The Agent

Zika virus (320x240)
credit: CDC/ Cynthia GoldsmithA colorized transmission electron micrograph of Zika virus. Virus particles (in blue) are 40 nm in diameter with an outer envelope and a dense inner core.

Zika virus, first identified in 1947 in Uganda, had been thought to produce a rare and mild disease until it suddenly emerged in Brazil in 2015 and spread explosively through South America, Central America, and the Caribbean. The virus arrived in the United States in the summer of 2016. 

Zika virus is transmitted primarily by mosquitoes that thrive in tropical climates and urban areas. The virus can cause Zika virus disease. In most cases Zika virus disease is a mild illness, but Zika virus can cause a serious birth defect known as microcephaly, in which babies have abnormally small heads and symptoms that range from mild developmental delays to a fatal condition. Zika virus can also cause a neurologic condition in adults known as Guillain-Barre syndrome that results in muscle weakness or even paralysis in the worst cases. 

Classification

Zika virus is a member of a family of viruses known as Flaviviruses. This is the same family to which dengue virus, yellow fever virus, and West Nile virus belong. Flaviviruses are enveloped viruses that contain genomes which consist of nonsegmented single-stranded positive-sense RNA. The viruses are transmitted to humans by infected mosquitoes.

Zika virus and the other flaviviruses are part of a larger group of viruses termed arboviruses (for arthropod-borne). The defining characteristic of these viruses is that they are transmitted to humans via the bite of infected arthropods, most commonly mosquitoes and ticks. They are maintained in nature through a complex cycle in which they rotate between a vertebrate animal host and a blood-feeding vector that carries the virus from one host to another. Another recently emergent arbovirus is chikungunya virus, which belongs to the Alphavirus family.

Transmission

A female Aedes aegypti mosquito in the process of acquiring a blood meal from a human host. (320x240
credit: CDC - Prof. Frank Hadley CollinsA female Aedes aegypti mosquito in the process of acquiring a blood meal from a human host.

Zika virus is transmitted through the bite of an infected female mosquito. Two types of Aedes mosquitoes are capable of transmitting Zika virus – Aedes aegypti and Aedes albopictus. These are the same species that spread dengue and chikungunya viruses. Aedes aegypti, which is found in tropical and subtropical regions, is the primary transmitter of Zika virus. Initially thought to be present only in 12 states in southern coastal areas of the United States, Aedes aegypti has now been found in about 30 states. Aedes albopictus can survive cooler temperatures and is found in over 30 states, but it may not be playing an important part in spreading Zika virus currently.

Mosquitoes become infected when they bite a person who is infected with the virus. The virus has to replicate and spread within the mosquito for it to be infectious to the next person the infected mosquito bites, and thus the virus spreads.

There is evidence that Zika virus can be transmitted through sexual contact, although this transmission route is much less common than spread via the bite of infected mosquitoes. The first known case of transmission within the United States resulted from sexual contact between a person who had traveled to Venezuela and a female partner in Dallas, Texas who had not traveled to any region where Zika is present. Male-to-male transmission has also been reported.

Additionally, there are reports of person-to-person transmission through an unknown route, although these cases are rare. Zika viral RNA has been detected in the saliva and urine of patients, but it is not clear if the virus can be transmitted through those fluids. 

Symptoms

Baby with microcephaly (320x240)
credit: Centers for Disease Control and PreventionBaby with microcephaly

Most people who become infected with Zika virus do not experience any symptoms. About one in five people will become sick, usually with a mild illness whose common symptoms are a mild fever, skin rash, joint pain, and conjunctivitis. The symptoms generally begin a few days after a bite from an infected mosquito and last about two to seven days. Because symptoms may be nonexistent or similar to other viruses (such as dengue virus), many people might never realize they have been infected with Zika virus.

In pregnant women, there is a much graver risk from Zika virus infection. In Brazil, an explosive epidemic of a condition known as microcephaly has been correlated with the outbreak of Zika virus. Microcephaly is an uncommon disorder in which a baby’s head is much smaller than normal due to abnormal brain development while in the womb or shortly after birth. Babies with this condition will often experience developmental delays later in life and some may have vision defects including blindness. The problems affecting babies with microcephaly can range from mild to severe and can sometimes be life-threatening. 

Microcephaly can be caused by a number of genetic and environmental factors, including Down syndrome and fetal exposure to a variety of toxins. However, the number of microcephaly cases in Brazil since the Zika virus outbreak began is about twenty times higher than normally would be expected. Such a congenital malformation has not been seen with any other flavivirus or other arthropod-borne virus.

Although experts were initially cautious about ascribing the cause of microcephaly to Zika virus, the link was strengthened by studies that detected the presence of Zika virus in the amniotic fluid and brains of microcephalic babies. Laboratory studies have further shown that Zika virus can infect and kill human fetal brain cells growing in cell culture and also in mice. By April 2016, the body of accumulated evidence was strong enough to arrive at a scientific consensus that Zika virus causes microcephaly. A large study of pregnant women in Columbia, where the viral outbreak peaked in February and where many women are due to give birth in the coming months, is expected to provide additional confirmation. 

