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Discuss the evidence that Zika virus infection causes congenital brain abnormalities and Guillain-Barré syndrome
Zika Virus (ZIKV) is an arthropod-borne RNA virus, transmitted by the bite of infected mosquitoes, primarily by Aedes mosquitoes species and is transmitted to humans via unprotected sex, blood transfusions, and vertical transmission through babies and infected pregnant women (Gubler & Musso, 2016). When a healthy mosquito bites an infected human ZIKV replicates in the salivary glands of mosquitoes and the virus passed down the transmission cycle (Kublin & Whitney, 2018). The incubation period (the time from exposure to symptoms) of ZIKV is about 15 days but these symptoms are generally mild and difficult to detect (Gubler & Musso, 2016). ZIKV destroys the neurones in the brain, WHO reported large numbers of adults with Guillain-Barré syndrome (GBS) and babies born with microcephaly (WHO, 2017). Recent studies suggest that ZIKV travels from the placenta of infected mothers to damage the neurones in the foetal brains (Wen, et al., 2017). Infection of the brain occurs during early stages of development and in natal/neonatal of maturation (Van den Pol, et al., 2017). There is strong evidence supporting the link between ZIKV causing congenital brain abnormalities and GBS.
ZIKV targets and destroys neuronal progenitor cells (NPCs can differentiate and proliferate into any type of cell in the brain) in the developing brain and activates innate immune response resulting in increased apoptosis (cell death), disrupted cell cycle, decreased number of cells, and decrease in specialized cell types (Wen, et al., 2017). Damage to neurones in foetal brains leads to neurological syndromes associated with ZIKV including GBS, acute myelitis (affects the spinal cord with acute onset of autonomic, motory, and sensory dysfunction – Donovan & DePiero, 2017), encephalitis (acute inflammation of the brain – Kennedy, et al., 2017) and brain ischemia (Gebre, et al., 2016).
Microcephaly is the most common congenital neurological disorder caused by ZIKV that reduces brain size and intellectual functioning (learning, reasoning, problem solving), social/practical skills as the brain develops (Wen, et al., 2017). Figure 1 shows a normal infant on the left and the progression of microcephaly from moderate to severe to the right. On average, the typical head size decreases in circumference from moderate to severe in infants infected with ZIKV.
Figure 1. Infants with moderate or severe microcephaly associated with ZIKV (Petersen, et al., 2016)
ZIKV is transmitted from infected mothers to foetal brains and more NPCs are destroyed causing decreased head size, such as microcephaly. Foetal ultrasound scans can detect microcephaly at early stages of development after infection of ZIKV. To prove that ZIKV causes microcephaly in babies, Wang & Ling (2016) carried out a cohort study on 88 pregnant women using ultrasound and found 72 were positive for ZIKV infection. ZIKV locates the infant and destroys the NPCs. The ultrasound detected microcephaly in 42 ZIKV-positive women before birth. This is clear evidence that microcephaly is caused by ZIKV infecting the foetal brains and this can be detected early using ultrasound imaging to detect any brain abnormalities.
According to a study by Besnard, et al. (2017), 1501 infants in Brazil are suspected of congenital ZIKV. They reported microcephaly at birth. Mostly these symptoms described are congenital (brain abnormality present from birth) and showed symptoms of ZIKV infection. Infection of ZIKV in placenta and glial cells, including microglia and astrocytes (different subtypes of glial neurones) in the brain lead to placenta unable to deliver enough oxygen and nutrients to the foetus (Wen, et al., 2017). The brain cells are unable to carry out normal metabolism and cellular functions; these cells start to die.
ZIKV can cause neurological disease, such as GBS and microcephaly through direct infection of cells. In the foetus, ZIKV can infect NPCs, leading to microcephaly. In adults, NPCs get infected and decreases the population of NPCs the brain (Li, et al., 2016). An international study by Méndez, et al. (2017) reported “108,087 people in Columbia all infected with the ZIKV, including 19,963 in pregnant women, 710 associated with microcephaly, 453 ZIKV associated to GBS cases and the remaining are still infected.” ZIKV can infect pregnant women, the foetus and anyone who are either healthy or immunocompromised. This evidence states that ZIKV can infect anyone but targets/destroys the NPCs in the brain and this causes most damage to the foetus in pregnant women because all infected babies develop brain abnormalities.
Reverse-transcription polymerase chain reaction (RT-PCR) is the most preferred method in identifying ZIKV via urine analysis and serum samples from ZIKV infected patients. An example of this is the study carried out by Rozé, et al. (2017), using urine RT-PCR analysis, confirmed 17 cases of the most recent ZIKV infections. RT-PCR method is widely available and has been used in many studies because of its reliability and accuracy in results (Lamb, et al., 2018).
In another major study by Li, et al. (2016) involved mice models infected with ZIKV and real-time RT-PCR of their brains, they identified the infected NPCs as a direct cause of microcephaly. Results showed that when ZIKV infected NPCs caused the following: viral replication in embryonic mouse brain cells, increased cell death, induced immune response and deregulation of microcephaly associated genes. The role of ZIKV in destroying brain cells is the result of infection which leads to brain damage and permanent loss of the functions of NPCs.
