Putting Neglected Tropical Diseases in the Spotlight: Lessons Learned from Chagas Disease - State of the Planet

Posted: 30 Jan 2020 02:17 PM PST

Putting Neglected Tropical Diseases in the Spotlight: Lessons Learned from Chagas Disease

Photos of a "kissing bug," whose feces can spread the parasite that causes Chagas disease. Photo: CDC

Today, January 30th 2020, is the inaugural World Neglected Tropical Diseases day. For the first time, global community leaders, health experts, civil society advocates, and policymakers have united to raise awareness about neglected tropical diseases (NTDs), in hopes of removing the "neglected" label from the group's name. But what are these NTDs, and why are they neglected?

NTDs are a mixed group of parasitic and bacterial diseases that disproportionately affect impoverished and under-represented minority groups around the world. Some examples of these diseases include soil-transmitted helminthiasis (caused by parasitic worms such as hookworm), trachoma, Chagas disease, leishmaniasis, and schistosomiasis, among others. These diseases affect 1.5 billion people, so they are not rare diseases, just hidden in the local and global agendas. Moreover, although NTDs cause a high disease burden in low- and middle- income countries, they also impose an under-appreciated burden in wealthier nations. The World NTD day can help lift the veil, to not only advocate for political and financial commitments in the battle against NTDs, but also celebrate the successes achieved so far in reducing the burden of these diseases.

The United Nations' 2030 Agenda for Sustainable Development includes promoting human health and well-being globally, recognizing the clear link between human health and sustainability. Poverty is considered the main structural determinant of NTDs because of its influence on living conditions and access to health services. Moreover, the burden created by these diseases feeds back into the social and economic situation, and combines with other determinants that generate health inequalities (such as gender and ethnicity) to keep the affected individuals and demographic groups in a poverty trap.

Here, I want to bring the attention to Chagas disease, which was the focus of my dissertation research. Chagas disease is one of the main NTDs affecting vulnerable communities in Latin America. Mild cases include swelling, fever, diarrhea, and vomiting. Longer-lasting cases can cause heart failure and cardiac arrest.

Chagas disease is caused by a parasite called Trypanosoma cruzi and it is transmitted by insect vectors from the subfamily Triatominae. Through Latin America and the southern USA, different species of Triatominae with different behaviors can transmit the disease, and they go by different common names. Here in the USA, they are commonly known as "kissing bugs." They are blood-sucking bugs with mostly nocturnal habits; the parasites are present in the insect's feces and as the bug feeds, it simultaneously defecates on the person (or animal) that is biting. Then, the parasite can infect the host through the lesion left behind by the bite. It doesn't seem very efficient, and yet it infects 5 million people in Latin America, according to the last regional epidemiological update by WHO, which is based on 10-year-old data. There are other ways in which people can get infected with the parasite: from mother to child during pregnancy, blood transfusion and through food contaminated with triatomine feces. In endemic areas, triatomine insects remain the main transmission route.

Chagas disease presents a disproportionately high disease burden on indigenous communities and poor rural peasants in the Gran Chaco eco-region extending over Argentina, Bolivia and Paraguay, where approximately 60 percent of infected people from Latin America come from. Particularly, a third of new cases transmitted by the triatomine vector in endemic areas occur in Bolivia and Argentina. During 2012-2017, I focused my dissertation work in this region, more specifically in rural communities of the Argentine Chaco region, mostly inhabited by indigenous communities. Although in the Argentine Chaco the overall prevalence of human infection with the parasite that causes Chagas disease has declined over the last 60 years, it remains high (27.8-71.1 percent) in rural communities. Access to diagnosis and treatment is one of the remaining challenges for sustainable control of Chagas disease in endemic areas, but also sustainable control of the vector needs to be achieved to prevent future infections.

We knew that there was a strong and positive association between vector abundance in the houses and the risk of infection in the householders, but how was this modified by their socio-economic conditions? And how can we use this information to better direct vector control actions and active case detection? Those are some of the questions that I aimed to answer in this research project.

