A human coronavirus responsible for the common cold massively kills dendritic cells but not monocytes

Copyright @ 2012, American Society for Microbiology.Human coronaviruses are associated with upper respiratory tract infections that occasionally spread to the lungs and other organs. Although airway epithelial cells represent an important target for infection, the respiratory epithelium is also composed of an elaborate network of dendritic cells (DCs) that are essential sentinels of the immune system, sensing pathogens and presenting foreign antigens to T lymphocytes. In this report, we show that in vitro infection by human coronavirus 229E (HCoV-229E) induces massive cytopathic effects in DCs, including the formation of large syncytia and cell death within only few hours. In contrast, monocytes are much more resistant to infection and cytopathic effects despite similar expression levels of CD13, the membrane receptor for HCoV-229E. While the differentiation of monocytes into DCs in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 requires 5 days, only 24 h are sufficient for these cytokines to sensitize monocytes to cell death and cytopathic effects when infected by HCoV-229E. Cell death induced by HCoV-229E is independent of TRAIL, FasL, tumor necrosis factor alpha, and caspase activity, indicating that viral replication is directly responsible for the observed cytopathic effects. The consequence of DC death at the early stage of HCoV-229E infection may have an impact on the early control of viral dissemination and on the establishment of long-lasting immune memory, since people can be reinfected multiple times by HCoV-229E

THERMODYNAMICS OF A BROWNIAN BRIDGE POLYMER MODEL IN A RANDOM ENVIRONMENT

We consider a directed random walk making either 0 or $+1$ moves and a Brownian bridge, independent of the walk, conditioned to arrive at point $b$ on time $T$. The Hamiltonian is defined as the sum of the square of increments of the bridge between the moments of jump of the random walk and interpreted as an energy function over the bridge connfiguration; the random walk acts as the random environment. This model provides a continuum version of a model with some relevance to protein conformation. The thermodynamic limit of the specific free energy is shown to exist and to be self-averaging, i.e. it is equal to a trivial --- explicitly computed --- random variable. An estimate of the asymptotic behaviour of the ground state energy is also obtained.Comment: 20 pages, uuencoded postscrip

The intensive care infection score - a novel marker for the prediction of infection and its severity

Background: The prediction of infection and its severity remains difficult in the critically ill. A novel, simple biomarker derived from five blood-cell derived parameters that characterize the innate immune response in routine blood samples, the intensive care infection score (ICIS), could be helpful in this respect. We therefore compared the predictive value of the ICIS with that of the white blood cell count (WBC), C-reactive protein (CRP) and procalcitonin (PCT) for infection and its severity in critically ill patients. Methods: We performed a multicenter, cluster-randomized, crossover study in critically ill patients between January 2013 and September 2014. Patients with a suspected infection for which blood cultures were taken by the attending intensivist were included. Blood was taken at the same time for WBC, ICIS, CRP and PCT measurements in the control study periods. Results of imaging and cultures were collected. Patients were divided into groups of increasing likelihood of infection and invasiveness: group 1 without infection or with possible infection irrespective of cultures, group 2 with probable or microbiologically proven local infection without blood stream infection (BSI) and group 3 with BSI irrespective of local infection. Septic shock was assessed. Results: In total, 301 patients were enrolled. CRP, PCT and ICIS were higher in groups 2 and 3 than group 1. The area under the receiver operating characteristic curve (AUROC) for the prediction of infection was 0.70 for CRP, 0.71 for PCT and 0.73 for ICIS (P < 0.001). For the prediction of septic shock the AUROC was 0.73 for CRP, 0.85 for PCT and 0.76 for ICIS. These AUROC did not differ fro

Plasmacytoid Dendritic Cells Capture and Cross-Present Viral Antigens from Influenza-Virus Exposed Cells

Among the different subsets of dendritic cells (DC), plasmacytoid dendritic cells (PDC) play a unique role in secreting large amounts of type I interferons upon viral stimulation, but their efficiency as antigen-presenting cells has not been completely characterized. We show here, by flow cytometry, with human primary blood PDC and with a PDC cell line, that PDC display poor endocytic capacity for soluble or cellular antigens when compared to monocyte-derived myeloid DC. However, immature PDC efficiently take up cellular material from live influenza-exposed cells, subsequently mature and cross-present viral antigens very efficiently to specific CD8+ T cells. Therefore, during viral infection PDC not only secrete immunomodulatory cytokines, but also recognize infected cells and function as antigen cross-presenting cells to trigger the anti-viral immune response

Simian virus 40 inhibits differentiation and maturation of rhesus macaque DC-SIGN+-dendritic cells

