Soluble antigens from the neurotropic pathogenAngiostrongylus cantonensisdirectly induce thymus atrophy in a mouse model

Abstract

The nematode Angiostrongylus cantonensis (A.C.) is a neurotropic pathogen; stage-III larva invade the human (non-permissive host) central nervous system (CNS) to cause eosinophilic meningitis or meningoencephalitis accompanied by immunosuppression. In an A.C.-infectedmouse (another non-permissive host) model, CNS damage-associated T cell immune deficiency and severe inflammation were proposed to result from activation of the hypothalamic-pituitary-adrenal (HPA) axis. However, glucocorticoids are anti-inflammatory agents. Additionally, while defects in thymic stromal/epithelial cells (TECs) are the major reason for thymic atrophy, TECs do not express the glucocorticoid receptor. Therefore, activation of the HPA axis cannot fully explain the thymic atrophy and inflammation. Using an A.C.-infected mouse model, we found that A.C.-infected mice developed severe thymic atrophy with dramatic impairments in thymocytes and TECs, particularly cortical TECs, which harbor CD4+CD8+ double-positive thymocytes. The impairments resulted from soluble antigens (sAgs) from A.C. in the thymuses of infected mice, as intrathymic injection of these sAgs into live mice and the addition of these sAgs to thymic cell culture resulted in thymic atrophy and cellular apoptosis, respectively. Therefore, in addition to an indirect effect on thymocytes through the HPA axis, our study reveals a novel mechanism by which A.C. infection in non-permissive hosts directly induces defects in both thymocytes and TECs via soluble antigens.

Infection-Associated Thymic Atrophy

“…Similarly, Liu et al. ( 97 ) observed that soluble antigen from A. cantonensis can lead to apoptosis of thymic stromal cells and thymocytes. In addition, F. tularensis is also found in thymus tissue during infection ( 78 ).…”

“…Increasing research evidence indicates the close and complex relationship between host and exosomes originating from pathogens. Interestingly, it is mentioned above that the administration of the soluble antigen of A. cantonensis into the thymus of mice can cause obvious thymic atrophy, as for mice directly infected with A. cantonensis ( 97 ). Given that soluble antigens of A. cantonensis may break down during a long journey from the brain to the thymus, we reasonably speculate that the transport of soluble antigens should rely on a more effective vector, with exosomes the suitable choice.…”

“…One is the activation of the HPA axis, which impairs thymocyte development ( 96 ). Another is the direct action of soluble antigen from A. cantonensis , which leads to increased apoptosis of thymic stromal cells and thymocytes ( 97 ).…”

Meningoencefalitis eosinofílica por Angiostrongylus cantonensis

“…Finalmente, otros resultados mostraron algunos mecanismos poco dilucidados en nuestro medio, producido por la infección del helminto. Tal es el caso de un artículo del 2017 que indica la posible atrofia del timo en modelos experimentales 18 y otro artículo en PlusOne que le atribuye a un proteosoma la regulación fundamental en el proceso de inducción de la infección en el sistema nervioso central 19 .…”

“…El estudio de Chen y Wang 18 en ratones, arroja que los productos de excreción/secreción ☞ http://archivosdeneurociencias.com MENINGOENCEFALITIS EOSINOFÍLICA POR ANGIOSTRONGYLUS CANTONENSIS del quinto estadio larval de Angiostrongylus cantonensis estimulan la activación de astrocitos y la generación de citocinas (Interleucina-1a e Interleucina-6) con el empleo del Factor nuclear de trascripción-Kb (NF kB) y de la vía de la proteína señalizadora Sonic Hedgehog (Shh). La prevención de la enfermedad cuando se viaja a áreas endémicas es de gran relevancia.…”