The first challenge was to measure socio-economic status in communities under structural poverty. Understanding poverty as a dynamic and multidimensional process (as opposed to a merely lack of resources) requires introducing the concept of social vulnerability, which considers the "defenselessness, insecurity, and exposure to risks, shocks and stress" experienced by households. However, in the context of low- and middle-income countries, socio-economic inequalities have been studied using proxy indicators such as educational attainment and household ownership of assets, which at best partially capture the full complexity of poverty. As a first step, we developed a social vulnerability index using methods from economics to measure the socio-economic status of the household. In an article published in Parasites and Vectors, we found that indigenous and migrant households had a higher social vulnerability compared to non-indigenous households, and that was associated with an increase in infected vectors in the house.

As a second step, we wanted to know how the vector abundance and the social vulnerability interacted to determine the actual risk of infection for householders. For this purpose, we conducted blood tests in the population, and we found that infection was more prevalent in indigenous people compared to non-indigenous people and that it increased both with the abundance of infected vectors and with household social vulnerability. We also found that the social factors modulated the effect of the abundance of infected vectors; vulnerable-household residents were exposed to a higher risk of infection even at low infected-vector abundance, and human mobility within the area determined a lower and more variable exposure to the vector over time. These results are described in a recent paper published in PloS NTD.

As a final step, we integrated these results in a risk map that showed high-priority areas. The approach we used can help identify the groups that are most at risk within apparently uniformly impoverished rural communities. The social vulnerability index may be adapted to identify the most vulnerable households affected by multiple health burdens.

Map showing areas at high risk for Chagas disease in the Argentine Chaco region. Image courtesy Maria del Pilar Fernandez

Although the approach proposed here can be applied more broadly, there is no universal protocol of intervention with respect to the determinants of health of NTDs. Intervention strategies oriented to reduce the impact of NTDs must be tailored to specific social contexts, capacities and resources available, in order to maximize their impact and cost-effectiveness. The synthetic approach that we used to assess socio-economic inequalities provides key information to tailor and guide targeted vector control actions, case detection and treatment of Chagas disease, and facilitate the integration with other health burdens, towards sustainability of interventions and greater reduction of health inequalities.

My experience working on Chagas disease has taught me that sustainable control of vector-borne transmitted diseases and other environmental health-related issues can only be achieved by thoroughly assessing the multiple biological, ecological, socio-economic, cultural and political factors involved. These are not isolated and independently acting factors but interact within a network involving multiple stakeholders with different perceptions and interests, in ever-changing contexts. As we face old and new challenges in our efforts to reduce the burden of NTDs and decrease health inequalities, globally and at national levels, we need to reflect on the lessons learned and the long-standing legacy of the pioneers in the field. As an early career researcher, I want to remain optimistic, and I hope that these efforts of putting NTDs in the spotlight will help us advance towards the Sustainable Development Goals by 2030.

Maria del Pilar Fernandez is a disease ecologist specializing on vector-borne disease transmission and a current Earth Institute postdoctoral fellow. Her research focuses on integrating traditional epidemiological research with an expanded perspective including eco-bio-social determinants, their eventual interactions and spatial patterns, through mathematical models. Her ultimate goal is to identify critical factors affecting disease transmission, which will aid in the design of improved intervention strategies to alleviate the biological and socio-economic burden of these diseases in affected communities.

The results of the Chagas disease research presented here stem from a broader long-term research program on the eco-epidemiology and control of Chagas disease in the municipality of Pampa del Indio, a highly endemic, mostly rural area of the Argentine Chaco. This project is led by Ricardo E. Gürtler at the University of Buenos Aires – CONICET. M. Sol Gaspe and Paula Sartor were also involved directly in the research presented here.

Putting a finger on the switch of a chronic parasite infection - MIT News

Posted: 21 Jan 2020 12:00 AM PST

Toxoplasma gondii (T. gondii) is a parasite that chronically infects up to a quarter of the world's population, causing toxoplasmosis, a disease that can be dangerous, or even deadly, for the immunocompromised and for developing fetuses. One reason that T. gondii is so pervasive is that the parasites are tenacious occupants once they have infected a host. They can transition from an acute infection stage into a quiescent life cycle stage and effectively barricade themselves inside of their host's cells. In this protected state, they become impossible to eliminate, leading to long-term infection.

