In humans, hantaviruses can cause haemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome (HCPS). Currently it is estimated that 150,000 to 200,000 cases of hantavirus disease occur each year, the majority being reported in Asia. However, human hantavirus infections are increasingly reported in the Americas and Europe. Although many of the underlying pathogenic mechanisms still remain unclear, recent evidence rather argues against a purely immune-mediated pathophysiology of human disease. Despite the high morbidity and case-fatality rates of HFRS and HCPS, respectively, no vaccine or drug is currently proven to be preventive or therapeutic. This review summarises clinical features and current epidemiological findings, as well as concepts regarding the immunology, pathogenesis and intervention strategies of human hantaviral diseases.

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IntroductionSeveral CD4 ϩ T-cell populations have been shown to regulate activation, differentiation, and effector functions of T cells. [1][2][3][4][5] Naturally occurring CD4 ϩ regulatory T cells (T Regs ), which constitutively express Foxp3 and the IL-2R␣ chain (CD25), are generated during normal T-cell development in the thymus and mediate suppression via a cytokine-independent, contact-dependent mechanism. 1,6 Others, such as IL-10-secreting Tr-1 cells 7 and TGF-␤-secreting Th3 cells, [8][9][10] constitute induced T Regs as they are generated in the periphery and exert cytokine-mediated suppression.Hepatitis C virus (HCV) readily establishes persistent infection in the majority of infected persons and cannot yet be prevented by vaccines. 11,12 The small percentage of patients (20%-40%) who spontaneously clear the virus and recover from hepatitis C mount vigorous HCV-specific CD4 ϩ and CD8 ϩ T-cell responses. [13][14][15][16][17][18][19] Memory T-cell responses are maintained for decades after recovery 19 and mediate protective immunity in HCV-recovered chimpanzees on rechallenge with homologous [20][21][22][23][24] and heterologous 25 HCV. Unfortunately, most patients (60%-80%) either do not mount an HCV-specific CD4 ϩ and CD8 ϩ T-cell response of sufficient vigor and breadth or their response is rapidly lost during HCV infection.The identification of those factors and mechanisms that contribute to the high incidence of HCV persistence is a field of intense investigation (for a review, see Racanelli and Rehermann 12 ). Most recently, an increased frequency of CD4 ϩ CD25 ϩ T cells has been described in the blood of patients with persistent HCV infection compared with those who spontaneously cleared HCV. [26][27][28][29] Based on this finding and the observation that in vitro depletion of CD25 ϩ T cells resulted in increased HCV-specific T-cell responsiveness, it has been proposed that CD4 ϩ CD25 ϩ cells contribute to HCV persistence by suppressing HCV-specific T-cell responses [26][27][28][29] and that they are absent or less functional after recovery from hepatitis C. The latter conclusion is based on limited information, however, because time and route of infection, length of recovery, and genotype sequence of the previously infecting virus are often unknown and not comparable among patients, so the immune status after recovery cannot be precisely assessed. Here, we compare frequency and function of Foxp3 ϩ -CD4 ϩ CD25 ϩ T cells with regulatory activity between HCVrecovered and persistently infected chimpanzees, the sole nonhuman species susceptible to HCV infection. The chimpanzees included in this study are well characterized with regard to For personal use only. on April 5, 2019. by guest www.bloodjournal.org From the clinical, virologic, and immunologic course of infection, including the demonstration of protective, T cell-based immunity in those chimpanzees that recovered spontaneously. 22,23 This study provides the first formal demonstration of CD4 ϩ CD25 ϩ T Regs that express Foxp3, display hypoprol...

Responsiveness of IEC lines to LPS is positively correlated with TLR 4 expression. Strategies targeting TLR 4 expression or TLR 4 mediated signaling may antagonize IEC activation by LPS.

