http://hdl.handle.net/2268/104 Search this channel search http://orbi.ulg.ac.be/simple-search http://hdl.handle.net/2268/150521 Title: Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion <br/> <br/>Author, co-author: Renoux, Virginie; Bisig, Bettina; Langers, Inge; Renaud, Bastin; Thiry, Marc; Deroanne, Christophe; Delvenne, Philippe; Jacobs, Nathalie <br/> <br/>Abstract: Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV-infected women clear the virus within two years. However, it remains unclear which immune cells are implicated in this process and no study has evaluated the direct interaction between HPVs and NK cells, a key player in host resistance to viruses and tumors. We demonstrated an NK-cell infiltration in HPV- associated preneoplastic cervical lesions. Since HPVs cannot grow in vitro, virus-like particles (VLPs) were used as a model for studying the NK-cell response against the virus. Interestingly, NK cells displayed higher cytotoxic activity and cytokine production (TNF-a and IFN-g) in the presence of HPV-VLPs. Using flow cytometry and microscopy, we observed that NK-cell stimulation was linked to rapid VLP entry into these cells by macropinocytosis. Using CD16+ and CD16- NK-cell lines and a CD16-blocking antibody, we demonstrated that CD16 is necessary for HPV–VLP internalization, as well as for degranulation and cytokine production. Thus, we show for the first time that NK cells interact with HPVs and can participate in the immune response against HPV-induced lesions. http://hdl.handle.net/2268/150110 Title: Plusieurs épidémies de fièvre hémorragique due au virus Ebola au Gabon, d'octobre 2001 à avril 2002 <br/> <br/>Author, co-author: Nkoghe Mba, Dieudonne; Formenty, P; Leroy, E M; Nnegue, S; Obame Edpu, S Y; Iba Ba; Allarangar, Y; Cabore, J; Bachy, C; Andraghetti, R; de Benoist, A C; Galanis, E; Rose, A; Bausch, D; Reynolds, M; Rollin, P; Choueibou, C; Shongo, R; Gergonne, B; Koné, L M; Yada, A; Roth, C; Toung Mve <br/> <br/>Abstract: Des épidémies de fièvre hémorragique virale à virus Ebola (FHVE) ont été rapportées de 1994 à 1996 dans la province de l’Ogooué Ivindo, une zone forestière située au Nord Est du Gabon. Chaque fois, les grands primates avaient été reconnus comme la source initiale de l’infection humaine. Fin novembre 2001 une nouvelle alerte est venue de cette province qui a rapidement était confirmée comme étant une épidémie de FHVE. La riposte a été organisée par le ministère de la santé publique avec l’aide d’une équipe internationale sous l’égide de l’OMS. Un système de surveillance active a été mis en place dans les trois districts touchés par l’épidémie (Zadié, Ivindo and Mpassa) afin d’organiser la détection des cas et le suivi de leur contacts. Une définition de cas a été adoptée, les cas suspects étaient isolés à l’hôpital, à domicile ou dans des lazarets, et des tests sérologiques étaient réalisés. Ces tests comportaient la détection de l’antigène ou des IgG spécifiques, et la RT-PCR. Un classement des cas était réalisé en fonction des résultats des tests biologiques et des données cliniques et épidémiologiques. Les sujets contacts étaient surveillés durant 21 jours. On a dénombré 65 cas dont 53 décès. Le premier cas humain, un chasseur, était décédé le 28 octobre 2001. L’épidémie s’est propagée grâce une transmission familiale et une contamination nosocomiale. Quatre foyers primaires distincts ont été mis en évidence ainsi qu’un cas isolé situé dans le Sud est du Gabon, à 580 km de l’épicentre, Les décès sont survenus dans un délai de 6 jours. Le dernier décès a été enregistré le 22 mars 2002 et la fin de l’épidémie déclarée le 6 mai 2002. L’épidémie s’est étendue au Congo voisin. Des morts inexpliquées d’animaux avaient été signalées dans les forêts environnantes dès le mois d’août 2001 : des grands primates et des