The Cytomegalovirus Homolog of Interleukin-10 Requires Phosphatidylinositol 3-Kinase Activity for Inhibition of Cytokine Synthesis in Monocytes

Human cytomegalovirus (CMV) has evolved numerous strategies for evading host immune defenses, including piracy of cellular cytokines. A viral homolog of interleukin-10, designated cmvIL-10, binds to the cellular IL-10 receptor and effects potent immune suppression. The signaling pathways employed by cmvIL-10 were investigated, and the classic IL-10R/JAK1/Stat3 pathway was found to be activated in monocytes. However, inhibition of JAK1 had little effect on cmvIL-10-mediated suppression of tumor necrosis factor alpha (TNF-α) production. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway had a more significant impact on TNF-α levels but did not completely relieve the immune suppression, demonstrating that cmvIL-10 stimulates multiple signaling pathways to modulate cell function

Methods for Detection of Matrix Metalloproteinases as Biomarkers in Cardiovascular Disease

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteolytic enzymes that degrade extracellular matrix (ECM) components like collagen, fibronectin, and laminin. While this activity is important for normal development, morphogenesis, and wound healing, deregulation of MMP activity has been implicated in a number of cardiovascular diseases, including congenital heart defects, atherosclerosis, myocardial infarction, and congestive heart failure. MMPs are good potential diagnostic indicators of cardiovascular disease, but current detection methods are time consuming and quite laborious. This review will discuss MMP biology, current methods for detection of MMPs from patient samples, and potential new developments in multiplexed analysis of MMPs

cmvIL-10 Stimulates the Invasive Potential of MDA-MB-231 Breast Cancer Cells

Cancer is the result of unregulated cell growth that leads to tumor formation, and in many cases, metastases. Although there are several risk factors associated with cancer, one area that remains poorly understood is the impact of infectious disease. Human cytomegalovirus (HCMV) is a member of the herpesvirus family that is highly prevalent in the population. HCMV usually causes clinical disease only in immune compromised individuals, but recent evidence suggests that HCMV may be strongly associated with some forms of cancer, particularly glioblastoma and breast cancer. We investigated the possibility that cmvIL-10, a viral cytokine with homology to human IL-10 that is secreted from infected cells, could act in a paracrine manner to alter the tumor microenvironment, induce cell signaling, and increase the invasive potential of cancer cells. We found that human MDA-MB-231 breast cancer cells express the IL-10 receptor and that exposure to cmvIL-10 results in activation of Stat3, a transcription factor strongly associated with enhanced metastatic potential and chemo- resistance. In addition, cmvIL-10 stimulated an increase in DNA synthesis and cell proliferation, protected MDA-MB-231 cells from etoposide-induced apoptosis, and also greatly enhanced chemotaxis toward epidermal growth factor (EGF). These results suggest a significant and wide-ranging role for cmvIL-10 in the progression of breast cancer and could have broad implications for the diagnosis and treatment of cancer in HCMV-positive patients

Development of a non-invasive liquid biopsy for detection of cmvIL-10

Human cytomegalovirus (HCMV) is a prevalent type of herpes virus in our population. HCMV infection has no effect on the majority of people, but in some cases HCMV is strongly correlated with various medical outcomes, such as breast cancer. We focus on the UL111A gene product of HCMV, which encodes the secreted protein cmvIL-10. CmvIL-10 is a homolog of human cytokine IL-10 (hIL-10), which has immunosuppressive effects and promotes proliferation and invasion of breast cancer cells in vitro. We are measuring cmvIL-10 in human blood and have found elevated levels of cmvIL-10 in cancer patients. Here, we are investigating the adaptation of the cmvIL-10 blood test for detection of the viral cytokine in saliva and urine. We are now conducting a study of healthy donors to monitor changes in cmvIL-10 levels over time in various body fluids. The results from this small pilot project may ultimately lead to an inexpensive and non-invasive diagnostic tool for detection of breast cancer

Co-Creation as an agonistic practice in the favela of Santa Marta, Rio de Janeiro

