Low-Level Parasite Persistence Drives Vasculitis and Myositis in Skeletal Muscle of Mice Chronically Infected with Trypanosoma cruzi

Weaver, Joseph D.; Hoffman, Victoria; Roffê, Ester; Murphy, Philip M.

doi:10.1128/iai.00081-19

Cited by 18 publications

(25 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5c ). Some T. cruzi strains have been reported to be myotropic in mice, with pathological outcomes that include paralyzing myositis and skeletal muscle vasculitis ( 32 ). Myocyte infections could also provide the parasite with access to myoglobin, a source of heme or iron that may contribute to a nutritional environment that is favorable for replication.…”

Section: Discussionmentioning

confidence: 99%

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

Ward

Lewis

Khan

et al. 2020

mBio

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Ward

Lewis

Khan

et al. 2020

mBio

View full text Add to dashboard Cite

show abstract

“…In immunocompetent individuals, most parasitic infections are generally considered self-limited, indicating the development and the maintenance of protective immune mechanisms against invading parasites (Okhuysen, 2001; Meamar et al, 2006; Saporito et al, 2013; Lanocha-Arendarczyk et al, 2018). However, multiple studies have suggested that host immune responses elicited during parasitic infections can mediate immunopathology and are responsible for many of the symptoms commonly observed during parasitic diseases (Phillips and Fox, 1984; Pesce et al, 2006; Babaei et al, 2016; Ivanova et al, 2019; Weaver et al, 2019). These immunopathological changes may include parasite-induced morphological, functional, physiological, and structural alterations in parasitized tissues/cells, rendering infected individuals susceptible to organ dysfunction as well as the development of severe forms of clinical disease (Solaymani-Mohammadi and Singer, 2013; Taniguchi et al, 2015; Gorosito Serran et al, 2017; Ma'ayeh et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases

Solaymani-Mohammadi

Eckmann

Singer

2019

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Parasitic diseases cause significant morbidity and mortality in the developing and underdeveloped countries. No efficacious vaccines are available against most parasitic diseases and there is a critical need for developing novel vaccine strategies for care. IL-21 is a pleiotropic cytokine whose functions in protection and immunopathology during parasitic diseases have been explored in limited ways. IL-21 and its cognate receptor, IL-21R, are highly expressed in parasitized organs of infected humans as well in murine models of the human parasitic diseases. Prior studies have indicated the ability of the IL-21/IL-21R signaling axis to regulate the effector functions (e.g., cytokine production) of T cell subsets by enhancing the expression of T-bet and STAT4 in human T cells, resulting in an augmented production of IFN-γ. Mice deficient for either IL-21 (Il21−/−) or IL-21R (Il21r−/−) showed significantly reduced inflammatory responses following parasitic infections as compared with their WT counterparts. Targeting the IL-21/IL-21R signaling axis may provide a novel approach for the development of new therapeutic agents for the prevention of parasite-induced immunopathology and tissue destruction.

show abstract

“…Protein p I -shifts due to PTMs revealed that the theoretical p I -value of the non-acetylated form of tropomyosin-beta is close to the p I -value of its experimentally acetylated counterpart, while additional acetylation of tropomyosin (LEKTIDDLEETLASAK + acetyl (K); acetyl (N-term)) does not significantly affect the p I -value [222]. Interestingly, a variety of contractile proteins are changed in chronic Chagas disease, an often fatal outcome of Trypanosoma cruzi infection, which is characterized by severe cardiomyopathy and chronic skeletal muscle myositis and vasculitis [223,224]. Protein changes were evaluated using 2DGE of specimens from end-stage chronic Chagas disease patients to gain insight into its pathophysiology [225].…”

Section: Top-down Proteomics Of Contractile Proteins From Skeletalmentioning

confidence: 99%

Characterization of Contractile Proteins from Skeletal Muscle Using Gel-Based Top-Down Proteomics

et al. 2019

View full text Add to dashboard Cite

The mass spectrometric analysis of skeletal muscle proteins has used both peptide-centric and protein-focused approaches. The term ‘top-down proteomics’ is often used in relation to studying purified proteoforms and their post-translational modifications. Two-dimensional gel electrophoresis, in combination with peptide generation for the identification and characterization of intact proteoforms being present in two-dimensional spots, plays a critical role in specific applications of top-down proteomics. A decisive bioanalytical advantage of gel-based and top-down approaches is the initial bioanalytical focus on intact proteins, which usually enables the swift identification and detailed characterisation of specific proteoforms. In this review, we describe the usage of two-dimensional gel electrophoretic top-down proteomics and related approaches for the systematic analysis of key components of the contractile apparatus, with a special focus on myosin heavy and light chains and their associated regulatory proteins. The detailed biochemical analysis of proteins belonging to the thick and thin skeletal muscle filaments has decisively improved our biochemical understanding of structure-function relationships within the contractile apparatus. Gel-based and top-down proteomics has clearly established a variety of slow and fast isoforms of myosin, troponin and tropomyosin as excellent markers of fibre type specification and dynamic muscle transition processes.

show abstract

Low-Level Parasite Persistence Drives Vasculitis and Myositis in Skeletal Muscle of Mice Chronically Infected with Trypanosoma cruzi

Cited by 18 publications

References 50 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

Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases

Characterization of Contractile Proteins from Skeletal Muscle Using Gel-Based Top-Down Proteomics

Contact Info

Product

Resources

About