céphalophes. Les prélèvements réalisés sur leurs carcasses confirmaient une épidémie animale concomitante. http://hdl.handle.net/2268/150106 Title: Concurrent chikungunya and dengue virus infections during simultaneous outbreaks, Gabon, 2007. <br/> <br/>Author, co-author: Leroy, Eric M.; Nkoghe Mba, Dieudonne; Ollomo, Benjamin; Nze-Nkogue, Chimene; Becquart, Pierre; Grard, Gilda; Pourrut, Xavier; Charrel, Remi; Moureau, Gregory; Ndjoyi-Mbiguino, Angelique; De-Lamballerie, Xavier <br/> <br/>Abstract: An outbreak of febrile illness occurred in Gabon in 2007, with 20,000 suspected cases. Chikungunya or dengue-2 virus infections were identified in 321 patients; 8 patients had documented co-infections. Aedes albopictus was identified as the principal vector for the transmission of both viruses. http://hdl.handle.net/2268/150105 Title: Rift Valley fever virus seroprevalence in human rural populations of Gabon. <br/> <br/>Author, co-author: Pourrut, Xavier; Nkoghe Mba, Dieudonne; Souris, Marc; Paupy, Christophe; Paweska, Janusz; Padilla, Cindy; Moussavou, Ghislain; Leroy, Eric M. <br/> <br/>Abstract: BACKGROUND: Rift Valley fever (RVF) is a mosquito-borne viral zoonosis caused by a phlebovirus and transmitted by Aedes mosquitoes. Humans can also be infected through direct contact with blood (aerosols) or tissues (placenta, stillborn) of infected animals. Although severe clinical cases can be observed, infection with RVF virus (RVFV) in humans is, in most cases, asymptomatic or causes a febrile illness without serious symptoms. In small ruminants RVFV mainly causes abortion and neonatal death. The distribution of RVFV has been well documented in many African countries, particularly in the north (Egypt, Sudan), east (Kenya, Tanzania, Somalia), west (Senegal, Mauritania) and south (South Africa), but also in the Indian Ocean (Madagascar, Mayotte) and the Arabian Peninsula. In contrast, the prevalence of RVFV has rarely been investigated in central African countries. METHODOLOGY/PRINCIPAL FINDINGS: We therefore conducted a large serological survey of rural populations in Gabon, involving 4,323 individuals from 212 randomly selected villages (10.3% of all Gabonese villages). RVFV-specific IgG was found in a total of 145 individuals (3.3%) suggesting the wide circulation of Rift Valley fever virus in Gabon. The seroprevalence was significantly higher in the lakes region than in forest and savannas zones, with respective rates of 8.3%, 2.9% and 2.2%. In the lakes region, RVFV-specific IgG was significantly more prevalent in males than in females (respectively 12.8% and 3.8%) and the seroprevalence increased gradually with age in males but not in females. CONCLUSIONS/SIGNIFICANCE: Although RVFV was suggested to circulate at a relatively high level in Gabon, no outbreaks or even isolated cases have been documented in the country. The higher prevalence in the lakes region is likely to be driven by specific ecologic conditions favorable to certain mosquito vector species. Males may be more at risk of infection than females because they spend more time farming and hunting outside the villages, where they may be more exposed to mosquito bites and infected animals. Further investigations are needed to determine the putative sylvan cycle of RVFV, including the mosquito species and the reservoir role of wild animals in the viral maintenance cycle. http://hdl.handle.net/2268/150103 Title: Clinical forms of chikungunya in Gabon, 2010. <br/> <br/>Author, co-author: Nkoghe Mba, Dieudonne; Kassa, Roland Fabrice; Caron, Melanie; Grard, Gilda; Mombo, Illich; Bikie, Branly; Paupy, Christophe; Becquart, Pierre; Bisvigou, Ulrich; Leroy, Eric Maurice <br/> <br/>Abstract: BACKGROUND: Chikungunya virus (CHIKV) has caused multiple outbreaks in tropical and temperate areas worldwide, but the clinical and biological