No abstract

Molecular mimicry of cytokines and cytokine receptors is a strategy used by poxviruses and herpesviruses to modulate host immunity. The human cytomegalovirus (HCMV) UL144 gene, situated in the UL/b' region of the viral genome, has amino-acid sequence similarity to members of the tumour necrosis factor receptor superfamily. We report that UL144 is a potent activator of NFkappaB-induced transcription in a TRAF6-dependent manner. This NFkappaB activation enhances expression of the chemokine CCL22 through the NFkappaB responsive elements found in its promoter. In contrast to the clinical HCMV isolates, extensively passaged laboratory strains lack the UL/b' region and hence do not encode UL144. Consistent with this, infection with viruses that carry UL/b' causes NFkappaB activation and CCL22 expression, a phenotype that is not observed after infections with strains lacking the UL/b' region. Moreover, knockdown of UL144, TRAF6 or NFkappaB by specific siRNA in infections with UL144-encoding HCMV prevents the activation of CCL22 expression normally observed after infection with UL/b' positive HCMV. Upregulation of CCL22, which attracts Th2 and regulatory T cells, may help HCMV evade immune surveillance.

We report here the first demonstration of dengue virus infection and vasoactive cytokine response of a cell of the mast cell/basophil lineage. Infection of KU812 cells was dependent on dengue-specific antibody and gave rise to infectious virions. This antibody-enhanced dengue virus infection triggered a four-to fivefold increase in the release of interleukin-1␤ (IL-1␤) and a modest increase for IL-6 but not for an alternate cytokine, granulocyte-macrophage colony-stimulating factor. The results suggest a potential role for mast cells/basophils in the pathogenesis of dengue virus-induced disease.

Vibrio cholerae is a globally distributed water-borne pathogen that causes severe diarrheal disease and mortality, with current outbreaks as part of the seventh pandemic. Further understanding of the role of environmental factors in potential pathogen distribution and corresponding V. cholerae disease transmission over time and space is urgently needed to target surveillance of cholera and other climate and water-sensitive diseases. We used an ecological niche model (ENM) to identify environmental variables associated with V. cholerae presence in marine environments, to project a global model of V. cholerae distribution in ocean waters under current and future climate scenarios. We generated an ENM using published reports of V. cholerae in seawater and freely available remotely sensed imagery. Models indicated that factors associated with V. cholerae presence included chlorophyll-a, pH, and sea surface temperature (SST), with chlorophyll-a demonstrating the greatest explanatory power from variables selected for model calibration. We identified specific geographic areas for potential V. cholerae distribution. Coastal Bangladesh, where cholera is endemic, was found to be environmentally similar to coastal areas in Latin America. In a conservative climate change scenario, we observed a predicted increase in areas with environmental conditions suitable for V. cholerae. Findings highlight the potential for vulnerability maps to inform cholera surveillance, early warning systems, and disease prevention and control.

Here we report the findings from the first two years of an arbovirus surveillance study conducted in Machala, Ecuador, a dengue endemic region (2014-2015). Patients with suspected dengue virus (DENV) infections (index cases, n=324) were referred from five Ministry of Health clinical sites. A subset of DENV positive index cases (n = 44) were selected, and individuals from the index household and four neighboring homes within 200-meters were recruited (n = 400). Individuals who entered the study, other than index cases, are referred to as associates. In 2014, 70.9% of index cases and 35.6% of associates had acute or recent DENV infections. In 2015, 28.3% of index cases and 12.8% of associates had acute or recent DENV infections. For every DENV infection captured by passive surveillance, we detected an additional three acute or recent DENV infections in associates. Of associates with acute DENV infections, 68% reported dengue-like symptoms, with the highest prevalence of symptomatic acute infections in children under 10 years of age. The first chikungunya virus (CHIKV) infections were detected on epidemiological week 12 in 2015. 43.1% of index cases and 3.5% of associates had acute CHIKV infections. No Zika virus infections were detected. Phylogenetic analyses of isolates of DENV from 2014 revealed genetic relatedness and shared ancestry of DENV1, DENV2 and DENV4 genomes from Ecuador with those from Venezuela and Colombia, indicating presence of viral flow between Ecuador and surrounding countries. Enhanced surveillance studies, such as this, provide high-resolution data on symptomatic and inapparent infections across the population.

