SummaryAedes aegypti mosquitoes are responsible for transmitting many medically important viruses such as those that cause Zika and dengue. The inoculation of viruses into mosquito bite sites is an important and common stage of all mosquito-borne virus infections. We show, using Semliki Forest virus and Bunyamwera virus, that these viruses use this inflammatory niche to aid their replication and dissemination in vivo. Mosquito bites were characterized by an edema that retained virus at the inoculation site and an inflammatory influx of neutrophils that coordinated a localized innate immune program that inadvertently facilitated virus infection by encouraging the entry and infection of virus-permissive myeloid cells. Neutrophil depletion and therapeutic blockade of inflammasome activity suppressed inflammation and abrogated the ability of the bite to promote infection. This study identifies facets of mosquito bite inflammation that are important determinants of the subsequent systemic course and clinical outcome of virus infection.

Human prion diseases can occur as an idiopathic disorder (sporadic Creutzfeldt-Jakob disease) or can be acquired, as is the case for variant Creutzfeldt-Jakob disease. These disorders are characterized by the accumulation of a protease-resistant form of the host-encoded prion protein termed PrP(Sc) in the brains of affected individuals. PrP(Sc) has been proposed to be the principal, if not sole, component of the infectious agent, with its accumulation in the central nervous system the primary event leading to neurodegeneration. A major question remains as to whether self-propagating structural differences in PrP(Sc) might account for the clinicopathological diversity evident in Creutzfeldt-Jakob disease and whether different prion protein types underlie the existence of different strains of causative agent. Here, we describe the results of a large-scale biochemical study of PrP(Sc) from autopsy-proved cases of variant Creutzfeldt-Jakob disease (n = 59) and compare these with cases of sporadic Creutzfeldt-Jakob disease (n = 170) in the United Kingdom over the period 1991 to 2002. The results show PrP(Sc) in variant Creutzfeldt-Jakob disease to be remarkably stereotyped. In contrast, considerable heterogeneity in PrP(Sc) exists both between and within cases of sporadic Creutzfeldt-Jakob disease.

Mosquito-borne infections are increasing in number and are spreading to new regions at an unprecedented rate. In particular, mosquito-transmitted viruses, such as those that cause Zika, dengue, West Nile encephalitis, and chikungunya, have become endemic or have caused dramatic epidemics in many parts of the world. Aedes and Culex mosquitoes are the main culprits, spreading infection when they bite. Importantly, mosquitoes do not act as simple conduits that passively transfer virus from one individual to another. Instead, host responses to mosquito-derived factors have an important influence on infection and disease, aiding replication and dissemination within the host. Here, we discuss the latest research developments regarding this fascinating interplay between mosquito, virus, and the mammalian host.

Key Points• D6 regulates the ability of lymphatic endothelial cells to discriminate between mature and immature dendritic cells. • D6 expression is regulated by inflammatory cytokines indicative of a preferential role in inflamed conditions.The mechanisms by which CC chemokine receptor (CCR)7 ligands are selectively presented on lymphatic endothelium in the presence of inflammatory chemokines are poorly understood. The chemokine-scavenging receptor D6 is expressed on lymphatic endothelial cells (LEC) and contributes to selective presentation of CCR7 ligands by suppressing inflammatory chemokine binding to LEC surfaces. As well as preventing inappropriate inflammatory cell attachment to LECs, D6 is specifically involved in regulating the ability of LEC to discriminate between mature and immature dendritic cells (DCs). D6 overexpression reduces immature DC (iDC) adhesion to LECs, whereas D6 knockdown increases adhesion of iDCs that displace mature DCs. LEC D6 expression is regulated by growth factors, cytokines, and tumor microenvironments. In particular, interleukin-6 and interferon-g are potent inducers, indicating a preferential role for D6 in inflamed contexts. Expression of the viral interleukin-6 homolog from Kaposi sarcoma-associated herpesvirus is also sufficient to induce significant D6 upregulation both in vitro and in vivo, and Kaposi sarcoma and primary effusion lymphoma cells demonstrate high levels of D6 expression. We therefore propose that D6, which is upregulated in both inflammatory and tumor contexts, is an essential regulator of inflammatory leukocyte interactions with LECs and is required for immature/mature DC discrimination by LECs. (Blood. 2013;121(18):3768-3777)

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