features of this disease are poorly described, particularly in Africa. We report a prospective study of clinical and biological features during an outbreak that occurred in Franceville, Gabon in 2010. METHODOLOGY/PRINCIPAL FINDINGS: We collected, in suspect cases (individuals presenting with at least one of the following symptoms or signs: fever, arthralgias, myalgias, headaches, rash, fatigue, nausea, vomiting, diarrhea, bleeding, or jaundice), blood samples, demographic and clinical characteristics and outcome. Hematological and biochemical tests, blood smears for malaria parasites and quantitative PCR for CHIKV then dengue virus were performed. CHIKV+ patients with concomitant malaria and/or dengue were excluded from the study. From May to July 2010, data on 270 laboratory-confirmed CHIK patients were recorded. Fever and arthralgias were reported by respectively 85% and 90% of patients, while myalgias, rash and hemorrhage were noted in 73%, 42% and 2% of patients. The patients were grouped into 4 clinical categories depending on the existence of fever and/or joint pain. On this basis, mixed forms accounted for 78.5% of cases, arthralgic forms 12.6%, febrile forms 6.7% and unusual forms (without fever and arthralgias) 2.2%. No cases of organ failure or death were reported. Elevated liver enzyme and creatinine levels, anemia and lymphocytopenia were the predominant biological abnormalities, and lymphocytopenia was more severe in patients with high viral loads (p = 0.01). CONCLUSIONS/SIGNIFICANCE: During CHIK epidemics, some patients may not have classical symptoms. The existence of unusual forms and the absence of severe forms of CHIK call for surveillance to detect any change in pathogenicity. http://hdl.handle.net/2268/150103 Title: Clinical forms of chikungunya in Gabon, 2010. <br/> <br/>Author, co-author: Nkoghe Mba, Dieudonne; Kassa, Roland Fabrice; Caron, Melanie; Grard, Gilda; Mombo, Illich; Bikie, Branly; Paupy, Christophe; Becquart, Pierre; Bisvigou, Ulrich; Leroy, Eric Maurice <br/> <br/>Abstract: BACKGROUND: Chikungunya virus (CHIKV) has caused multiple outbreaks in tropical and temperate areas worldwide, but the clinical and biological features of this disease are poorly described, particularly in Africa. We report a prospective study of clinical and biological features during an outbreak that occurred in Franceville, Gabon in 2010. METHODOLOGY/PRINCIPAL FINDINGS: We collected, in suspect cases (individuals presenting with at least one of the following symptoms or signs: fever, arthralgias, myalgias, headaches, rash, fatigue, nausea, vomiting, diarrhea, bleeding, or jaundice), blood samples, demographic and clinical characteristics and outcome. Hematological and biochemical tests, blood smears for malaria parasites and quantitative PCR for CHIKV then dengue virus were performed. CHIKV+ patients with concomitant malaria and/or dengue were excluded from the study. From May to July 2010, data on 270 laboratory-confirmed CHIK patients were recorded. Fever and arthralgias were reported by respectively 85% and 90% of patients, while myalgias, rash and hemorrhage were noted in 73%, 42% and 2% of patients. The patients were grouped into 4 clinical categories depending on the existence of fever and/or joint pain. On this basis, mixed forms accounted for 78.5% of cases, arthralgic forms 12.6%, febrile forms 6.7% and unusual forms (without fever and arthralgias) 2.2%. No cases of organ failure or death were reported. Elevated liver enzyme and creatinine levels, anemia and lymphocytopenia were the predominant biological abnormalities, and lymphocytopenia was more severe in patients with high viral loads (p = 0.01). CONCLUSIONS/SIGNIFICANCE: During CHIK epidemics, some patients may not have classical symptoms. The existence of unusual forms and the absence of severe forms