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Tag: Trypanosoma cruzi

Domestic Dog Infection with Trypanosoma cruzi from Northern and Southern Regions of Mexico

Reactive StatPak immunochromatography test results from dogs sampled between December 2018 and October 2019 in Reynosa, Tamaulipas and Tuxtla Gutierrez, Chiapas, Mexico.
Reactive StatPak immunochromatography test results from dogs sampled between December 2018 and October 2019 in Reynosa, Tamaulipas and Tuxtla Gutierrez, Chiapas, Mexico.

Background: Chagas disease or American trypanosomiasis, caused by Trypanosoma cruzi and vectored by triatomines, affects millions of people worldwide. In endemic countries including Mexico, infections in domestic animals, such as dogs, may affect the risk of human disease when they serve as a source of infection to vectors that subsequently infect humans. Materials and Methods: We conducted a cross-sectional study of 296 dogs from two cities near the northern and southern borders of Mexico: Reynosa, Tamaulipas, and Tuxtla Gutierrez, Chiapas. Infection was measured based on testing of blood using T. cruzi quantitative PCR (qPCR) and up to three antibody detection assays. The StatPak immunochromatographic assay was used to screen samples and the indirect fluorescent antibody (IFA) and multiplex microsphere immunoassay (MIA) tests were used as secondary tests on all samples that screened positive and a subset of negatives. Serologic positivity was defined based on reactivity on at least two independent tests. Results: Of the 280 samples tested for parasite DNA, two (0.7%) were positive, one of which (0.4%) was confirmed as T. cruzi discrete typing unit TcIV. Overall, 72 (24.3%) samples were reactive for T. cruzi antibodies via StatPak of which 8 were also positive using MIA and 2 were also positive using IFA (including one of the PCR-positive dogs). Overall, nine dogs (3.4%) met study criteria of positivity based on either/both serology or PCR tests. Positive dogs were found in both regions of Mexico; five (2.7%) from Reynosa and four (3.6%) from Tuxtla Gutierrez. We found no association between infection status and state of origin, sex, age group, breed group, neighborhood, and whether other pets lived in the home. Conclusion: Our results re-emphasize dogs’ utility as sentinels for T. cruzi in Mexico and underscore the need for improved veterinary diagnostic tests and parasite surveillance at the household level in endemic countries.

Edward Davila, Nadia A Fernandez-Santos, José Guillermo Estrada-Franco, Lihua Wei, Doireyner Daniel Velázquez-Ramírez, Rosario García-Miranda, Cesar Irecta Nájera, Raúl Cruz-Cadena, Carlos Guichard-Romero, Carlos Rodriguez, Rick Tarleton, Mario A Rodríguez-Pérez, Héctor Ochoa-Díaz-López, Gabriel L Hamer, Sarah A Hamer. Vector Borne Zoonotic Dis. 2024 Jul 1. doi: 10.1089/vbz.2023.0110

The Unfortunate Abundance of Trypanosoma cruzi in Naturally Infected Dogs and Monkeys Provides Unique Opportunities to Advance Solutions for Chagas Disease

Trypanosoma cruzi, the protozoan parasite and cause of Chagas disease, is widely distributed in many vertebrate and triatomine species throughout North, Central, and South America. Variations in housing quality largely determines human infection risk in the Americas. However, the southern U.S. contains widespread, infected triatomine vectors and captive species and domesticated animals with active T. cruzi infection or at high risk of becoming infected and developing Chagas disease. There is a critical need for better detection and intervention strategies, principally focused on human infection throughout the Americas, but mainly in the U.S., for high-value dogs employed in government and other work. In addition to this economic impact, the concentration of largely unavoidable T. cruzi infections in U.S. dogs provides an incomparable opportunity to answer questions related to T. cruzi infection and Chagas disease that are impossible or unethical to address in humans. As the course of T. cruzi infection and Chagas disease, the immune response to infection, and the response to therapeutics are highly similar across the range of mammalian host species, information obtained from studies in other species can directly inform researchers on how to best detect, manage, and treat T. cruzi infection and Chagas disease in humans.

