Highly competent, non-exhausted CD8+ T cells continue to tightly control pathogen load throughout chronic Trypanosoma cruzi infection

Pack, Angela D.; Collins, Matthew H.; Rosenberg, Charles S.; Tarleton, Rick L.

doi:10.1371/journal.ppat.1007410

Cited by 37 publications

(48 citation statements)

References 82 publications

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“…One of the major challenges in Chagas disease research is to determine how T. cruzi survives as a lifelong infection, despite eliciting a vigorous immune response which is able to reduce the parasite burden by >99%. Exhaustion of the parasite-specific CD8 + T cell response does not appear to be the reason ( 12 ). Alternative explanations include the possibility that T. cruzi is able to persist in immune-tolerant tissue sites ( 13 ) and the potential for the parasite to assume a nondividing dormant form that does not trigger an overt immune response ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

In Vivo Analysis of Trypanosoma cruzi Persistence Foci at Single-Cell Resolution

Ward

Lewis

Khan

et al. 2020

mBio

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Infections with Trypanosoma cruzi are usually lifelong despite generating a strong adaptive immune response. Identifying the sites of parasite persistence is therefore crucial to understanding how T. cruzi avoids immune-mediated destruction. However, this is a major technical challenge, because the parasite burden during chronic infections is extremely low. Here, we describe an integrated approach involving comprehensive tissue processing, ex vivo imaging, and confocal microscopy, which allowed us to visualize infected host cells in murine tissue with exquisite sensitivity. Using bioluminescence-guided tissue sampling, with a detection level of <20 parasites, we showed that in the colon, smooth muscle myocytes in the circular muscle layer are the most common infected host cell type. Typically, during chronic infections, the entire colon of a mouse contains only a few hundred parasites, often concentrated in a small number of cells each containing >200 parasites, which we term mega-nests. In contrast, during the acute stage, when the total parasite burden is considerably higher and many cells are infected, nests containing >50 parasites are rarely found. In C3H/HeN mice, but not BALB/c mice, we identified skeletal muscle as a major site of persistence during the chronic stage, with most parasites being found in large mega-nests within the muscle fibers. Finally, we report that parasites are also frequently found in the skin during chronic murine infections, often in multiple infection foci. In addition to being a site of parasite persistence, this anatomical reservoir could play an important role in insect-mediated transmission and have implications for drug development. IMPORTANCE Trypanosoma cruzi causes Chagas disease, the most important parasitic infection in Latin America. Major pathologies include severe damage to the heart and digestive tract, although symptoms do not usually appear until decades after infection. Research has been hampered by the complex nature of the disease and technical difficulties in locating the extremely low number of parasites. Here, using highly sensitive imaging technology, we reveal the sites of parasite persistence during chronic-stage infections of experimental mice at single-cell resolution. We show that parasites are frequently located in smooth muscle cells in the circular muscle layer of the colon and that skeletal muscle cells and the skin can also be important reservoirs. This information provides a framework for investigating how the parasite is able to survive as a lifelong infection, despite a vigorous immune response. It also informs drug development strategies by identifying tissue sites that must be accessed to achieve a curative outcome.

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Section: Introductionmentioning

confidence: 99%

In Vivo Analysis of Trypanosoma cruzi Persistence Foci at Single-Cell Resolution

Ward

Lewis

Khan

et al. 2020

mBio

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“…Infection with Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas disease, triggers both innate (1)(2)(3), and adaptive (4)(5)(6) immune responses that aim at the control of the parasite load both in tissues and peripheral blood [Reviewed in (7)]. However, these mechanisms do not succeed in the complete eradication of the parasite, which results in parasite persistence (8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease

et al. 2020

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“…The reason why the immune system is not able to eradicate the infection is unresolved. It does not appear to involve exhaustion of the CD8 + IFN-γ + T cell response, which continues to suppress, but not eliminate, the parasite burden throughout the long chronic stage [26]. These findings have questioned the feasibility of developing an effective anti-T. cruzi vaccine.…”

Section: Introductionmentioning

confidence: 99%

Drug-cured experimental Trypanosoma cruzi infections confer long-lasting and cross-strain protection

et al. 2020

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Background The long term and complex nature of Chagas disease in humans has restricted studies on vaccine feasibility. Animal models also have limitations due to technical difficulties in monitoring the extremely low parasite burden that is characteristic of chronic stage infections. Advances in imaging technology offer alternative approaches that circumvent these problems. Here, we describe the use of highly sensitive whole body in vivo imaging to assess the efficacy of recombinant viral vector vaccines and benznidazole-cured infections to protect mice from challenge with Trypanosoma cruzi. Methodology/Principal findings Mice were infected with T. cruzi strains modified to express a red-shifted luciferase reporter. Using bioluminescence imaging, we assessed the degree of immunity to re-infection conferred after benznidazole-cure. Those infected for 14 days or more, prior to the onset of benznidazole treatment, were highly protected from challenge with both homologous and heterologous strains. There was a >99% reduction in parasite burden, with parasites frequently undetectable after homologous challenge. This level of protection was considerably greater than that achieved with recombinant vaccines. It was also independent of the route of infection or size of the challenge inoculum, and was long-lasting, with no significant diminution in immunity after almost a year. When the primary infection was benznidazole-treated after 4 days (before completion of the first cycle of intracellular infection), the degree of protection was much reduced, an outcome associated with a minimal T. cruzi-specific IFN-γ + T cell response. Conclusions/Significance Our findings suggest that a protective Chagas disease vaccine must have the ability to eliminate parasites before they reach organs/tissues, such as the GI tract, where once established, they become largely refractory to the induced immune response.

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Highly competent, non-exhausted CD8+ T cells continue to tightly control pathogen load throughout chronic Trypanosoma cruzi infection

Cited by 37 publications

References 82 publications

In Vivo Analysis of Trypanosoma cruzi Persistence Foci at Single-Cell Resolution

In Vivo Analysis of Trypanosoma cruzi Persistence Foci at Single-Cell Resolution

IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease

Drug-cured experimental Trypanosoma cruzi infections confer long-lasting and cross-strain protection

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