of CHIK call for surveillance to detect any change in pathogenicity. http://hdl.handle.net/2268/150103 Title: Clinical forms of chikungunya in Gabon, 2010. <br/> <br/>Author, co-author: Nkoghe Mba, Dieudonne; Kassa, Roland Fabrice; Caron, Melanie; Grard, Gilda; Mombo, Illich; Bikie, Branly; Paupy, Christophe; Becquart, Pierre; Bisvigou, Ulrich; Leroy, Eric Maurice <br/> <br/>Abstract: BACKGROUND: Chikungunya virus (CHIKV) has caused multiple outbreaks in tropical and temperate areas worldwide, but the clinical and biological features of this disease are poorly described, particularly in Africa. We report a prospective study of clinical and biological features during an outbreak that occurred in Franceville, Gabon in 2010. METHODOLOGY/PRINCIPAL FINDINGS: We collected, in suspect cases (individuals presenting with at least one of the following symptoms or signs: fever, arthralgias, myalgias, headaches, rash, fatigue, nausea, vomiting, diarrhea, bleeding, or jaundice), blood samples, demographic and clinical characteristics and outcome. Hematological and biochemical tests, blood smears for malaria parasites and quantitative PCR for CHIKV then dengue virus were performed. CHIKV+ patients with concomitant malaria and/or dengue were excluded from the study. From May to July 2010, data on 270 laboratory-confirmed CHIK patients were recorded. Fever and arthralgias were reported by respectively 85% and 90% of patients, while myalgias, rash and hemorrhage were noted in 73%, 42% and 2% of patients. The patients were grouped into 4 clinical categories depending on the existence of fever and/or joint pain. On this basis, mixed forms accounted for 78.5% of cases, arthralgic forms 12.6%, febrile forms 6.7% and unusual forms (without fever and arthralgias) 2.2%. No cases of organ failure or death were reported. Elevated liver enzyme and creatinine levels, anemia and lymphocytopenia were the predominant biological abnormalities, and lymphocytopenia was more severe in patients with high viral loads (p = 0.01). CONCLUSIONS/SIGNIFICANCE: During CHIK epidemics, some patients may not have classical symptoms. The existence of unusual forms and the absence of severe forms of CHIK call for surveillance to detect any change in pathogenicity. http://hdl.handle.net/2268/150103 Title: Clinical forms of chikungunya in Gabon, 2010. <br/> <br/>Author, co-author: Nkoghe Mba, Dieudonne; Kassa, Roland Fabrice; Caron, Melanie; Grard, Gilda; Mombo, Illich; Bikie, Branly; Paupy, Christophe; Becquart, Pierre; Bisvigou, Ulrich; Leroy, Eric Maurice <br/> <br/>Abstract: BACKGROUND: Chikungunya virus (CHIKV) has caused multiple outbreaks in tropical and temperate areas worldwide, but the clinical and biological features of this disease are poorly described, particularly in Africa. We report a prospective study of clinical and biological features during an outbreak that occurred in Franceville, Gabon in 2010. METHODOLOGY/PRINCIPAL FINDINGS: We collected, in suspect cases (individuals presenting with at least one of the following symptoms or signs: fever, arthralgias, myalgias, headaches, rash, fatigue, nausea, vomiting, diarrhea, bleeding, or jaundice), blood samples, demographic and clinical characteristics and outcome. Hematological and biochemical tests, blood smears for malaria parasites and quantitative PCR for CHIKV then dengue virus were performed. CHIKV+ patients with concomitant malaria and/or dengue were excluded from the study. From May to July 2010, data on 270 laboratory-confirmed CHIK patients were recorded. Fever and arthralgias were reported by respectively 85% and 90% of patients, while myalgias, rash and hemorrhage were noted in 73%, 42% and 2% of patients. The patients were grouped into 4 clinical categories depending on the existence of fever and/or joint pain. On this basis, mixed forms