Molecular Fingerprinting of Zika Infected Cells Reveal New Drug Targets

Highlights

• A research team studied the protein expression patterns of human neural cells infected with Zika virus.
• The study found that over 500 proteins were either down regulated or up-regulated due to Zika infection.
• There were changes in gene expression associated with brain cell formation and development which explained symptoms of Zika like microcephaly.

Zika virus (ZIKV) affects cell division and changes the expression pattern of more than a hundred genes associated with the formation and the subsequent development of brain cells. The virus is transmitted by the Aedes mosquitoes and causes symptoms like mild fever, conjunctivitis, joint and muscle pain and skin rash. These symptoms usually occur for a period of 2 to 7 days; however, this virus is also known to cause microcephaly and Guillain-Barré syndrome. This study highlights the mechanisms that could trigger such neurological symptoms.

Though microcephaly is known to be caused by this virus, the cellular changes that lead to the development of this condition has so far been unknown. The principal investigator and researcher of the study Dr. Stevens Rehen who works for the D' Or Institute for Research and Education (IDOR) said that detailing the foundations of Zika virus is a crucial step in developing therapy against the infection.

Depletion of Human Neural Stem Cells:

In an earlier study conducted by Dr. Stevens and colleagues, it was found that the Brazilian strain of the Zika virus that infected human neural cells, lead to the complete depletion of the human neural stem cells when compared with cells that were not infected. This study formed the foundation for the current study as it identified the effect of the Zika viral infection on brain cells although the pathway that lead to the depletion was not identified.

Interactome of Zika Infected Cells:

The research team began to determine the cellular and molecular interactions of the Zika virus in the given cellular network, called the interactome map. Investigating the interactome map would reveal

• the cellular targets of the virus
• the pathway of the infection
• the cellular mechanisms modulated by the virus

An understanding of these factors will aid in identifying potential targets for drug therapy against the virus and could aid in designing better treatment. The microcephaly caused among newborns has been a great cause of concern and an understanding of the mechanisms that contribute to the development of this condition would provide insights into possible mechanisms of prevention.

Molecular Fingerprinting:

Zika virus strain from Brazil was found to be more virulent than other strains of the Zika virus. Therefore in this study, Zika virus strain from a Brazilian patient was isolated and used to infect human neural cells. The infected cells were then organized into 3D aggregates, called neurospheres, which resembled the fetal brain tissue that was normally found during the early stages of brain development. The next step in the research involved understanding the molecular fingerprinting of cells infected with the virus as well as normal uninfected cells by identifying the expression patterns as well as the status of various genes and proteins.

The study found that

• There was an alteration of the expression levels (either down-regulation or up-regulation) of more than 500 proteins in the infected neurospheres when compared with neurospheres of cells that were not infected.
• Some of the proteins that were altered included those that were associated with fixing damage to DNA or those that were involved in maintaining chromosome stability. 
• Certain proteins that were required for the normal cellular growth became silent or did not exert their function in cells that were infected with the Zika virus. This could be the reason behind the early death of cells that were infected with the Zika virus when compared to normal cells.
• The genes that were associated with specialization of cells were also found to become silent among the infected neurospheres. This process occurred before the development of the specialized brain cells which could be one of the factors that contribute to the neurological symptoms associated with this infection.
• The proteins that were required for the multiplication and development of the virus were found to be present in abundance; this is probably a mechanism of invasion that is adopted by the virus to increase its numbers.

The study that is titled "Zika virus disrupts molecular fingerprinting of human neurospheres" and published in the Journal Scientific Reports consists of a complete list of all human proteins which were found to be altered in neurospheres that were infected by the Zika virus.

The first author of the study who is an assistant professor at the Federal University of Rio de Janeiro Dr.Patricia Garcez when asked about the significance of the study findings said that they provided an insight into the molecular mechanisms that were involved in Zika infection that occurred during brain development and provide a clue to some of the consequences that are witnessed in the brain of newborns who are affected by microcephaly.

Zika virus infection was considered a 'public health emergency' by the WHO in 2016 as the number of infected cases began to increase. The most alarming symptom associated with this condition was the development of microcephaly among newborns. This created a stir among pregnant women, with increased alarm, especially in Brazil. The current study highlights the pathways and the proteins that were involved in brain cell infection, providing insights into possible drug targets.

References :

1. Zika virus - (http://www.who.int/mediacentre/factsheets/zika/en/)

Source: Medindia