Influenza A virus infection of macrophages and virus-induced pro-inflammatory gene expression are regarded to contribute to severity of influenza A virus-caused diseases. Although some data are available on cytokine production by influenza A virus-infected macrophages, systematic comparisons of the virus types are currently considered to be of high relevance in humans (pandemic H1N1/2009, seasonal H1N1, seasonal H3N2, highly pathogenic avian influenza H5N1) on pro-inflammatory potential, and relevant underlying cellular signalling events are missing. Here, we show that the infection of human monocyte-derived macrophages with pandemic H1N1/2009 (A/HH/01/2009), seasonal H1N1/1999 (A/New Caledonia/20/99), seasonal H3N2/2004 (A/California/7/2004) or highly pathogenic H5N1/2004 (A/Thailand/1(Kan-1)/04) results in similar infection rates. However, the investigated H1N1 strains caused delayed and decreased apoptosis in comparison with H3N2/2004 or H5N1/2004. Moreover, human macrophage infection with H3N2/2004 or H5N1/2004 but not with H1N1 viruses was associated with pronounced pro-inflammatory cytokine production and activation of relevant mitogen-activated protein kinase pathways as indicated by phosphorylation of p38, JNK and ERK 1/2. These findings are in line with clinical observations indicating enhanced disease severity in H3N2- or H5N1-infected patients compared to individuals infected with pandemic H1N1/2009 or seasonal H1N1.

Comparison of pro-inflammatory cytokine expression and cellular signal transduction in human macrophages infected with different influenza A viruses.

The question whether human cytomegalovirus may affect cancer diseases has been discussed (very controversially) for decades. There are convinced believers and strict opponents of the idea that HCMV might be able to play a role in the course of cancer diseases. In parallel, the number of published reports on the topic is growing. Recently published and presented (Ranganathan P, Clark P, Kuo JS, Salamat S, Kalejta RF. A Survey of Human Cytomegalovirus Genomic Loci Present in Glioblastoma Multiforme Tissue Samples. 35th Annual International Herpes Workshop, Salt Lake City, 2010) data on HCMV detection in glioblastoma tissues and colocalisation of HCMV proteins with cellular proteins known to be relevant for glioblastoma progression motivated us to recapitulate the current state of evidence.

Oncomodulation by human cytomegalovirus: novel clinical findings open new roads

The human cytomegalovirus (HCMV), a ubiquitous herpes virus, establishes after (in healthy individuals typically subclinical) primary infection a lifelong persistence characterised by more or less frequent subclinical reactivations. It is an important pathogen in immunocompromised individuals and currently investigated for a plethora of diVerent questions and aspects [1–25]. The (possible) relationship between HCMV and cancer has been discussed for decades [1]. Detection of viral DNA, mRNA and/or antigens in tumour tissues as well as seroepidemiologic evidence suggested a role of HCMV infection in several human malignancies. However, controversial clinical results from diVerent groups had raised skepticism about a role of HCMV in cancer [1]. A major point of concern is that HCMV is not considered to be a tumour virus due to a lack of proven transformation potential in human cells. To explain the frequent presence of HCMV in tumour tissues, we proposed the concept of oncomodulation [26]. Oncomodulation means that HCMV may infect tumour cells and increase their malignancy. We postulated that tumour cells provide a genetic environment, characterised by disturbances in intracellular signalling pathways, transcription factors, and tumour suppressor proteins, that enables HCMV to exert its oncomodulatory potential while it cannot be manifested in normal cells (Fig. 1) [1]. Our experimental Wndings and those of others supported the concept of oncomodulation. Sub-cutaneous injection of long-term persistently HCMV-infected neuroblastoma cells resulted in enhanced tumour growth and metastasis formation compared to non-infected cells [26]. Subsequent in vivo Wndings by others supported the oncomodulatory eVects of HCMV or murine cytomegalovirus proteins expressed in transformed cells [1]. HCMV-induced oncomodulation may result from the activity of virus regulatory proteins and noncoding RNAs which inXuence properties of tumour cells including cell proliferation, survival, invasion, immunogenicity, tumour angiogenesis, and chromosomal stability [1]. Although it is necessary to stress that no Wnal conclusion about the (frequency of the) presence of HCMV in cancer cells and its eVects on tumour biology can be drawn, recent pathological Wndings from diVerent groups using highly sensitive techniques for virus detection indicated the presence of genome and antigens of HCMV in tumour cells (but not in adjacent normal tissue) of a great proportion of patients with malignancies, such as colon cancer, malignant glioma, prostatic carcinoma, and breast cancer [1, 27–30]. These observations indicated that HCMV causes low-grade infection in tumour cells probably sustained by persistent virus replication. The establishment of low-grade infection by HCMV in tumour cells provides an explanation why HCMV was not detected in tumour cells by diVerent other groups [1, 31– 33]. These groups used pathological methods established for the detection of active HCMV replication, characterised by high HCMV titres and presence of high levels of HCMV proteins and HCMV genome that obviously fail to detect low-level replication. It might be helpful to exemplarily discuss pathological Wndings from glioma patients. Cobbs et al. [27] reported HCMV infection of tumour cells but not of surrounding normal brain tissue in a high percentage of gliomas. These Wndings were not conWrmed by Lau et al. [31] or Polterman et al. [32], who both did not detect M. Michaelis · H. W. Doerr · J. Cinatl Jr (&) Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany e-mail: cinatl@em.uni-frankfurt.de