This paper explores the potential of ‘Co-Creation’ to develop new understandings of neighbourhood disadvantage in collaboration with civil society partners. It argues that there is a growing need for collaborative knowledge production with communities carrying vernacular knowledges previously invalidated by dominant epistemologies. The first part of the paper undertakes a reconceptualization of ‘co-creation’, a term usually associated with citizen involvement in neoliberal contexts, redeveloping it as a ‘critical artistic practice’ (Chantal Mouffe, 2013) in which new ways of imagining the city can be articulated. The second part of the paper examines the practice of Co-Creation as a participatory methodology involving artists, researchers and stakeholders in developing ‘agonistic spaces’ by scrutinizing a five-day workshop conducted in the Rio de Janeiro favela of Santa Marta to explore multiple understandings and meanings of this neighbourhood. Through an analysis of creative workshop activities such as photovoice and mapping exercises, the authors explore the potential of the Co-Creation approach to construct new subjectivities that can help subvert existing configurations of power. The conclusion formulates some recommendations about future strategies to maximise Co-Creation’s potential to engage communities in collaborative knowledge production about their neighbourhoods and bring about positive change.

Role of human cytomegalovirus in breast cancer

Cancer results from unregulated cell growth that invades neighboring tissues. While there are many known risk factors for cancer, one area that remains largely unexplored is the impact of infectious disease. Human cytomegalovirus (HCMV) is highly prevalent in the population and has also been found in several types of tumors. We are investigating the possibility that a viral protein released from infected cells, cmvIL-10, promotes tumor metastasis by enhancing the invasive potential of breast cancer cells. These results will clarify the role of HCMV in breast cancer progression and could have broad implications for the diagnosis and treatment of cancer

Virus-Host Co-evolution: Determining the Origin of Human Cytomegalovirus US27 and US28

G protein-coupled receptors (GPCR) are the largest family of cell surface proteins, found in organisms from yeast to humans. Human cytomegalovirus (HCMV) is a widespread pathogen that is particularly skilled at evading immune detection and defense mechanisms, largely due to extensive co-evolution with its host’s immune system. One aspect of this co-evolution involves the acquisition of four virally encoded GPCR homologs: US27, US28, UL33 and UL78. In this research, phylogenetic analysis was used to investigate the origins of the US27 and US28 genes, which are adjacent in the viral genome. The results indicate that both US27 and US28 share the same common ancestor, human chemokine receptor CX3CR1, suggesting that a single human gene was captured and a viral gene duplication event occurred. While the evolutionary purpose of the gene duplication event remains unclear, experimental evidence indicates that each gene has evolved distinct, important functions during virus infection

Stranger in a Strange Land: Old Chair, New University

There are opportunities and challenges associated with appointing a chair from within and from outside the organization. This discussion will consider multiple aspects and focus on considerations for changing institutions to assume the chair position

Human Cytomegalovirus Interleukin-10 Promotes Proliferation and Migration of MCF-7 Breast Cancer Cells

Breast cancer is the most common malignancy affecting women worldwide. While a small fraction of breast cancers have a hereditary component, environmental and behavioral factors also impact the development of cancer. Human cytomegalovirus (HCMV) is a member of the Herpesviridae family that is widespread in the general population and has been linked to several forms of cancer. While HCMV DNA has been found in some breast cancer tissue specimens, we wanted to investigate whether a secreted viral cytokine might have an effect on cancerous or even pre-cancerous cells. HCMV encodes an ortholog of the human cellular cytokine interleukin-10 (IL-10). The HCMV UL111A gene product is cmvIL-10, which has 27% sequence identity to IL-10 and binds the cellular IL-10 receptor (IL-10R) to induce downstream cell signaling. We found that MCF-7 human breast cancer cells express IL-10R and that exposure to cmvIL-10 results in enhanced proliferation and increased chemotaxis of MCF-7 cells. PCR arrays revealed that treatment with cmvIL-10 alters expression of cell adhesion molecules and increases MMP gene expression. In particular, MMP-10 gene expression was found to be significantly up-regulated and this correlated with an increase in cell-associated MMP-10 protein produced by MCF-7 cells exposed to cmvIL-10. These results suggest that the presence of cmvIL-10 in the tumor microenvironment could contribute to the development of more invasive tumors