The increase in number of GBS cases during ZIKV outbreak provides evidence for the link between ZIKV infection and GBS (Caro-Artal, 2018). GBS is a neuromuscular disorder that causes respiratory difficulties (ZIKV infection causes paralysis to the muscles that control breathing), progressive weakness (due to impaired functioning of muscles), and pain. GBS is caused by an infection, such as the ZIKV which leads to myelin destruction in neurones (Wijdicks & Klein, 2017). Also, GBS is aserious autoimmune disorder (where the immune system attacks healthy neurones) with a 5% death rate and up to 20% of patients are left with a significant disability (Gebre, et al., 2016).
To prove that ZIKV is the cause of GBS, Mécharles, et al. (2016) conducted a case study report on an immunocompromised patient whom initially had no symptoms of ZIKV infection. As infection goes unnoticed and continues replicating, there is a loss of temperature sensation below the thoracic region of the spine, an indication of acute myelitis. RT-PCR analysis confirm ZIKV infection in the cerebral spinal fluid. Microscopic examination of the central nervous system (CNS) reveals inflammation because of the CD8+ T-Cells (or cytotoxic T cells) and accumulation of cytokines (Schwartzmann, et al., 2017). CD8 is a co-receptor on T-cells that recognise MHC (major histocompatibility complex) class I molecules on the neurones that are infected and these cytotoxic T cells secrete cytokines, damaging the neurones (Murphy & Weaver, 2017). The patient suffered from GBS as well as encephalitis because of onset infection has damaged the myelin and the immune system attacks healthy nerve cells. The presence of ZIKV in the cerebrospinal fluid of a patient infected with ZIKV suggests that the virus might be neurotropic (Mécharles, et al., 2016). This case study provides strong evidence of ZIKV causing GBS because the virus exhibits neurotropism to neurones in the CNS but initially the patient developed no symptoms and then the innate immune response caused inflammation which resulted in damage to the neurones because the virus had already destroyed the myelin; ZIKV remained undetected by the immune system.
Neurotropic viruses, such as ZIKV can invade and infect the CNS which includes the spinal cord and brain. Neurotropic viruses enter the CNS through peripheral nerves or by crossing the blood-brain barrier (Luethy, et al., 2015). There is strong evidence to support that ZIKV is neurotropic because ZIKV enters through the CNS and damages the neurones in the brain causing microcephaly or GBS. There is a relationship between ZIKV and neurotropism to neurones in the brain. Huang, et al. (2016) injected ZIKV into the brain of mice. Results showed large increases in apoptosis of neurones in the spine. The neurones in the spine are a cell type implicated in microcephaly, therefore the mice had microcephaly because the cells that regulated this condition have been destroyed by the virus.
To better understand the mechanisms of ZIKV and its effects, Kumar, et al. (2016) analysed the RNA sequence from ZIKV involved in targeting neurones in the brain. The research examined the role of retinoic acid response element (RARE) in RNA sequence of ZIKV strains. Method involved RARE sequences inserted into host DNA after reverse transcription. Results indicated disruption in brain development causing microcephaly. The RARE in RNA sequence from ZIKV causes brain abnormalities because RNA contains specific instructions to produce proteins that target the neurones in the brain.
ZIKV RNA is found in the brain cells of all infected patients and the proteins produced destroy these cells. Segments of RNA from the ZIKV encodes for the proteins NS4B and NS4A which inhibit the Akt-mTOR signalling pathway in neural stem cells (NSCs are cells that differentiate into neurones and glial cells, unlike NPCs) in the foetus (Jun, et al., 2017). Akt-mTOR signalling pathway controls programmed cell death and is a key pathway for neural development (Liang, et al., 2016). ZIKV infection of foetal NSCs causes inhibition of the Akt-mTOR pathway, leading to defective neuropathogenesis (development of disease of the nervous system) and activation of programmed cell death. NS4A and NS4B suppress the Akt-mTOR pathway and stops the cell-cycle because of DNA damage. Proteins target the DNA of the host NSC for post-translational modifications which modifies the DNA sequence to take control of the infected cell and produce more viral proteins (Liang, et al., 2016). These viral proteins target other neurones and the process repeats, until all these cells are destroyed. Therefore, the RNA of ZIKV plays a pivotal role in neurotropism because all the evidence supports the fact that ZIKV targets/destroys the NPCs and NSCs in the foetus.
Overall, ZIKV causes microcephaly and GBS in most cases with congenital brain abnormalities, but also causes encephalitis and acute myelitis which are rare neurological congenital conditions identified in few cases.Infected NPCs become viral factories to produce more viral particles, leading to an increasing number of infected cells over time (Qian, et al., 2017). After destruction of NPCs, there is permanent damage and loss of function of neuronal cells. The case study conducted by Mécharles, et al. (2016) on an immunocompromised patient provides strong evidence that ZIKV causes GBS because ZIKV is a neurotropic virus. ZIKV must be a neurotropic virus because all the evidence supports ZIKV targets only the neurones, specifically the NPCs and no other cells in the body. This explains why ZIKV causes congenital brain abnormalities because foetal brains are more susceptible to infection as the virus progressively destroys these neurones. According to the WHO situation report of ZIKV spread, 31 countries reported microcephaly and 23 countries reported increased incidence of GBS. WHO also states that global risk assessment has not changed and ZIKV continues to spread (WHO, 2017). There is strong evidence that proteins produced from ZIKV destroy brain cells and cause brain abnormalities, as mentioned, RARE sequences from ZIKV inserted into host DNA causes disruption in cell signalling and in brain development. The proteins NS4B and NS4A play a pivotal role in inhibiting the Akt-mTOR signalling in neural stem cells and causes cell death.
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