Another complication of Zika virus is Guillain-Barre syndrome, a rare condition in which the body’s immune system attacks part of the nervous system. Symptoms include muscular weakness and tingling in the arms and legs. In the most severe cases, a person may be almost completely paralyzed and the respiratory muscles affected, and the patient will require hospitalization. Most people recover, but some may continue to experience some degree of weakness. This syndrome can be also be caused by a number of other viruses.

Zika virus disease is usually diagnosed based on symptoms, prior mosquito bites, and travel history. In some cases, infection is confirmed through laboratory testing using a polymerase chain reaction-based test and isolation of the virus from blood samples. 

Outbreaks

Zika virus world map, Sept. 2016 (320x240)
credit: CDCMap of active Zika virus transmission, as of Sept. 2016

Zika virus was first isolated in 1947 in the Zika Forest of Uganda (named after the word Zika which means "overgrown" in the local language) from a rhesus monkey during a survey to detect yellow fever infections in primates. It was subsequently identified in humans in 1952 in Uganda and Tanzania. Over the next couple of decades, there was evidence of human infections in other African countries, including an outbreak in Nigeria in 1973; human infections were also reported in countries in Asia.

The first known large outbreak of Zika virus occurred on remote Yap Island in the Pacific Ocean in 2007, with an estimated number of 5,000 cases of mild disease. This was followed in 2013-2014 with an outbreak in French Polynesia, with an estimated number of 20,000 cases. It was during this outbreak that an unusual increase in the number of Guillain-Barre syndrome cases was first noted.

The current Zika virus outbreak began in Brazil in 2015 (although the virus was probably introduced into the country some time in 2014), and it spread rapidly to many other countries in South America, Central America, and the Caribbean. Since the current outbreak began, around 60 countries and territories have for the first time reported Zika virus transmission; including prior outbreaks, a total of 73 countries have experienced Zika virus transmission since 2007.

It is estimated that approximately 500,000 cases of Zika virus infection have occurred in Brazil, although exact numbers are not known because of the difficulty in keeping track of the large number of cases and the fact that many infections go unnoticed. After Brazil, Columbia has been the most affected country with around 20,000 estimated cases.

More than 1,500 cases of microcephaly or other fetal abnormalities linked to Zika virus have been reported in Brazil. The first cases of Zika-associated microcephaly were detected in Columbia in April 2016. Altogether, microcephaly and other central nervous system malformations thought to be associated with Zika virus infection have been reported in 31 countries. An increased incidence of Guillain-Barre syndrome has been reported in 23 countries.

Zika Virus in the United States

As of September 2017, more than 5,400 cases of symptomatic Zika virus disease, that resulted from travel to areas where Zika virus infected mosquitoes were present, have been reported in the United States. Travel-associated cases have been reported in all states except Alaska. The highest number of cases is in New York and Florida, followed by California and Texas. Of these cases, 46 were sexually transmitted.

Approximately 2000 pregnant women have had laboratory evidence of Zika virus infection, with nearly 100 cases of birth defects or pregnancy losses tied to Zika infection. Some of these pregnant women have not yet given birth and continue to be monitored.

Local transmission of Zika virus has been occurring in the U.S. territories of Puerto Rico, American Samoa, and the U.S. Virgin Islands since the beginning of 2016. Over 37,000 infections have been acquired locally in these territories, almost all in Puerto Rico; over 4,000 pregnant women have had laboratory evidence of infection. 

The first cases of Zika virus infection by mosquitoes within the United States, that did not involve travel, were reported in July 2016. The initial cases were limited to one neighborhood in Miami, Fla.; several weeks later local transmission was reported in a second neighborhood in the Miami area, the South Beach area that is popular with tourists. Locally acquired cases have also been reported in the Brownsville area of Texas.

By the end of 2016, there were 224 laboratory confirmed cases acquired through local mosquito transmission. With the exception of 6 cases in Texas, all of the remaining cases occurred in Florida.

From January through August 2017, there have been approximately 230 travel-associated cases of infection reported in the United States, but none that were acquired as a result of local mosquito-borne transmission.

The Problem

Distribution of Aedes mosquitoes (320x240)
credit: CDCDistribution of the Aedes aegypti mosquito in the United States as of April 2016

Spread of Zika Virus

Zika virus has emerged in the Americas, without warning, and is spreading rapidly. Cases have been reported in over 55 countries, and it is expected that Zika virus will continue to expand its range into additional regions where the Aedes mosquitoes are found, including areas of the United States. The mosquitoes that transmit Zika virus are present in about 30 states during the warmer months, so much of the United States is potentially at risk with Florida and Texas considered among the highest risk states especially in poor, urban neighborhoods.

Zika virus has been spreading locally in the U.S. territory of Puerto Rico since the beginning of 2016 and began spreading locally in the United States in the summer of 2016. The CDC took the unusual step of advising pregnant women to avoid travel to areas of Miami-Dade county in Florida where Zika virus was transmitted by local mosquitoes.

