A DNA-based view reveals hidden Zika spread

by Colin O’Leary
figures by Rebecca Clements

News of viral epidemics spreads faster than the viruses themselves. Once the virus arrives, how do we determine where it came from? How do scientists monitor the arrival and spread beyond keeping track of the number of cases at a given time? Instead of sifting through medical records in search of the first infected person—the elusive “patient zero”—studying the genome, or the genetic material, of a virus provides insight into how viruses can start spreading before we even know that they’ve arrived. Moreover, studying the genomes of emerging viruses helps scientists understand how these viruses are able to circulate undetected in a population for weeks or months, laying the groundwork for the epidemics that we’ve heard so much about.

Clinical cases and viral DNA can track viral spread

When one considers the spread of a virus, it is easy to think of a one-way, branching arrow that broadly defines the locations and pathway of spread. Prime examples of this pattern include the recent movement of Zika virus up from Brazil to the Caribbean and then into the United States. However, when considering the spread of a virus and the factors that lead to where and how quickly it spreads, such a map does not offer all of the necessary information.

Genomic approaches, however, which study the genetic material of viruses, can accomplish these feats. These studies involve the sequencing of entire genomes, which is analogous to spelling out all of the words of a novel. Genomic studies can be used to peer into the genetic code of viruses, and have also been used in studies of other organisms like yeast and humans. With viruses, the genome sequences can be compared to find changes (known as mutations) between them; to extend our book analogy, mutations are like typos in the words that tell the story (Figure 1). Scientists then study these mutations to determine if and how they help the virus spread. Small pieces of DNA can also act as genetic beacons for tracking a virus as it travels, similar to how a package can be tracked from warehouse to doorstep. As will be discussed below, scientists recently used the changes that they identified between Zika virus samples to map the spread of Zika throughout the Americas.

Figure 1: Mutations are like typos. Genomes are like books written in only four letters: A, T, G, and C. When a mutation occurs, these letters get mixed up and passed along to future generations. Therefore, scientists can study these genetic “typos” to track the spread of viruses over time and around the world. — *Figure 1:* Mutations are like typos. Genomes are like books written in only four letters: A, T, G, and C. When a mutation occurs, these letters get mixed up and passed along to future generations. Therefore, scientists can study these genetic “typos” to track the spread of viruses over time and around the world.

When tracing the path of a viral disease, the primary difference between mapping clinical cases and studying viral genomes is sensitivity, which is the ability to tell whether a symptom (such as a fever) is actually the result of an infection. Consider the symptoms that most viruses cause. Yes, there are the frightening symptoms (e.g. hemorrhagic fever and microcephaly) that come to mind, but most viral infections cause “flu-like symptoms” that include malaise, fever, and headaches, or they can be asymptomatic; you may remember that the vast majority of Zika infections caused no symptoms. When tracking the spread of an emerging (or re-emerging) virus, the difficulty in defining clear-cut cases of viral infection makes it challenging to establish paths of transmission and define affected areas.

Genome sequencing reveals hidden Zika spread in Florida

Genomics can reveal what the infection-tracking maps cannot. In a study on Zika spread in the Americas, researchers determined that, in several cases, Zika virus was circulating in areas months before the first cases were officially diagnosed in those regions. By examining the genomes of Zika virus samples from across the Americas and how they changed over time, researchers were able to determine how long it took the viruses that they found to evolve from the original strain of the virus. For example, if these models predict that a virus that existed in a population in Florida would have taken five months to evolve, but the first clinical case occurred nine months later, then the virus likely circulated undetected for four months. Importantly, this is not the only incident where viruses arrived long before we detected them. Other studies showed that the same phenomenon that was observed with Zika spread also applied to Chikungunya virus.

Additionally, genomics can tell us more about viral spread than just the timing. Viral spread is commonly presented in the media through the “patient zero” model. During the Zika epidemic, the biggest headlines surrounded the first cases in Puerto Rico, Florida, and eventually Massachusetts. The question that is often asked is which patient introduced the virus to an area? While there is always a single patient zero from the perspective of counting clinical cases, viral genomics tells us that the reality is much more complicated; there are often several patient zeroes (Figure 2). For example, in the case of the 2016 Zika epidemic in Florida, it is now believed that at least four, and potentially forty, different patient zeroes existed. By sequencing Zika virus genomes from individual patients and seeing how they differed, researchers concluded that the viruses in some Zika patients in Florida were clearly different from others, which indicated that they came from unique viruses.

Figure 2: Diagraming the “Patient Zero” model. The image on the left shows a scenario in which a single patient, “patient zero” (red circle), is the original source of all subsequent infections (black circles). The image on the right shows how multiple patient zeroes can be responsible for spreading a disease throughout the population. — *Figure 2:* Diagramming the “Patient Zero” model. The image on the left shows a scenario in which a single patient, “patient zero” (red circle), is the original source of all subsequent infections (black circles). The image on the right shows how multiple patient zeroes can be responsible for spreading a disease throughout the population.

Viral genomes as a new standard for viral detection

These recent studies of Zika virus have demonstrated that the conventional means used to track viral spread may not be able to keep pace with newly emerging and re-emerging viral infections. Unfortunately, this is not a new phenomenon. Studies on the spread of 2009 H1N1 influenza (swine flu) in Africa revealed that, despite the lack of clinically declared cases throughout the continent, swine flu circulated through African populations at high levels. Understanding viral spread is critically dependent on confirmed clinical cases in which patients present unambiguous symptoms. This information is unreliable or unobtainable in some parts of the world.

The tide may be turning though, as increased efforts are made to study viral genomes to understand spread and prevent future epidemics. Groups in the United States are using genomic approaches to track circulating flu strains before they spark the next epidemic. Proposals for increased genomic screening of water and food sources to monitor potential viral pathogens are also being discussed. Perhaps our difficultly in accurately understanding the spread of Zika and other viruses has taught us the importance of monitoring viruses in newer, smarter ways.

Colin O’Leary is a Ph.D. student in the Virology program at Harvard Medical School.

For more information:

The CDC website provides lots of information on Zika virus infection, including basic facts regarding preventative measures, areas where Zika risk is high, and health effects.
This News & Views article from the journal Nature offers a high-level overview of recent publications that use genomics to track the spread of Zika virus throughout the Western hemisphere.
If you need to brush up on your molecular biology, check out this primer on the causes and consequences of genetic mutations.