. There is currently no vaccine for ZIKV, but research done to understand its connection with microcephaly will make it more of a possibility to procure one. Most adults who are infected with the virus are asymptomatic. Therefore, a prevention approach to vaccine development aiming to give protection to women living in infected areas planning to become pregnant is pertinent if cases of microcephaly are to decrease worldwide.