Researchers used to think that a combination of genes were involved in triggering the parasite's transition into its chronic stage, due to the complexity of the process and because a gene essential for differentiation had not been identified. However, new research from Sebastian Lourido, Whitehead Institute member and assistant professor of biology at MIT, and MIT graduate student Benjamin Waldman has identified a sole gene whose protein product is the master regulator, which is both necessary and sufficient for the parasites to make the switch. Their findings, which appeared online in the journal Cell on Jan. 16, illuminate an important aspect of the parasite's biology and provide researchers with the tools to control whether and when T. gondii transitions, or undergoes differentiation. These tools may prove valuable for treating toxoplasmosis, since preventing the parasites from assuming their chronic form keeps them susceptible to both treatment and elimination by the immune system.

T. gondii spreads when a potential host, which can be any warm-blooded animal, ingests infected tissue from another animal — in the case of humans, by eating undercooked meat or unwashed vegetables — or when the parasite's progeny are shed by an infected cat, T. gondii's target host for sexual reproduction. When T. gondii parasites first invade the body, they are in a quickly replicating part of their life cycle, called the tachyzoite stage. Tachyzoites invade a cell, isolate themselves by forming a sealed compartment from the cell's membrane, and then replicate inside of it until the cell explodes, at which point they move on to another cell to repeat the process. Although the tachyzoite stage is when the parasites do the most damage, it's also when they are easily targetable by the immune system and medical therapies.

In order for the parasites to make their stay more permanent, they must differentiate into bradyzoites, a slow-growing stage, during which they are less susceptible to drugs and have too little effect on the body to trigger the immune system. Bradyzoites construct an extra-thick wall to isolate their compartment in the host cell and encyst themselves inside of it. This reservoir of parasites remains dormant and undetectable until, under favorable conditions, they can spring back into action, attacking their host or spreading to new ones.

Although the common theory was that multiple genes collectively orchestrate the transition from tachyzoite to bradyzoite, Lourido and Waldman suspected that there was instead a single master regulator.

"Differentiation is not something a parasite wants to do halfway, which could leave them vulnerable," Waldman says. "Multiple genes means more chances for things to go wrong, so you would want a master regulator to ensure that differentiation happens cleanly."

To investigate this hypothesis, Waldman used CRISPR-based screens to knock out T. gondii genes, and then tested to see if the parasite could still differentiate from tachyzoite to bradyzoite. Waldman monitored whether the parasites were differentiating by developing a strain of T. gondii that fluoresces in its bradyzoite stage. The researchers also performed a first-of-its-kind single-cell RNA sequencing of T. gondii in collaboration with members of Alex Shalek's lab in the MIT Department of Chemistry. This sequencing allowed the researchers to profile the genes' activity at each stage in unprecedented detail, shedding light on changes in gene expression during the parasite's cell-cycle progression and differentiation.

The experiments identified one gene, which the researchers named Bradyzoite-Formation Deficient 1 (BFD1), as the only gene both sufficient and necessary to prevent the transition from tachyzoite to bradyzoite: the master regulator. Not only was T. gondii unable to make the transition without the BFD1 protein, but Waldman found that artificially increasing its production induced the parasites to become bradyzoites, even without the usual stress triggers required to cue the switch. This means that the researchers can now control Toxoplasma differentiation in the lab.

These findings may inform research into potential therapies for toxoplasmosis, or even a vaccine.

"Toxoplasma that can't differentiate is a good candidate for a live vaccine, because the immune system can eliminate an acute infection very effectively," Lourido says.

The researchers' findings also have implications for food production. T. gondii and other cyst-forming parasites that use BFD1 can infect livestock. Further research into the gene could inform the development of vaccines for farm animals as well as humans.

"Chronic infection is a huge hurdle to curing many parasitic diseases," Lourido says. "We need to study and figure out how to manipulate the transition from the acute to chronic stages in order to eradicate these diseases."

This study was supported by an NIH Director's Early Independence Award, a grant from the Mathers Foundation, the Searle Scholars Program, the Beckman Young Investigator Program, a Sloan Fellowship in Chemistry, the National Institutes of Health, and the Bill and Melinda Gates Foundation.

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