Downloaded from www.microbiologyresearch.org by IP: 54.242.161.225 On: Thu, 19 May 2016 13:26:23 Short Communication Infection of in vivo differentiated human mast cells with hantaviruses Sven Guhl, 1 3 Renate Franke, 2 3 Anika Schielke, 3 Reimar Johne, 3 Detlev H. Kru ¨ ger, 2 Magda Babina 1 and Andreas Rang 2 Correspondence Andreas Rang andreas.rang@charite.de 1 Department of Dermatology and Allergy, University Hospital Charite ´ , D-10098 Berlin, Germany 2 Institute of Virology, Helmut-Ruska-Haus, University Hospital Charite ´ , D-10098 Berlin, Germany 3 Federal Institute for Risk Assessment, Diedersdorfer Weg 1, D-12277 Berlin, Germany Received 25 December 2009 Accepted 8 January 2010 Increased vascular permeability is a key feature of the pathological symptoms caused by hantaviruses. Here, we analysed the interaction between hantaviruses and mast cells, which regulate vascular homeostasis. In highly purified human skin mast cells increasing amounts of Hantaan (HTNV) and, to a lower extent, Prospect Hill (PHV) virions were produced. Replication was confirmed by the production of viral plus-strand RNA as determined by a virus strand-specific RT-PCR. PHV but not HTNV elicited early expression of beta interferon, MxA, ISG15 and CCL5 consistent to studies with other cell types. The data demonstrate that mature mast cells are permissive to infection with hantaviruses. This interaction might contribute to the development of vascular leakage syndrome. Hantaviruses (family Bunyaviridae) are characterized by a tripartite single-stranded RNA genome of negative polarity within an enveloped virion. The natural hosts are mainly rodents, in which the virus persists without obvious pathogenic symptoms. Transmission to humans via the respiratory tract can cause haemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syn- drome (HCPS) with case fatality rates up to 50 %, depending on the hantavirus species involved. HCPS caused by New World hantaviruses leads to progressive pulmonary oedema, respiratory insufficiency and myocardial depression. HFRS caused by Old World hantaviruses generally is associated with retroperitoneal oedema and can pass through a febrile, hypotensive, oliguric and diuretic phase. Increased vascular permeability and thrombocytopenia are key features in both HCPS- and HFRS-patients and almost all severe cases are complicated by shock (Khaiboullina et al., 2005; Peters et al., 1999; Schmaljohn & Hjelle, 1997; Scho ¨nrich et al., 2008). The mechanisms and viral determinants responsible for the pathogenesis are unclear. Hantaviruses can infect different cell types like endothelial, epithelial and dendritic cells (Raftery et al., 2002; Zaki et al., 1996). In these cells cytopathic effects have not been observed. However, subtle modulation of cell motility and permeability of primary endothelial cells and cell layers, respectively, by hantaviruses has been described previously (Gavrilovskaya et al., 2002, 2008). Furthermore, infection was associated with increased levels of inflammatory cytokines and chemokines including tumor necrosis factor- alpha (TNF-a), interleukin (IL)-1b and CCL5 in cell culture as well as in infected patients (Geimonen et al., 2002; Linderholm et al., 1996; Sundstrom et al., 2001; Temonen et al., 1996). Based on these and other observations, direct modulation of endothelial cell function and/or immuno- pathological responses to the infection are currently thought to cause HCPS and HFRS (Khaiboullina et al., 2005; Peters et al., 1999; Schmaljohn & Hjelle, 1997; Scho ¨nrich et al., 2008). Mast cells (MC) can modulate vascular homeostasis and play a crucial role in allergy and anaphylaxis, but it has become increasingly clear that the physiological relevance of MC lies in the regulation of innate and acquired immune responses. MC originate from haematopoietic progenitor cells, but undergo terminal differentiation exclusively in tissues in which they become ultimately resident tissue MC (Kirshenbaum et al., 1999). MC maturation occurs in close contact with the surrounding tissue and only MC, which have undergone tissue- dependent maturation can therefore be regarded as natural, in situ differentiated MC. Mature MC reside in mucosal and connective tissues in close proximity to the endothelial cell layer of blood vessels and are most prominent in those regions close to the external environment like the skin and mucosa of the lung and digestive tracts. This localization and expression of several toll-like receptors by human MC coincides with their function as immune sentinels that participate in defence against pathogens, such as nematodes, bacteria and certain fungi (Galli et al., 2005; Heib et al., 2008; Kneilling & Rocken, 2009; Kulka & Metcalfe, 2006; Marshall, 2004; Mekori & Metcalfe, 2000). MC produce an extensive array of different vasoactive and inflammatory cytokines, chemokines, bioactive amines, 3These authors contributed equally to this work. Supplementary tables are available with the online version of this paper. Journal of General Virology (2010), 91, 1256–1261 DOI 10.1099/vir.0.019505-0 1256 019505 G 2010 SGM Printed in Great Britain