accounted for 78.5% of cases, arthralgic forms 12.6%, febrile forms 6.7% and unusual forms (without fever and arthralgias) 2.2%. No cases of organ failure or death were reported. Elevated liver enzyme and creatinine levels, anemia and lymphocytopenia were the predominant biological abnormalities, and lymphocytopenia was more severe in patients with high viral loads (p = 0.01). CONCLUSIONS/SIGNIFICANCE: During CHIK epidemics, some patients may not have classical symptoms. The existence of unusual forms and the absence of severe forms of CHIK call for surveillance to detect any change in pathogenicity. http://hdl.handle.net/2268/150101 Title: Phylogeography, risk factors and genetic history of hepatitis C virus in Gabon, central Africa. <br/> <br/>Author, co-author: Njouom, Richard; Caron, Melanie; Besson, Guillaume; Ndong-Atome, Guy-Roger; Makuwa, Maria; Pouillot, Regis; Nkoghe Mba, Dieudonne; Leroy, Eric; Kazanji, Mirdad <br/> <br/>Abstract: BACKGROUND: The epidemiological and molecular characteristics of hepatitis C virus (HCV) infection in the general population have been poorly investigated in Africa. The aim of this study was to determine the prevalence, genotype distribution and epidemic history of HCV in the Gabonese general population. METHODS/PRINCIPAL FINDINGS: A total of 4042 sera collected from adults in 220 villages in all nine administrative areas of the country were screened for antibodies to HCV. HCV NS5B region sequencing was performed for molecular characterization and population genetic analyses. Of 4042 tested sera, 455 (11.2%) were positive. The seroprevalence of HCV varied significantly by administrative area, with the highest rate in Ogooue-Lolo province (20.4%) and the lowest in Ogooue-Maritine province (3.7%). History of parenteral injections, past hospital admission and age over 55 years were independent risk factors for HCV infection (p<0.0001). Phylogenetic analyses showed that 91.9% of the strains were genotype 4 (HCV-4), 5.7% genotype 1 and 2.2% genotype 2. HCV-4 strains were highly heterogeneous, with more than eight subtypes; subtype 4e predominated (57.3%). Coalescence analyses indicated that subtype 4e was the oldest, with an estimated most recent common ancestor of 1702 [95% CI, 1418-1884]. The epidemic profile indicated that it spread exponentially during the first part of the 20th century, probably by iatrogenic transmission. CONCLUSIONS/SIGNIFICANCE: These results confirm the endemicity of HCV subtype 4e in Gabon and show that its spread is due to a cohort effect, with previous, possibly iatrogenic events. More extensive epidemiological studies are needed to better characterize the route of transmission and the dissemination of HCV in Gabon. http://hdl.handle.net/2268/150056 Title: The presentation of neuroendocrine self in the thymus: a sheer necessity for a peaceful coevolution of the neuroendocrine and adaptive immune systems <br/> <br/>Author, co-author: Geenen, Vincent http://hdl.handle.net/2268/149798 Title: Risk factors for Zaire ebolavirus--specific IgG in rural Gabonese populations. <br/> <br/>Author, co-author: Nkoghe Mba, Dieudonne; Padilla, Cindy; Becquart, Pierre; Wauquier, Nadia; Moussavou, Ghislain; Akué, Jean Paul; Ollomo, Benjamin; Pourrut, Xavier; Souris, Marc; Kazanji, Mirdad; Gonzalez, Jean-Paul; Leroy, Eric <br/> <br/>Abstract: BACKGROUND: In Gabon, several Ebolavirus outbreaks have occurred exclusively in the northeastern region. We conducted a large serosurvey to identify areas and populations at risk and potential demographic, clinical, and behavioral risk factors. METHODS: Blood samples and clinical and sociodemographic data were collected from 4349 adults and 362 children in a random sample of 220 villages in the 9 provinces of Gabon. An enzyme-linked immunosorbent assay was used to detect Zaire ebolavirus (ZEBOV)-specific IgG, and thin blood smears were used to detect parasites. Logistic regression was implemented using Stata software (Stata), and a probability level of <.05 was considered to be statistically significant. RESULTS: The prevalence of ZEBOV-specific IgG was 15.3% overall, increasing to 32.4% (P< .001) in forest areas. No sociodemographic risk factors were found, but the antibody prevalence increased linearly up to 20 years of age. Chronic arthralgia and amicrofilaremia were the only factors associated with ZEBOV seropositivity. CONCLUSIONS: These findings confirm the endemicity of ZEBOV in Gabon and its link to the ecosystem. Human antibody positivity would appear to be to the result of exposure to contaminated fruits. http://hdl.handle.net/2268/149795 Title: Prevalence, genetic diversity and antiretroviral drugs resistance-asszociated mutations among untreated HIV-1-infected pregnant women in Gabon, Central Africa <br/> <br/>Author, co-author: CARON, Mélanie; LEKANA-DOUKI, Sonia Etenna; MAKUWA, Maria; OBIANG-NDONG, Guy-Patrick; BIBA, Olivia; Nkoghe Mba, Dieudonne; KAZANJI, Mirdad <br/> <br/>Abstract: BACKGROUND: In Africa, the wide genetic diversity of HIV has resulted in emergence of new strains, rapid spread of this virus in sub-Saharan populations and therefore spread of the HIV epidemic throughout the continent. METHODS: To determine the prevalence of antibodies to HIV among a high-risk population in Gabon, 1098 and 2916 samples were collected from pregnant women in 2005 and 2008, respectively. HIV genotypes were evaluated in 107 HIV-1-positive samples to determine the circulating subtypes of strains and their resistance to antiretroviral drugs (ARVs). RESULTS: The seroprevalences were 6.3% in 2005 and 6.0% in 2008. The main subtype was recombinant CRF02_AG (46.7%), followed by the subtypes A (19.6%), G (10.3%), F (4.7%), H (1.9%) and D (0.9%) and the complex recombinants CRF06_cpx (1.9%) and CRF11_cpx (1.9%); 12.1% of subtypes could not be characterized. Analysis of ARVs resistance to the protease and reverse transcriptase coding regions showed mutations associated with extensive subtype polymorphism. In the present study, the HIV strains showed reduced susceptibility to ARVs (2.8%), particularly to protease inhibitors (1.9%) and nucleoside reverse transcriptase inhibitors (0.9%). CONCLUSIONS: The evolving genetic diversity of HIV calls for continuous monitoring of its molecular epidemiology in Gabon and in other central African countries. http://hdl.handle.net/2268/149753 Title: Phenotypical and Genotypical Surveillance of Macrolide and Lincosamide Resistance in Group B Streptococcus in Belgium <br/> <br/>Author, co-author: DESCY, Julie; Ackermans, Yannick; BOREUX, Raphaël; MEEX, Cécile; Rémont, Leslie; Rodriguez Cuns, Grisel; MELIN, Pierrette <br/> <br/>Abstract: Background: Constant increase of erythromycin (E) and clindamycin (C) resistance (R) has been observed worldwide among isolates of group B streptococci (GBS). In Belgium, through the 2000s, E R increased rapidly from 10% to up to 30%. Therefore phenotypical and molecular surveillance of E and C R has to be conducted. Methods: 275 clinical isolates (N1) were obtained from a Belgian surveillance for invasive GBS disease in newborns (59 isolates with 32 early- and 27 late-onset diseases) and adults (216 strains) during 2008 to 2011 and 53 isolates (N2) from vagino-rectal colonization in pregnant women in 2010. E and C MICs were determined by using Etest® (EUCAST interpretive criteria). Furthermore, for the E R isolates, the inducible (iMLS), constitutive (cMLS) and M phenotypes were assessed by a double disk diffusion test; the distribution of genes encoding RNA methylases and efflux pumps was investigated by PCR. Results: Of the N1 and N2 isolates, 92 (33.5%) and 15 (28.3%) were respectively R to E, with