BackgroundToll-like receptors (TLRs) and macrophages play an important role in rheumatoid arthritis (RA). Currently, it is not clear whether inflammatory M1 or anti-inflammatory M2 predominate among the resident macrophages in the synovium. In the present study, we set out to investigate the impact of TLR stimulation on monocyte-derived M1 and M2 macrophage function and phenotype by mimicking the exposure to abundant TLR agonists as occurs in the context of RA. The response of macrophage subsets to TLR2 and TLR4 activation was evaluated on cluster of differentiation (CD) marker profile; cytokine secretion; gene expression; and NF-κB, interferon regulatory factors 3 and 7 (IRF3/7), and mitogen-activated protein kinase (MAPK) activation.MethodsHuman monocytes were isolated from peripheral blood of healthy individuals and patients with RA and differentiated into M1-like and M2-like macrophages by granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), respectively. Cells were either (1) stimulated with TLR ligands Pam3 or lipopolysaccharide (LPS) or (2) classically activated via interferon (IFN)-γ/LPS. Cytokine production was measured by enzyme-linked immunosorbent assay, and gene expression was measured by qPCR. Cells were stained for CD markers and analyzed by fluorescence-activated cell sorting. NF-κB, IRF3/7, and MAPKs were detected by Western blotting.ResultsMonocyte-derived macrophages of healthy donors (HD) or patients with RA displayed comparable subset-specific phenotypes upon exposure to TLR agonists. CD14 and CD163 marker expression on M2 macrophages did not change upon TLR2 and TLR4 engagement. By contrast, M2 gene markers HMOX1, FOLR2, and SLC40A1 were decreased. Importantly, M2 macrophages derived from HD or patients with RA showed both a decreased ratio of interleukin (IL)-10/IL-6 and IL-10/IL-8 upon stimulation with TLR2 ligand Pam3 compared with TLR4 ligand LPS. Gene expression of TLR2 was increased, whereas TLR4 expression was decreased, by TLR ligand stimulation. MAPKs p38, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase were activated more strongly in M2 than in M1 macrophages by Pam3 or LPS.ConclusionsWe show that the anti-inflammatory activity of M2 macrophages is reduced in the presence of abundant TLR2 ligands without significant changes in cell surface markers. Thus, the classical M1/M2 paradigm based on cellular markers does not apply to macrophage functions in inflammatory conditions such as RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1447-1) contains supplementary material, which is available to authorized users.

In man, infection with South American Andes virus (ANDV) causes hantavirus cardiopulmonary syndrome (HCPS). HCPS due to ANDV is endemic in Southern Chile and much of Argentina and increasing numbers of cases are reported all over South America. A case-fatality rate of about 36% together with the absence of successful antiviral therapies urge the development of a vaccine. Although T-cell responses were shown to be critically involved in immunity to hantaviruses in mouse models, no data are available on the magnitude, specificity and longevity of ANDV-specific memory T-cell responses in patients. Using sets of overlapping peptides in IFN-γ ELISPOT assays, we herein show in 78 Chilean convalescent patients that Gn-derived epitopes were immunodominant as compared to those from the N- and Gc-proteins. Furthermore, while the relative contribution of the N-specific response significantly declined over time, Gn-specific responses remained readily detectable ex vivo up to 13 years after the acute infection. Tetramer analysis further showed that up to 16.8% of all circulating CD3+CD8+ T cells were specific for the single HLA-B*3501-restricted epitope Gn465–473 years after the acute infection. Remarkably, Gn465–473–specific cells readily secreted IFN-γ, granzyme B and TNF-α but not IL-2 upon stimulation and showed a ‘revertant’ CD45RA+CD27−CD28−CCR7−CD127− effector memory phenotype, thereby resembling a phenotype seen in other latent virus infections. Most intriguingly, titers of neutralizing antibodies increased over time in 10/17 individuals months to years after the acute infection and independently of whether they were residents of endemic areas or not. Thus, our data suggest intrinsic, latent antigenic stimulation of Gn-specific T-cells. However, it remains a major task for future studies to proof this hypothesis by determination of viral antigen in convalescent patients. Furthermore, it remains to be seen whether Gn-specific T cells are critical for viral control and protective immunity. If so, Gn-derived immunodominant epitopes could be of high value for future ANDV vaccines.

Expression of IL‐18 in intestinal epithelial cells (IEC) has been implicated in Th1 cell‐mediated chronic intestinal inflammation and anti‐tumor immunity. However, physiological regulatory factors have not been identified. Besides their effects on proliferation and restitution, immunomodulatory functions have been attributed to short chain fatty acids (SCFA). We investigated the effect of SCFA (butyrate, propionate, acetate) on expression of IL‐18 in IEC in vitro and in vivo. Expression of IL‐18 mRNA and protein in human carcinoma‐derived HT‐29 and Caco‐2 cells was analyzed by reverse transcription‐PCR and Western blot. Transcriptional regulation of IL‐18 gene expression was determined by transient transfection of wild‐type and mutated IL‐18 promoter. Further, in vivo expression of IL‐18 in the intestine from butyrate‐treated and untreated mice was assessed by immunohistochemistry. IL‐18 mRNA and the IL‐18 protein were expressed in IEC, while IL‐18 secretion was not observed. Butyrate and acetate increased intracellular IL‐18 content in a time‐ and dose‐dependent fashion. In contrast to proinflammatory stimuli butyrate potently activated the IL‐18 promoter, indicating that IL‐18 is regulated at the transcriptional level by SCFA. Furthermore, a 108‐bp sequence in the proximal region was identified to be essential for IL‐18 promoter activation by butyrate. As proof of principle butyrate effects were confirmed in vivo by demonstration of increased IL‐18 protein expression in IEC from butyrate‐treated mice. In conclusion, SCFAup‐regulate IL‐18 protein expression in IEC, suggesting a potential regulatory contribution of these luminal constituents to T cell mediated inflammatory and neoplastic intestinal conditions.

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