Oncomodulation by human cytomegalovirus: evidence becomes stronger.

The euphoria of stem cell therapy has diminished, allowing scientists, clinicians and the general public to seriously re-examine how and what types of stem cells would effectively repair damaged tissue, prevent further tissue damage and/or replace lost cells. Importantly, there is a growing recognition that there are substantial person-to-person differences in the outcome of stem cell therapy. Even though the small molecule pharmaceuticals have long remained a primary focus of the personalized medicine research, individualized or targeted use of stem cells to suit a particular individual could help forecast potential failures of the therapy or identify, early on, the individuals who might benefit from stem cell interventions. This would however demand collaboration among several specialties such as pharmacology, immunology, genomics and transplantation medicine. Such transdisciplinary work could also inform how best to achieve efficient and predictable stem cell migration to sites of tissue damage, thereby facilitating tissue repair. This paper discusses the possibility of polarizing immune responses to rationalize and individualize therapy with stem cell interventions, since generalized "one-size-fits-all" therapy is difficult to achieve in the face of the diverse complexities posed by stem cell biology. We also present the challenges to stem cell delivery in the context of the host related factors. Although we focus on the mesenchymal stem cells in this paper, the overarching rationale can be extrapolated to other types of stem cells as well. Hence, the broader purpose of this paper is to initiate a dialogue within the personalized medicine community by expanding the scope of inquiry in the field from pharmaceuticals to stem cells and related cell-based health interventions.

/pdf/personalizing-stem-cell-research-and-therapy-the-arduous-2fj5irglaq.pdf

Personalizing Stem Cell Research and Therapy: The Arduous Road Ahead or Missed Opportunity?

The present invention relates to a beta-herpesvirus, preferably a recombinant beta-herpesvirus, wherein the beta-herpesvirus comprises at least one heterologous nucleic acid, wherein the at least one heterologous nucleic acid comprises a gene encoding a cellular ligand.

Vaccine comprising beta-herpesvirus

Hematopoietic stem cell transplantation (HSCT) is a promising therapeutic option against hematopoietic malignancies. Infection with cytomegalovirus (CMV) and tumor relapse are complications that limit the success of HSCT. In theory, CMV infection can facilitate tumor relapse and growth by inhibiting “graft take” and reconstitution of the immune system or by inducing the secretion of tumor cell growth-promoting cytokines. Conversely, one can also envisage an anti-tumoral effect of CMV by cytopathic/oncolytic infection of tumor cells, by inducing the secretion of death ligands for tumor cell apoptosis, and by the activation of systemic innate and adaptive immunity. Here we will briefly review the current knowledge about tumor control in a murine model of CMV infection and liver-adapted B cell lymphoma, with a focus on a putative implication of CD49+NKG2D+ hepatic natural killer cells.

/pdf/activation-of-hepatic-natural-killer-cells-and-control-of-3vnkns1ugc.pdf

Activation of hepatic natural killer cells and control of liver-adapted lymphoma in the murine model of cytomegalovirus infection

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Activation of hepatic natural killer cells and control of liver-adapted lymphoma in the murine model of cytomegalovirus infection