Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

Abstract

dInfectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80 ؉ macrophages, and T. cruzi tetramer-specific CD8 ؉ T lymphocytes capable of producing gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) but not interleukin-17 (IL-17). T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus, T. cruzi infection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses. Vasculitis is a general term for a spectrum of diseases involving leukocyte infiltration of the blood vessel wall. Many subtypes of vasculitis are recognized based on the types of blood vessels involved and the nature of the underlying immunopathology. In some cases, an association of vasculitis with specific infectious agents has been reported; for example, polyarteritis nodosa (PAN) has been associated with hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV infections (1). However, it has been difficult to establish either causality or pathogenetic mechanisms, in part because of the low prevalence of vasculitis and the lack of good animal models (2). In this regard, while studying the chronic phase of C57BL/6J mice infected with the myotropic Colombiana strain of Trypanosoma cruzi, the infectious cause of Chagas' disease in humans, we noticed that the majority of animals developed hind limb paralysis associated with severe systemic necrotizing vasculitis affecting arteries and arterioles in skeletal muscle. Lesions were also present in many other tissues. A review of the literature identified several studies from 1970 to 2000 that described perivascular inflammation and frank arteritis in chronically T. cruzi-infected mouse skeletal muscle, aorta, nerves, and heart (3-9); however, the underlying immunologic mechanisms of disease were not defined. Interestingly, Okumura et al. reported necrotizing arteritis in small arteries beneath the peritoneal lining of the bowel and, occasionally, of the aorta and coronary arteries of T. cruzi-infected mice, which was at that time interpreted as "allergic necrotizing angiitis" (10). Dias et al. reported obliterative changes of the small and medium-sized branches of coronary...

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

“…Skeletal muscle of mice chronically infected with T. cruzi is heavily infiltrated with T lymphocytes and mononuclear phagocytes but not neutrophils. Previously, we used flow cytometry to identify CD4 ϩ and CD8 ϩ T cells as well as F4/80 ϩ macro-phages as the main leukocyte subsets infiltrating skeletal muscle during the chronic phase of infection of C57BL/6 mice with the myotropic Colombiana strain of T. cruzi (24). Both CD4 ϩ and CD8 ϩ T cells were highly activated (CD62L Ϫ CD44 hi ) and produced the type I cytokines IFN-␥ and TNF-␣.…”

“…We previously reported that in C57BL/6 mice chronically infected with the myotropic strain Colombiana, the organism is detected rarely and only in skeletal muscle myocytes; however, parasite DNA can be found in other tissues, including heart and peripheral nerve (24). In heart, there is mild perivascular inflammation in the chronic phase but little if any myocarditis.…”

Putting Infection Dynamics at the Heart of Chagas Disease

“…For example, parasites were detected in the central vein of the adrenal gland in several small autopsy studies at frequencies of 5% [6], 30% [4] and 50% [83]. Progressive multi-organ vasculitis has been reported in mice infected with the high virulence Colombiana (TcI) strain [84]. …”

“…It is not known how trypomastigotes transit between tissues and the circulation. The trypomastigote surface glycoprotein gp85 does have high avidity for vascular endothelial cells [96] and vasculitis can be a feature of chronic infections [84]. Nevertheless, superinfection experiments indicate that the majority of parasites entering the blood of chronically infected hosts are expected to be rapidly opsonized and cleared, mainly in the liver by Kupffer cells [19].…”

O papel da proteína rP21 na replicação parasitária in vitro e na infecção aguda experimental por Trypanosoma cruzi

“…Tais alterações são invariavelmente acompanhadas de intenso infiltrado de células mononucleares, inicialmente composto por macrófagos e neutrófilos, e posteriormente por linfócitos, plasmócitos, eosinófilos e mastócitos (ANDRADE, 1999;MARCON et al, 2011). Granulomas não-necrosantes pode estar presente com células gigantes multinucleadas (ROFFÊ et al, 2016). A destruição de nervos parassimpáticos na região epicárdico-mediastinal tem sido documentada, sugerindo um potencial mecanismo para ocorrência de arritmias e morte súbita (MIRANDA et al, 2011;BONNEY et al, 2019).…”