A new climate for vector-borne diseases

The first time Melissa Nolan, PhD, MPH was confronted with a public health issue, she didn’t even know there was such a thing. While still a pre-med student, Nolan took part in a clinical medicine program in a poor, rural community in Nicaragua. She helped doctors administer anti-parasitic medication to school-aged children.

But the medication wasn’t solving the problem. Children would often become reinfected because of poor hygiene at home. “Why aren’t we eliminating these parasites from the environment?” she asked her physician mentor. “You shouldn’t go into medicine,” he responded, “you should go into public health,” she recalls. The experience set the trajectory for the rest of Nolan’s professional life. 

Before that trip, “all I knew was that I could choose to be a doctor, lawyer or teacher. But I realized there was this whole prevention side of things.”

Today, Nolan is an assistant professor at the Arnold School of Public Health at the University of South Carolina in Columbia. She is an expert in the epidemiology of vector-borne infectious diseases, particularly those related to poverty in the US and Latin America. 

In the US, vector-borne diseases - those passed to people via an insect bite - are becoming alarmingly more common. Since 2004, the number of people diagnosed with a vector-borne disease has more than tripled, according to the Centers for Disease Control. These include diseases caused by viruses such as Chikungunya and Zika that are transmitted by mosquitos, and those caused by bacteria and parasites such as Lyme, Rocky Mountain Spotted Fever and Chagas spread by tick bites.

Diseases transmitted by ticks are of particular concern — the number of people diagnosed with a tickborne disease more than doubled between 2004 and 2016 and accounted for 77% of all vector-borne disease cases. But because current blood tests only pick up a fraction of all cases, the skyrocketing numbers present an impending public health crisis.

A new climate for disease

Increasing temperatures fueled by climate change together with global travel, trade and migration are making it easier for disease-carrying insects to expand into new areas.  

In response, the CDC is stepping up surveillance and control measures. In July of 2021, the agency made funding available over the next five years to either establish new “Centers of Excellence in Vector Borne Diseases” or shore up existing ones. 

Nolan is in charge of writing the protocols for the southeastern centers located at four universities across Florida. At the U of SC, Nolan is investigating ways to better diagnose diseases, with a particular interest in Chagas. “It is the most neglected of all tropical diseases,” she says. “There are 7 million people infected worldwide but less than 1% receive treatment.”  Chagas is endemic in Latin America but has spread to pockets in the southwestern US, where its prevalence has grown dramatically, and the vectors that host the parasite are becoming more diverse. 

Chagas is caused by the parasite Trypanosoma cruzi, which is transmitted to animals and people by Triatominae insects - more famously called “kissing bugs” because they preferentially bite people around the mouth. 

A complicating factor in diagnosing and studying the disease is the diversity of the parasite. There are at least six genetically distinct strains of T. cruzi. Specific strains are associated with particular habitats, hosts, and disease symptoms. But all versions of the parasite can pass to people through contact with feces from an infected insect. This can happen if a person scratches a bug bite and inadvertently rubs the insect’s feces into the wound, for example, or by consuming food or beverages contaminated with infected feces. The disease can also be transmitted through a blood transfusion, organ transplant, or from mother to infant. Left untreated, 20-30% of infected people develop a chronic illness that primarily affects the heart, causing arrhythmia and damage that can lead to heart failure.

More than 300,000 people are living with T. cruzi infection in the US, according to the CDC. The majority were infected in Latin America. Earlier this year, however, the CDC announced that up to 10,000 people in the US have locally acquired Chagas infections, flagging it as a potential new public health threat. 

“Everyone knows it’s here,” says Nolan. “We just have to educate physicians to test for it.” 

Accurate testing before it’s too late

Clinicians typically test for the parasite by looking for antibodies in a blood sample. But the accuracy of antibody tests decreases the longer a person has been infected, says Nolan.
 