a higher rate among serotype V (p <0.001) and serotype IV (p <0.05). Among these 107 E-R isolates, 100 (93.5%) exhibited the MLS phenotype (R to E and CC): 73 were cMLS with E MIC50 >256 mg/L and 27 iMLS with E MIC50/MIC90 12/>256 mg/L. The M phenotype (R to E and S to C) was expressed by 7 (6.5%) of E R isolates with E MIC50/MIC90 4/12 mg/L. One colonizing strain presented a newly described resistance mechanism in GBS: the L phenotype (S to E and R to C) with a C MIC at 8 mg/L. For cMLS, the most common E R genotype was ermB (66%) (p <0.05) followed by ermTR (29%) and ermB+ermTR (5%). All iMLS isolates harbored an ermTR gene except 3 (2 with ermB, 1 with both ermB and ermTR); and all M phenotype were positive for mefA/B gene. Conclusions:1) In Belgium, by year 2010, prevalence of macrolides R in GBS exceeded 30%, 2) MLS R phenotypes (target-site modification) were the majority mechanism; M phenotype (efflux R mechanism) was also prevalent. 3) E and C susceptibility testing and surveillance are mandatory to guide prophylaxis and treatment of serious GBS infections in penicillin-allergic patients (at high risk for anaphylaxis) but also to identify emergence of newly acquired resistance mechanisms such as the L phenotype. http://hdl.handle.net/2268/149713 Title: Dual-specificity phosphatase 3 knockout female mice are resistant to LPS and to polymicrobial induced septic shock in TNF dependent manner. <br/> <br/>Author, co-author: Singh, Pratibha; Dejager, Lien; Singh, Maneesh; Amand, Mathieu; Musumeci, Lucia; Moutschen, Michel; Mustelin, Tomas; Libert, Claude; Rahmouni, Souad <br/> <br/>Abstract: We report the generation of dual-specificity phosphatase 3 (DUSP3) deficient mice. These mice develop normally and do not exhibit any spontaneous phenotype. However, VHR-/- females, but not males, are resistant to LPS- and to polymicrobial infection-induced septic shock. After LPS injection, while VHR-/- males and VHR+/+ mice of both genders, displayed an increased serum levels of TNF-α and IFN, the levels of these cytokines remained significantly low in the VHR-/- females. In vitro experiments using peritoneal macrophages showed the same results suggesting that the systemic cytokines profiles observed are macrophages-dependent. Adoptive transfer of VHR-/- females bone marrow to irradiated VHR+/+ female mice, but not to VHR-/- or VHR+/+ males, protected them from death after administration of LPS. Interestingly, VHR-/- females were sensitive to TNF-α- induced lethality. We also report that the decrease of TNF-α production observed in VHR-/- female’s macrophages after LPS activation was associated with a decreased ERK1/2, but not MEK1/2, activation. Interestingly, pervanadate (PTP pan inhibitor) treatment prior to LPS activation restored ERK1/2 activation in the VHR-deficient macrophages, suggesting that VHR is targeting one of the ERK1/2 PTPs or DUSPs. These results, together with our observation that DUSP3 is the most highly expressed phosphatase in macrophages, suggest a key non-redundant role of VHR as positive regulator of TNF-α in innate immune response in females. http://hdl.handle.net/2268/148093 Title: Leptospira spp. prevalence in small mammal populations in Cotonou, Benin <br/> <br/>Author, co-author: Houemenou, Gualbert; Ahmed, A.; Libois, Roland; Hartskeerl, R.A. <br/> <br/>Abstract: The aim of this study was to assess the Leptospira prevalence in small animals in Cotonou, the capital of Benin. Rodents and shrews were captured in urban and periurban settings and determined as species of the genera Rattus, Mastomys, and Crocidura. Kidney specimens of 90 animals were examined using a real-time PCR assay specific for leptospires that belong to pathogenic species. Leptospiral DNA was amplified from kidney tissues ranging from 13.3% (8/60) in Rattus rattus to 100.0% (1/1) in