Hantaviruses

Hantaviruses www.selleckchem.com/products/erastin.html are

transmitted to humans by inhalation of virus-containing aerosols that are derived from the excreta of hantavirus-infected rodents. These natural reservoir hosts remain asymptomatic, although they are persistently infected. In striking contrast, hantaviruses are eliminated in humans at the cost of severe symptoms such as pulmonary or renal failure. Currently, no suitable vaccines or therapeutics are available for prevention or treatment of human hantavirus infections [7, 8]. Hantaviruses are not directly cytopathic for infected cells, suggesting that the antiviral immune response itself causes hantavirus-associated syndromes [9, 10]. In accordance, hantaviruses trigger an unusually potent reaction of CD8+ T lymphocytes, that is devoid of regulatory T cells, and still detectable years after resolution [11-14]. Human CD8+ T cells are stimulated by HLA class I (HLA-I) molecules that present antigen-derived peptides. The latter are generated by proteasomes in the cytoplasm from newly synthesized viral proteins, translocated into the ER by TAP molecules, and loaded Panobinostat cell line onto HLA-I molecules before being shuttled to the cell surface. Moreover, uptake and processing of exogenous antigens for HLA-I presentation to CD8+ T cells is pivotal for the generation of antiviral immune responses [15]. This cross-presentation represents

an important function of DCs. Accordingly, most viruses have developed sophisticated strategies to subvert antigen presentation by BCKDHA HLA-I molecules [16]. The PRRs that recognize viral components

include endosomal and cytosolic receptors for RNA and DNA [17]. TLR3 and TLR4 have been implicated as sensors of hantavirus particles [18-20]. Recently, hantavirus-derived RNA was identified as a stimulus of retinoic acid inducible gene I (RIG-I), a cytoplasmic sensor of virus-derived RNA [21]. TLR ligation events result in recruitment of the adaptor molecule MyD88 with the exception of TLR3, which uses TIR domain containing adaptor inducing IFN-β (TRIF) for downstream signaling [22]. Hantavirus are known to potently induce HLA-I on various cell types including DCs [23], but how detection of hantaviral virions translates into HLA-I-restricted T-cell responses and which viral sensors are involved are as yet unknown. In this study, we elucidate in detail how hantaviruses modulate the HLA-I antigen presentation machinery. We used A549 cells, a human lung epithelial cell line, for analyzing the effect of Hantaan virus (HTNV) on the HLA-I antigen presentation machinery. In HTNV-infected A549 cells, productive infection was established (Fig. 1A) and intracellular flow cyto-metric analysis revealed enhanced HLA-I expression (Fig. 1B). Moreover, HLA-I and β2m surface expression was increased upon HTNV infection (Fig. 1C).

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