Dendritic cells (DC) are the initiators and modulators of the immune responses. Some species of pathogenic microorganisms have developed immune evasion strategies by controlling antigen presentation function of DC. Simian virus 40 (SV40) is a DNA tumor virus of rhesus monkey origin. It can induce cell transformation and tumorigenesis in many vertebrate species, but often causes no visible effects and persists as a latent infection in rhesus monkeys under natural conditions. To investigate the interaction between SV40 and rhesus monkey DC, rhesus monkey peripheral blood monocyte-derived DC were induced using recombinant human Interleukin-4 (rhIL-4) and infective SV40, the phenotype and function of DC-specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN)+ DC were analyzed by flow cytometry (FCM) and mixed lymphocyte reaction (MLR). Results showed that SV40 can down-regulate the expression of CD83 and CD86 on DC and impair DC-induced activation of T cell proliferation. These findings suggest that SV40 might also cause immune suppression by influencing differentiation and maturation of DC

Plasmacytoid Dendritic Cells Capture and Cross-Present Viral Antigens from Influenza-Virus Exposed Cells

Among the different subsets of dendritic cells (DC), plasmacytoid dendritic cells (PDC) play a unique role in secreting large amounts of type I interferons upon viral stimulation, but their efficiency as antigen-presenting cells has not been completely characterized. We show here, by flow cytometry, with human primary blood PDC and with a PDC cell line, that PDC display poor endocytic capacity for soluble or cellular antigens when compared to monocyte-derived myeloid DC. However, immature PDC efficiently take up cellular material from live influenza-exposed cells, subsequently mature and cross-present viral antigens very efficiently to specific CD8+ T cells. Therefore, during viral infection PDC not only secrete immunomodulatory cytokines, but also recognize infected cells and function as antigen cross-presenting cells to trigger the anti-viral immune response

HIV/SIV Infection Primes Monocytes and Dendritic Cells for Apoptosis

Subversion or exacerbation of antigen-presenting cells (APC) death modulates host/pathogen equilibrium. We demonstrated during in vitro differentiation of monocyte-derived macrophages and monocyte-derived dendritic cells (DCs) that HIV sensitizes the cells to undergo apoptosis in response to TRAIL and FasL, respectively. In addition, we found that HIV-1 increased the levels of pro-apoptotic Bax and Bak molecules and decreased the levels of anti-apoptotic Mcl-1 and FLIP proteins. To assess the relevance of these observations in the context of an experimental model of HIV infection, we investigated the death of APC during pathogenic SIV-infection in rhesus macaques (RMs). We demonstrated increased apoptosis, during the acute phase, of both peripheral blood DCs and monocytes (CD14+) from SIV+RMs, associated with a dysregulation in the balance of pro- and anti-apoptotic molecules. Caspase-inhibitor and death receptors antagonists prevented apoptosis of APCs from SIV+RMs. Furthermore, increased levels of FasL in the sera of pathogenic SIV+RMs were detected, compared to non-pathogenic SIV infection of African green monkey. We suggest that inappropriate apoptosis of antigen-presenting cells may contribute to dysregulation of cellular immunity early in the process of HIV/SIV infection

Differentiation of mouse bone marrow derived stem cells toward microglia-like cells

<p>Abstract</p> <p>Background</p> <p>Microglia, the macrophages of the brain, have been implicated in the causes of neurodegenerative diseases and display a loss of function during aging. Throughout life, microglia are replenished by limited proliferation of resident microglial cells. Replenishment by bone marrow-derived progenitor cells is still under debate. In this context, we investigated the differentiation of mouse microglia from bone marrow (BM) stem cells. Furthermore, we looked at the effects of FMS-like tyrosine kinase 3 ligand (Flt3L), astrocyte-conditioned medium (ACM) and GM-CSF on the differentiation to microglia-like cells.</p> <p>Methods</p> <p>We assessed <it>in vitro-</it>derived microglia differentiation by marker expression (CD11b/CD45, F4/80), but also for the first time for functional performance (phagocytosis, oxidative burst) and <it>in situ </it>migration into living brain tissue. Integration, survival and migration were assessed in organotypic brain slices.</p> <p>Results</p> <p>The cells differentiated from mouse BM show function, markers and morphology of primary microglia and migrate into living brain tissue. Flt3L displays a negative effect on differentiation while GM-CSF enhances differentiation.</p> <p>Conclusion</p> <p>We conclude that <it>in vitro-</it>derived microglia are the phenotypic and functional equivalents to primary microglia and could be used in cell therapy.</p