Rick L. Tarleton, Ashley B. Saunders, Bruno Lococo, Maria Gabriela Alvarez Gianni, Susana Laucella, Carolyn L. Hodo, Gregory K. Wilkerson, Sarah A. Hamer. Zoonoses. 2024. Vol. 4(1). DOI: 10.15212/ZOONOSES-2024-0005

Positive clinical outcome using a modified dosing regimen of benznidazole in dogs at high risk for infection or acutely infected with Trypanosoma cruzi

Serum cardiac troponin I results for the 4 dogs.
Serum cardiac troponin I results for the 4 dogs.

 

Trypanosoma cruzi infection in dogs can cause heart failure and sudden death with few treatment options available. A litter of 4 dogs living in a T cruzi endemic area were randomized to prophylaxis and nonprophylaxis groups as part of a study evaluating a modified benznidazole dosing regimen administered twice weekly to prevent T cruzi infection during a vector transmission season. The 2 dogs that received prophylaxis remained healthy without T cruzi infection or cardiac disease for >2 years. One dog that did not receive prophylaxis died unexpectedly with acute T cruzi-induced pancarditis, and the second dog tested positive for T cruzi and developed complex arrhythmias with markedly increased cardiac troponin I and improved with a higher benznidazole treatment dose. Although the small sample size precludes definitive conclusions, we describe the potential clinical benefit of prophylactic and early treatment with modified benznidazole dosing regimens for dogs with T cruzi infection.

Sukjung Lim, Stephanie Collins, Sarah A Hamer, Rick L Tarleton, Ashley B Saunders. J Vet Intern Med. 2024 Mar 18. doi: 10.1111/jvim.17028.

Two CTEGD trainees receive AHA fellowships

Photos of Graduate student Baihetiya “Barna” Baierna and postdoctoral fellow Mayara Bertolini
Graduate student Baihetiya “Barna” Baierna and postdoctoral fellow Mayara Bertolini received fellowships from the American Heart Association, supporting their research and education. Both are studying parasites in the University of Georgia’s Center for Tropical and Emerging Global Diseases. (Photos courtesy of CTEGD)

 

Baihetiya “Barna” Baierna, a cellular biology graduate student in Silvia Moreno’s laboratory, received an American Heart Association Pre-doctoral Fellowship. It will fund her training for the next two years as she studies the mitochondrion of Toxoplasma gondii.

Baierna grew up wanting to follow in her mother’s footsteps as a scientist.

“My mom worked for the regional CDC in China and I was interested in science since a young age,” Baierna said.

After completing her undergraduate degree in biochemistry, she was sure she wanted to continue her training in graduate school. After being accepted into the Department of Cellular Biology program, she joined the Moreno Laboratory.

Toxoplasma gondii infects approximately one third of the world human population. The infection can cause serious complications in people with a suppressed immune system. Baierna’s research aims at validating novel T. gondii mitochondrial proteins as novel chemotherapeutic targets for improved chemotherapy of toxoplasmosis. This is important because the present drugs are not effective against the chronic stages of the infection. She has developed novel strategies for the discovery of new mitochondrial proteins and already found a novel enzymatic activity highly divergent from the mammalian counterpart. The outcome of this project will expand the knowledge of the T. gondii mitochondrion, as well as helping with the identification of viable drug targets.

“An AHA Fellowship is a very competitive award, but Barna deserves it and we are very proud of her,” said Moreno.

“Preparing the grant proposal was a great learning experience and it will help me with my career development,” said Baierna, “I’m very happy that it was funded.”

Mayara Bertolini, a post-doctoral fellow in Roberto Docampo’s laboratory, received an American Heart Association Post-doctoral Fellowship. It will support her training for one year.

After receiving her bachelor’s degree, Bertolini obtained her master’s degree in a lab that Docampo had set up in Brazil working on T. cruzi. From there she decided to pursue her Ph.D. at the University of Georgia. She completed her Ph.D. in 2023.

Trypanosoma cruzi is the parasite that causes Chagas disease. At least 6 million people, mostly in South America, are infected with the parasite. T. cruzi is transmitted to humans through the feces of an insect commonly referred to as the kissing bug. While Chagas disease was first discovered in 1909, there is still a lot that is unknown about the biology of T. cruzi. This lack of knowledge has hindered drug development. Bertolini’s project is focused on the role of polyphosphate during the Trypanosoma cruzi life cycle.

“This is the second fellowship from the AHA that Mayara has received. She got a two-year pre-doctoral fellowship before and has done outstanding work,” said Docampo.