There is short window of a few days after the onset of symptoms when antibody levels are high, and blood tests can detect the infection. But the parasite eventually hides in smooth muscle tissue and becomes dormant, shedding comparatively little nucleic acid into the bloodstream. 

PCR, the current molecular diagnostic standard, is more sensitive and can pick up more cases, but still typically only detects about 50% of infections. With almost half of the infections going undetected, often the first sign that someone has Chagas is heart failure, which of course, is too late, says Nolan.

Nolan is currently researching whether digital PCR (dPCR) can detect more cases, since it performs better when trying to pick up a faint signal. “If PCR can find a needle in a haystack, dPCR is like laying that haystack flat across the ground so one can see it better and find the needle,” Nolan explains. 

To perform dPCR, Nolan works with multiple QIAGEN products that she has incorporated into her lab’s workflow. These include TissueLyser, which homogenizes samples into a slurry. The result gets fed into QIAcube HT and then into QIAgility, which further prepares the sample for dPCR with QIAcuity. The entire workflow is completely automated, which saves precious time. 

Her evidence suggests dPCR can identify an additional 10% of infections. But the data is preliminary, she says, and “there is a lot we can do to continue to improve the detection.” Even 10% of 7 million people, however, “from a public health perspective, is huge,” she adds.

Poor detection rates are, unfortunately, a hallmark of many vector-borne diseases. For example, molecular tests only pick up about 30% of patients infected with West Nile virus, says Nolan - and that’s about the same detection rate for Rocky Mountain Spotted fever.

“If you could extend the detection window for any vector-borne disease with dPCR, that would have great power,” she adds.

A smaller world for outbreaks

In parallel to her research in the US, Nolan is also studying Chagas in Latin America. In a project with the University of El Salvador, she is evaluating the feasibility of a screening program to detect Chagas during pregnancy. Latin American women often become infected as children. But “we don’t know why some women transmit it in utero, and others don’t,” Nolan says. Part of the project is to compare PCR results to dPCR to see if researchers can learn anything about how and when during the parasite’s life-cycle it infects fetuses. 

Correctly identifying Chagas disease infection is critical, she says, it has lifesaving implications for both mom and baby. Moreover, her group would like to identify a marker of the infection—a protein that could be used to screen pregnancies to identify babies who would need treatment after birth or as a drug target to stop transmission during pregnancy in the first place. The potential public health benefits of the project are so immense, it has attracted the support of Gabriela Roberta Rodríguez de Bukele, the first lady of El Salvador.

Of her work on Chagas: “She’s an outstanding scientist and has emerged as one of our nation’s important Chagas’ disease investigators,” says Peter Hotez, Co-Director of Texas Children’s Hospital Center for Vaccine Development and Dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, Texas. Hotez was Nolan’s PhD advisor. “She is also fearless,” he adds. She goes into difficult situations across the most impoverished areas of Central America.” 

Part of this fearlessness may stem from her desire to help those less fortunate. Nolan was only 12 years old when she first experienced how unjust the world can be. While on a church-sponsored mission trip to Venezuela with her family, Nolan met a girl about the same age as herself. Nolan knew no Spanish, so the girl wrote her name in the palm of Nolan’s hand: Daniella. Nolan reciprocated. Daniella became Nolan’s playmate for the trip, but she never stopped thinking about her Spanish-speaking friend. The experience left an imprint that would inspire her for years to come. As she grew older, she found herself thinking about how the trajectory of Daniella’s life was so different than her own, based merely on the environment in which she was born. 

But the world is now more connected than it ever was. And global healthcare outreach and accessibility is not just ethical, it can prevent outbreaks from escalating to the point of COVID-19. The coronavirus pandemic has shown how a local pathogen outbreak can spread with lightning speed in our globalized world. 

“Our world is getting smaller,” says Nolan, “and vector-borne diseases are encroaching into new areas.” If technology such as dPCR can help detect more infections accurately and early, “it would allow us to take more immediate action. It could save lives.”