Widespread infection by Zika virus was worrisome because the virus had not previously existed in the Americas, and therefore virtually no one was immune to the virus; there existed the potential for millions of people to become infected. One study estimated that approximately 90 million people could become infected during the first wave of the epidemic, including about 1.65 million childbearing women and potentially affecting tens of thousands of pregnancies. 

As with other mosquito-borne diseases, the outbreak in the United States and Europe has been less extensive than in the developing countries afflicted by Zika virus, at least in part due to better surveillance, mosquito control, and healthcare infrastructure.

Zika Virus Complications

The full range of symptoms and complications that can be brought about by Zika virus is not completely established yet because in the past there has not been an outbreak involving as many people. However, based on the present and growing body of scientific research, experts have confirmed that Zika virus can cause microcephaly in babies born to Zika-infected pregnant women. The risk to the fetuses of infected pregnant women appears to extend throughout pregnancy and not only during the first trimester as initially thought. This is the first time that a birth defect has been attributed to the bite of an virus-infected mosquito.

Although scientists had not formally confirmed a link between Zika virus infection and microcephaly at the time, the strong correlation prompted the World Health Organization to declare a global health emergency Feb. 1, 2016. This is a rare move for the WHO, and it signaled that the Zika virus outbreak is considered to be serious. Pregnant women have been advised not to travel to countries where Zika virus is circulating and in an unprecedented move, health authorities in several countries affected by Zika virus have urged women to delay having children. In June 2016, the WHO issued new guidelines that advise pregnant women living in areas where the disease is spreading to consider delaying pregnancy to avoid having babies with birth defects. 

Treatment and Prevention

There is currently no cure for Zika virus disease and no drugs to treat it. Scientists have begun the process of developing a vaccine, but it is expected to take years to develop one that would be widely available.

For now, mosquito control is considered the best way to prevent infection and combat Zika virus. This includes personal protection measures when outdoors such as minimizing exposed skin and using mosquito repellents that contain DEET and by eliminating places in which the Aedes mosquitoes can breed such as outdoor containers that collect pools of stagnant water. However, this can be a challenging undertaking especially in densely populated areas and less developed countries, and people living in places without window screens and air conditioning are at higher risk.

Transmission Concerns

The realization that Zika can be transmitted not only by mosquitoes but also through sexual contact, even if it is a relatively rare occurrence, further complicates the containment of the virus.

The possibility of transmission through blood transfusions is an additional concern. In August 2016, new guidelines were issued in the United States for the screening of donated blood at blood collection centers. Although there is currently no licensed test to screen potential blood donors, newly available tests have begun to be used in some states.

As with other large viral outbreaks, there is always the concern that the virus could mutate into a form that increases its transmission rate or ability to cause disease. 

The spread of Zika virus, as well as other emerging Aedes mosquito-transmitted diseases, such as dengue and chikungunya, is due in part to man-made factors. Urbanization and possibly climate change create additional environments for the Aedes mosquitoes to live and breed, and human migration facilitates the spread of viruses around the globe. Air travelers can easily spread viruses when they become infected in one country and then board a plane to travel to another country and pass on the virus. Because the majority of Zika virus-infected people do not have any symptoms, it is not possible to detect infected people entering a country.

The Research

Although Zika virus was discovered in 1947, there is been little research conducted on the virus because until recently it was considered an obscure virus that caused only sporadic and relatively mild illness in Africa and Southern Asia. With the jump into the Americas, the large increase in the number of human cases, and the link to more severe illness, research into Zika virus has taken on a much greater importance and urgency.  

Dr. Rebecca Rico-Hesse, professor of molecular virology and microbiology, and her colleagues are involved in a number of experiments to isolate and analyze Zika virus samples to learn more about the virus and how it replicates. They would also like to determine the potential for transmission of Zika virus in mosquitoes collected in the Houston area. 

In one published study, Drs. Rico-Hesse, Jason Kimata, and their colleagues investigated the host cell types and entry factors that aid in mediating the sexual transmission of Zika virus. They infected two types of human prostate cells - stromal cells and epithelial cells - with three isolates of Zika virus that were obtained from persons infected in the Americas. Using a variety of techniques, they found that prostrate cells express several well-characterized factors used by flaviviruses to attach to cells, and that Zika virus, but not dengue virus, can infect and replicate in these cells. The results indicated that Zika virus can infect prostate stromal mesenchymal stem cells, epithelial cells, and organoids made with a combination of these cells. They further found that Zika virus appears to favor infection of prostrate stromal cells over epithelial cells; this could possibly indicate a preference for infection of stem cells in general. Overall, the results of this study suggest Zika viral replication occurs in the human prostate, and can account for the secretion of Zika virus in semen, thus leading to sexual transmission.

The long-term goals of research on Zika virus include developing more accurate tests to detect the virus in infected people (current tests have limitations in that they detect only recent infections or detect infections with other related viruses), obtaining more knowledge about the transmission paths of the virus, understanding how the virus causes disease, and developing a safe and effective vaccine against Zika virus.