Structure of the Extracellular Portion of CD46 Provides Insights into Its Interactions with Complement Proteins and Pathogens

The human membrane cofactor protein (MCP, CD46) is a central component of the innate immune system. CD46 protects autologous cells from complement attack by binding to complement proteins C3b and C4b and serving as a cofactor for their cleavage. Recent data show that CD46 also plays a role in mediating acquired immune responses, and in triggering autophagy. In addition to these physiologic functions, a significant number of pathogens, including select adenoviruses, measles virus, human herpes virus 6 (HHV-6), Streptococci, and Neisseria, use CD46 as a cell attachment receptor. We have determined the crystal structure of the extracellular region of CD46 in complex with the human adenovirus type 11 fiber knob. Extracellular CD46 comprises four short consensus repeats (SCR1-SCR4) that form an elongated structure resembling a hockey stick, with a long shaft and a short blade. Domains SCR1, SCR2 and SCR3 are arranged in a nearly linear fashion. Unexpectedly, however, the structure reveals a profound bend between domains SCR3 and SCR4, which has implications for the interactions with ligands as well as the orientation of the protein at the cell surface. This bend can be attributed to an insertion of five hydrophobic residues in a SCR3 surface loop. Residues in this loop have been implicated in interactions with complement, indicating that the bend participates in binding to C3b and C4b. The structure provides an accurate framework for mapping all known ligand binding sites onto the surface of CD46, thereby advancing an understanding of how CD46 acts as a receptor for pathogens and physiologic ligands of the immune system

Arboviral Etiologies of Acute Febrile Illnesses in Western South America, 2000–2007

Over recent decades, the variety and quantity of diseases caused by viruses transmitted to humans by mosquitoes and other arthropods (also known as arboviruses) have increased around the world. One difficulty in studying these diseases is the fact that the symptoms are often non-descript, with patients reporting such symptoms as low-grade fever and headache. Our goal in this study was to use laboratory tests to determine the causes of such non-descript illnesses in sites in four countries in South America, focusing on arboviruses. We established a surveillance network in 13 locations in Ecuador, Peru, Bolivia, and Paraguay, where patient samples were collected and then sent to a central laboratory for testing. Between May 2000 and December 2007, blood serum samples were collected from more than 20,000 participants with fever, and recent arbovirus infection was detected for nearly one third of them. The most common viruses were dengue viruses (genera Flavivirus). We also detected infection by viruses from other genera, including Alphavirus and Orthobunyavirus. This data is important for understanding how such viruses might emerge as significant human pathogens

Natural transmission of Leishmania infantum through experimentally infected Phlebotomus perniciosus highlights the virulence of Leishmania parasites circulating in the human visceral leishmaniasis outbreak in Madrid, Spain

International audienceAbstractA human leishmaniasis outbreak is occurring in the Madrid region, Spain, with the parasite and vector involved being Leishmania infantum and Phlebotomus perniciosus respectively. The aim of this study was to investigate the virulence of L. infantum isolates from the focus using a natural transmission model. Hamsters were infected by intraperitoneal inoculation (IP) or by bites of sand flies experimentally infected with L. infantum isolates obtained from P. perniciosus collected in the outbreak area (IPER/ES/2012/BOS1FL1 and IPER/ES/2012/POL2FL6) and a well characterized L. infantum strain JPCM5 (MCAN/ES/98/LLM-877). Hamster infections were monitored by clinical examination, serology, culture, parasite burden, Giemsa-stained imprints, PCR, histopathology and xenodiagnostic studies. Establishment of infection of L. infantum was achieved with the JPCM5 strain and outbreak isolates by both P. perniciosus infective bites or IP route. However, high virulence of BOS1FL1 and POL2FL6 isolates was highlighted by the clinical outcome of disease, high parasite detection in spleen and liver, high parasitic loads and positivity of Leishmania serology. Transmission by bite of POL2FL6 infected flies generated a slower progression of clinical disease than IP infection, but both groups were infective to P. perniciosus by xenodiagnosis at 2 months post-infection. Conversely, hamsters inoculated with JPCM5 were not infective to sand flies. Histopathology studies confirmed the wide spread of POL2FL6 parasites to several organs. A visceral leishmaniasis model that mimics the natural transmission in nature allowed us to highlight the high virulence of isolates that are circulating in the focus. These findings contribute to a better understanding of the outbreak epidemiology

Uso de medicamentos armazenados em domicílio em uma população atendida pelo Programa Saúde da Família The use of medicines storaged in the household in a population assisted by Family Health Program

Abordar epidemiologicamente o uso de medicamentos impõe reconhecer que tal prática não se limita a fatores farmacoterapêuticos. O armazenamento adequado e a preservação de medicamentos são fatores fundamentais para a sua eficácia. O presente estudo teve como objetivo verificar a forma de armazenamento/uso de medicamentos em uma comunidade atendida pelo Programa/Estratégia Saúde da Família no município de Cristino Castro (PI), bem como o grau de conhecimento a respeito dos medicamentos mantidos sob sua guarda. Os dados foram obtidos em visitas domiciliares a 52 famílias, a partir de observações e da aplicação de um questionário. Observaram-se baixa renda e baixa escolaridade da população, fatores agravantes na efetiva orientação terapêutica e acesso aos fármacos. Elevado percentual dos medicamentos estocados é adquirido sem prescrição. Destacamos a classe dos antimicrobianos, reforçando o perigo da automedicação. 62% dos responsáveis pela guarda não possuem a orientação mínima para assegurar o uso racional, e 66% não tem ciência da toxicidade. 54,10% dos medicamentos estavam ao alcance de crianças e animais domésticos e 15,92% não possuíam rótulo ou qualquer identificação. Algumas famílias mantêm em estoque medicações básicas, outras acumulam um "arsenal terapêutico".<br>To approach the epidemiological use of medicines is necessary to recognize that such practice is not strictly limited to pharmacotherapy. The appropriate storage and the preservation of medicines are fundamental factors for effectiveness. This study was aimed at verifying the storage form/use of medicines in a community assisted by the Family Health Program in the district of Cristino Castro (PI, Brazil), as well as the level of the people's knowledge regarding drugs storage at home. The data were obtained visiting 52 families, starting with observations and applying a questionnaire. It was observed a low income and education levels, a fact that contributes in the effective therapeutic orientation. High percentage of the stored medicines is acquired without prescription. It is worth of mention the presence of a big amount of antimicrobial, reinforcing the danger of the self medication. 62% of those who take care of drugs have no information about their rational use, and 66% are not conscious of the toxicity. 54.10% of the medicines were at children's and domestic animals reach and 15.92% didn't possess label or any identification. Some families maintain in stock, basic medications, another accumulate a "therapeutic arsenal"