“AHA Fellowships are very competitive and I’m thrilled my proposal was selected,” said Bertolini. “In addition to supporting my training, there is support for career development and networking opportunities.”

 

The story originally appeared at https://research.uga.edu/news/two-ctegd-trainees-receive-aha-fellowships/

Trypanosoma cruzi heme responsive gene (TcHRG) plays a central role in orchestrating heme uptake in epimastigotes

Trypanosoma cruzi, a heme auxotrophic parasite, can control intracellular heme content by modulating heme responsive gene (TcHRG) expression when a free heme source is added to an axenic culture. Herein, we explored the role of TcHRG protein in regulating the uptake of heme derived from hemoglobin in epimastigotes. We demonstrate that the endogenous TcHRG (protein and mRNA) responded similarly to bound (hemoglobin) and free (hemin) heme. Endogenous TcHRG was found in the flagellar pocket boundaries and partially overlapping with the mitochondrion. On the other hand, endocytic null parasites were able to develop and exhibited a similar heme content compared to wild type when fed with hemoglobin, indicating that endocytosis is not the main entrance pathway for hemoglobin-derived heme in this parasite. Moreover, the overexpression of TcHRG led to an increase in heme content when hemoglobin was used as the heme source. Taken together, these results suggest that the uptake of hemoglobin-derived heme likely occurs through extracellular proteolysis of hemoglobin via the flagellar pocket, and this process is governed by TcHRG. In sum, T. cruzi epimastigotes control heme homeostasis by modulating TcHRG expression independently of the available source of heme.

Evelyn Tevere, Cecilia Beatriz Di Capua, Nathan Michael Chasen, Ronald Drew Etheridge, Julia Alejandra Cricco. FEBS J. 2023 Dec 13. doi: 10.1111/febs.17030.

Chagas disease research in the news

Rick Tarleton

DDN Dialogues

Rick Tarleton was recently interviewed for the Drug Discovery News podcast. Listen as he talks about his research into new drug treatments for Chagas disease.

A written transcript is available on DDN’s website.

KFF Health News

Rick Tarleton, along with Drew Etheridge‘s lab, was featured in a KFF Health News story about Chagas disease that has been picked up by a number of media outlets.

KFF Health News (Spanish translation)

NBC News

California Healthline

News Medicine

CNN

Sun Herald

The San Diego Union-Tribune

cGAS-STING Pathway Activation during Trypanosoma cruzi Infection Leads to Tissue-Dependent Parasite Control

FIGURE 1. T. cruzi activates the cGAS-STING pathway in primary cells to induce a modest IFN-I response.

 

Host cell invasion by Trypanosoma cruzi is a markedly silent process, with limited host transcriptional changes indicative of innate immune recognition, except for a modest type I IFN (IFN-I) response. In this study, we show that T. cruzi-induced IFN-β production was nearly abolished in primary murine cGAS-/- or stimulator of IFN genes (STING)-deficient (STINGGt) macrophages and fibroblasts. T. cruzi infection did not impact the ability of IFN-regulatory factor reporter macrophages to respond to classical cGAS-STING agonists, indicating that the limited IFN-β induction is not due to active parasite suppression. cGAS-/-, STINGGt, and IFN-α/β receptor-/- (IFNAR-/-) macrophages infected with T. cruzi yielded significantly higher numbers of amastigotes compared with wild-type macrophages; however, the impact of the STING pathway during infection in vivo is more complex. Despite an initial increase in parasite growth, STINGGt and IFNAR-/- mice ultimately had lower parasite burden in footpads as compared with wild-type mice, demonstrating a role for IFN-I expression in potentiating parasite growth at the infection site. STING pathway activation had little impact on parasite levels in the skeletal muscle; however, in the heart, cGAS-/- and STINGGt mice, but not IFNAR-/- mice, accumulated higher acute parasite loads, suggesting a protective role of STING sensing of T. cruzi in this organ that was independent of IFN-I. Together, these results demonstrate that host cGAS-STING senses T. cruzi infection, enhancing parasite growth at the site of entry, and contributes to acute-phase parasite restriction in the heart, a major site of tissue damage in chronic T. cruzi infection.

Natasha Perumal, Brooke White, Fernando Sanchez-Valdez, Rick L Tarleton. J Immunol. 2023 Aug 21;ji2300373. doi: 10.4049/jimmunol.2300373.