Epstein-Barr virus (EBV) is a well-established B-cell-tropic virus associated with various lymphoproliferative diseases of both B-cell and non-B-cell origin.EBV is associated with a number of T-cell lymphomas; however, in vitro studies utilizing prototypical EBV type 1 (EBV-1) laboratory strains have generally failed to readily infect mature T cells in culture. The difficulties in performing in vitro T-cell experiments have left questions regarding the role of EBV in the pathogenesis of EBV-positive T-cell lymphoproliferative diseases largely unresolved. We report here that the EBV type 2 (EBV-2) strain displays a unique cell tropism for T cells. In remarkable contrast to EBV-1, EBV-2 readily infects primary T cells in vitro, demonstrating a propensity for CD8 ؉ T cells. EBV-2 infection of purified T cells results in expression of latency genes and ultimately leads to T-cell activation, substantial proliferation, and profound alteration of cytokine expression. The pattern of cytokine production is strikingly skewed toward chemokines with roles in lymphocyte migration, demonstrating that EBV-2 has the ability to modulate normal T-cell processes. Collectively, these novel findings identify a previously unknown cell population potentially utilized by EBV-2 to establish latency and lay the foundation for further studies to elucidate the role of EBV in the pathogenesis of T-cell lymphoproliferative diseases. IMPORTANCE The ability of EBV to infect T cells is made apparent by its association with a variety of T-cell lymphoproliferative disorders.However, studies to elucidate the pathogenic role of EBV in these diseases have been limited by the inability to conduct in vitro T-cell infection experiments. Here, we report that EBV-2 isolates, compromised in the capacity to immortalize B cells, infect CD3 ؉ T cells ex vivo and propose a working model of EBV-2 persistence where alteration of T-cell functions resulting from EBV-2 infection enhances the establishment of latency in B cells. If indeed EBV-2 utilizes T cells to establish a persistent infection, this could provide one mechanism for the association of EBV with T-cell lymphomas. The novel finding that EBV-2 infects T cells in culture will provide a model to understand the role EBV plays in the development of T-cell lymphomas. While Epstein-Barr virus (EBV) establishes lifelong latency in B cells and is associated with B-cell malignancies, it is also associated with malignancies and diseases that originate from T cells, including NK/T-cell lymphomas (1), hemophagocytic lymphohistiocytosis (2), hydroa vacciniforme (HV) (3), and chronic active EBV (CAEBV) (4, 5). In these diseases, EBV can be detected in CD4 ϩ T cells, CD8 ϩ T cells, or ␥␦ T cells (6, 7), with the virus predominantly existing as a latent infection (8, 9). The etiology of these T-cell diseases, and in particular whether EBV infection of T cells is an aberrancy in a virus known for its B-cell tropism in vitro and in vivo, remains unknown.Based on genetic differences in the Epstein-Barr nuclear ...

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and the inflammation-driven neoplasm Kaposi's sarcoma (KS). A triad of processes, including abnormal proliferation of endothelial cells, aberrant angiogenesis, and chronic inflammation, characterize KS lesions. STAT3 is a key transcription factor governing these processes, and deregulation of STAT3 activity is linked to a wide range of cancers, including PEL and KS. Using primary human endothelial cells (ECs), I demonstrate that KSHV infection modulated STAT3 activation in two ways: (i) KSHV induced uncoupling of canonical tyrosine (Y) and serine (S) phosphorylation events while (ii) concomitantly inducing the phosphorylation and inactivation of TRIM28 (also known as KAP-1 or TIF-1␤), a newly identified negative regulator of STAT3 activity. KSHV infection of primary ECs induced chronic STAT3 activation characterized by a shift from the canonical dual P-STAT3 Y705 S727 form to a mono P-STAT3 S727 form. Expression of the latent protein kaposin B promoted the unique phosphorylation of STAT3 at S727, in the absence of Y705, activated the host kinase mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), and stimulated increased expression of STAT3-dependent genes, including CCL5, in ECs. TRIM28-mediated repression of STAT3 is relieved by phosphorylation of S473, and in vitro kinase assays identified TRIM28 S473 as a bona fide target of MK2. Together, these data suggest that kaposin B significantly contributes to the chronic inflammatory environment that is a hallmark of KS by unique activation of the proto-oncogene STAT3, coupled with MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28.

During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, host gene expression is severely restricted by a process of global mRNA degradation known as host shutoff, which rededicates translational machinery to the expression of viral proteins. A subset of host mRNAs is spared from shutoff, and a number of these containcis-acting AU-rich elements (AREs) in their 3′ untranslated regions. AREs are found in labile mRNAs encoding cytokines, growth factors, and proto-oncogenes. Activation of the p38/MK2 signal transduction pathway reverses constitutive decay of ARE-mRNAs, resulting in increased protein production. The viral G-protein-coupled receptor (vGPCR) is thought to play an important role in promoting the secretion of angiogenic molecules from KSHV-infected cells during lytic replication, but to date it has not been clear how vGPCR circumvents host shutoff. Here, we demonstrate that vGPCR activates the p38/MK2 pathway and stabilizes ARE-mRNAs, augmenting the levels of their protein products. Using MK2-deficient cells, we demonstrate that MK2 is essential for maximal vGPCR-mediated ARE-mRNA stabilization. ARE-mRNAs are normally delivered to cytoplasmic ribonucleoprotein granules known as processing bodies (PBs) for translational silencing and decay. We demonstrate that PB formation is prevented during KSHV lytic replication or in response to vGPCR-mediated activation of RhoA subfamily GTPases. Together, these data show for the first time that vGPCR impacts gene expression at the posttranscriptional level, coordinating an attack on the host mRNA degradation machinery. By suppressing ARE-mRNA turnover, vGPCR may facilitate escape of certain target mRNAs from host shutoff and allow secretion of angiogenic factors from lytically infected cells.