Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes

Abstract

Background HTLV-1 infects over 20 million people worldwide and causes a progressive neuroinflammatory disorder in a subset of infected individuals called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The detection of HTLV-1 specific T cells in the cerebrospinal fluid (CSF) suggests this disease is immunopathologically mediated and that it may be driven by viral antigens. Exosomes are microvesicles originating from the endosomal compartment that are shed into the extracellular space by various cell types. It is now understood that several viruses take advantage of this mode of intercellular communication for packaging of viral components as well. We sought to understand if this is the case in HTLV-1 infection, and specifically if HTLV-1 proteins can be found in the CSF of HAM/TSP patients where we know free virus is absent, and furthermore, if exosomes containing HTLV-1 Tax have functional consequences. Results Exosomes that were positive for HTLV-1 Tax by Western blot were isolated from HAM/TSP patient PBMCs (25/36) in ex vivo cultures by trapping exosomes from culture supernatants. HTLV-1 seronegative PBMCs did not have exosomes with Tax (0/12), (Fisher exact test, p = 0.0001). We were able to observe HAM/TSP patient CSF (12/20) containing Tax + exosomes but not in HTLV-1 seronegative MS donors (0/5), despite the absence of viral detection in the CSF supernatant (Fisher exact test p = 0.0391). Furthermore, exosomes cultivated from HAM/TSP PBMCs were capable of sensitizing target cells for HTLV-1 specific CTL lysis. Conclusion Cumulatively, these results show that there are HTLV-1 proteins present in exosomes found in virus-free CSF. HAM/TSP PBMCs, particularly CD4 + CD25 + T cells, can excrete these exosomes containing HTLV-1 Tax and may be a source of the exosomes found in patient CSF. Importantly, these exosomes are capable of sensitizing an HTLV-1 specific immune response, suggesting that they may play a role in the immunopathology observed in HAM/TSP. Given the infiltration of HTLV-1 Tax-specific CTLs into the CNS of HAM/TSP patients, it is likely that exosomes may also contribute to the continuous activation and inflammation observed in HAM/TSP, and may suggest future targeted therapies in this disorder. Electronic supplementary material The online version of this article (10.1186/s40169-018-0204-7) contains supplementary material, which is available to authorized users.

Intercellular transmission of Seneca Valley virus mediated by exosomes

“…Exosomes are small vesicles with a diameter of 40-150 nm [7]. Most model cells secrete exosomes, which contain multiple substances, including large amounts of proteins and nucleic acids, and transport substances to various cells [8][9][10]. The virus enters cells through endocytic pathways during the process of exosome formation and completes its assembly and release [11].…”

The Biology and Therapeutic Applications of Red Blood Cell Extracellular Vesicles

“…Additionally, they are present in almost all biological fluids, such as blood, urine, breast milk, cerebrospinal fluid, saliva, semen, etc. [11][12][13][14][15][16][17]. Further characterizations are based on the different sizes and biogenesis of EVs.…”

“…Apoptotic bodies are much larger, ranging from 800 to 5000 nm in diameter, and are generated by blebbing of plasma membrane from cells undergoing apoptosis. Hence, apoptotic bodies represent the fragments of dying cells and differ from exosomes and microvesicles in property (Figure 1) [17][18][19][20][21][22]. In this chapter, we will collectively term both exosomes and microvesicles as EVs with apoptotic bodies excluded.…”

Roles of Semaphorins in Neurodegenerative Diseases

“…HAM/TSP causes alteration of CNS axonal transport based on the presence of APP deposits Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org /10.5772/intechopen.82046 in the axons, a classical marker of defects in fast axonal transport [134,135]. Immunological studies have shown a chronic infiltration of activated CD4+ and CD8+-T-cells into the CNS [136].…”

“…In the cytoplasm of infected lymphocytes, Tax activates NF-kB pathway responsible for proliferation and differentiation of T-cells, whereas in the nucleus, Tax activates the ATP/CREB pathway. Tax can also be secreted via endoplasmic reticulum-Golgi apparatus and by exosomes [136][137][138][139][140][141]. Tax secreted from activated peripheral blood mononuclear cells (PBMCs) could explain the presence of Tax in the plasma and CSF of infected patients and carriers [141].…”