Diagnosis and Treatment of a Natural Infection with Trypanosoma Cruzi (Chagas Disease) in a Symptomatic De Brazza’s Monkey (Cercopithecus Neglectus) in Alabama

Trypanosoma cruzi, the causative agent of Chagas disease, is a zoonotic, vector-borne, protozoan hemoflagellate with a wide host range. An 11-yr-old, captive-bred male De Brazza’s monkey (Cercopithecus neglecus) presented with weight loss despite normal appetite. Examination revealed hypoglycemia, nonregenerative anemia, and many trypanosomes on a blood smear. A whole blood sample was PCR-positive for T. cruzi discrete typing unit TcIV and the monkey seroconverted using two different methods. The monkey was treated with the standard human dose of benznidazole twice daily for 60 d; however, blood obtained over the next 1.5 yr posttreatment remained PCR-positive for T. cruzi. A second course of benznidazole at a higher dose but lower frequency for 26 wk was required for the monkey to convert to sustained PCR-negative status. The monkey recovered with no apparent lasting effects.

Stephanie McCain, Richard R Sim, Bridget Weidner, Anne E Rivas, Brooke White, Lisa D Auckland, Rick L Tarleton, Sarah Hamer. J Zoo Wildl Med. 2023 Jul;54(2):412-416. doi: 10.1638/2022-0095

Frequency Variation and Dose Modification of Benznidazole Administration for the Treatment of Trypanosoma cruzi Infection in Mice, Dogs, and Nonhuman Primates

Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and nonhuman primates (NHP). Collectively, these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ~2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment for T. cruzi infection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available.

Juan M Bustamante, Brooke E White, Gregory K Wilkerson, Carolyn L Hodo, Lisa D Auckland, Wei Wang, Stephanie McCain, Sarah A Hamer, Ashley B Saunders, Rick L Tarleton. Antimicrob Agents Chemother. 2023 Apr 11;e0013223. doi: 10.1128/aac.00132-23.

Delayed Activation of T Cells at the Site of Infection Facilitates the Establishment of Trypanosoma cruzi in Both Naive and Immune Hosts

Although parasite entry through breaks in the skin or mucosa is one of the main routes of natural transmission of Trypanosoma cruzi, little is known about the host cell types initially invaded nor the ability of those host cells to initiate immune responses at the site of infection. To gain insights into these early events, we studied the fate of fluorescently tagged T. cruzi delivered subcutaneously in mouse footpads or ears. We demonstrate that the majority of parasites introduced into the skin initially proliferate there until 8 to 10 days postinfection, when the parasite load decreases. This decline in parasite numbers is dependent on the presence of an intact T cell compartment and on the ability of hosts to produce gamma interferon (IFN-γ). Many of the parasite-containing cells at the initial infection site display a macrophage/monocyte phenotype but with low expression of activation markers, suggesting that these cells provide an early niche for T. cruzi proliferation, rather than being active in parasite control. It is only after the first round of T. cruzi replication and release from host cells that signs of immune activation and control of parasites become apparent. The delay in the activation and failure to rapidly control parasite replication are observed even when T. cruzi-primed T cells are present, such as in chronically infected mice. This failure of a primed immune system to recognize and react prior to extensive parasite expansion at the infection site likely poses a significant challenge for the development of vaccines aiming to prevent T. cruzi infection. IMPORTANCE Trypanosoma cruzi, the parasite causing Chagas disease, usually infects through the mucosa or breaks in the skin, but little is known about the parasite’s fate at the site of entry or the early events involving immune control there. Here, we track the local proliferation and subsequent dissemination of fluorescently tagged T. cruzi and the initial immune response at the point of entry. We show that T. cruzi preferentially infects innate immune cells in the skin and that the stimulation of an adaptive T cell response does not occur until after the release of parasites from this first round of infected host cells. This first immunologically “silent” proliferation occurs even in the presence of a strong immune T cell memory generated by previous infection. This capacity of T. cruzi to establish infections while avoiding initial immune recognition has important implications for the potential to develop vaccines to prevent T. cruzi infection.

Angel M Padilla, Charles Rosenberg, Peter Cook, Fernando Sanchez-Valdez, Caroline McElhannon, Rick L Tarleton. mSphere. 2023 Jan 25;e0060122. doi: 10.1128/msphere.00601-22.