Crocidura spp. with an average of 18.9% (17/90) of the animals caught at 15 locations. Clade-specific Taqman PCR on 10 samples placed six of these within clade 1 comprising the species L. kirschneri, L. interrogans, L. meyeri, and L. noguchii and four within clade 2 consisting of species L. weilii, L. alexanderi, L. borgpetersenii, and L. santarosai. Phylogenetic analysis of partial sequences of the amplicons of seven samples of these 10 samples revealed that four of the clade 1 samples could equally be assigned to L. interrogans and L. kirschneri and three samples fromclade 2 belonged to L. borgpetersenii. Results presented in the paper indicate that small mammals present a major public health risk for acquiring leptospirosis in Cotonou, Benin and will contribute to a raised awareness amongst health care workers and decision makers and hence promote appropriate clinical management of cases. http://hdl.handle.net/2268/147917 Title: NEONATAL INVASIVE GROUP B STREPTOCOCCAL (GBS) INFECTIONS IN EUROPE <br/> <br/>Author, co-author: MELIN, Pierrette; Berner, Reinhard; Afshar, Baharak; Baldassarri, Lucilla; Detcheva, Antoaneta; de la Rosa, Manuel; Kunze, Mirjam; Kriz, Paula; Efstratiou, Androulla; Hufnagel, Markus; Kilian, Mogens; SEIDEL, Laurence; Telford, John <br/> <br/>Abstract: Objectives: To describe clinical characteristics and capsular type of GBS isolates responsible of invasive infections in infants from Belgium, Bulgaria, Czech-Republic, Denmark, Germany, Italy, Spain and United Kingdom, representing one of the main objectives of the DEVANI (DEsign of a Vaccine Against Neonatal Infections) project. Methods: Surveillance of invasive GBS infections in infants was performed from mid-2008 through December 2010. For each case, a standardized case report form was filled. Samples from cases were processed using local procedures. GBS isolates were characterised in national central labs using standardised type-specific (Ia, Ib-IX) latex agglutination and molecular typing methods. Results: Data on 188 infants with invasive infection were analysed: 144 (60.6%) early onset diseases (EOD) and 74 (39.4%) late onset diseases (LOD). In EOD, mean/median ages at onset were 14/0 hours and the male:female ratio was 1.25. The predominant manifestation at onset was respiratory distress (42% cases); 83% cases were associated with sepsis/bacteremia, 15% with pneumonia and 6% with meningitis. Late-prenatal screening cultures were obtained from 51% of cases’ mothers and only half of these were positive for GBS. Non-elective C-section, intrapartum fever and rupture of membrane (>18h) were more frequent in EO-cases’ mothers versus healthy babies’ GBS-positive mothers. The major serotypes were III (43%), V (21%) and Ia (18%). In LOD, mean/median ages at onset were 42/34 days and the male:female ratio was 0.9. The predominant characteristic at onset was fever (62% cases); 70% cases were associated with sepsis and 30% with meningitis. Very rare manifestations were osteomyelitis and cellulitis. Serotype III was highly predominant (80.6%) followed mainly by Ia (12.5%). Death rates were 4.7/1.5% in EOD/LOD. Conclusions: Clinical presentations were associated with age at onset of infection. Serotype III predominated in neonatal infections. Prenatal screening was not universal neither sensitive. Study funded through the European Commission Seventh Framework. http://hdl.handle.net/2268/147905 Title: Pili genes pattern in Group B streptococci from newborn infections and pregnant women in Europe (DEVANI Project) <br/> <br/>Author, co-author: Imperi, Monica; Rinaudo, Daniela; Creti, Roberta; Pataracchia, Marco; Rosini, Roberto; Nuccitelli, Annalisa; Kriz, Paula; Kilian, Mogens; Hufnagel, Markus; Efstratiou, Androulla; de la Rosa, Manuel; MELIN, Pierrette; Detcheva, Antoaneta; Baldassarri, Lucilla; Maione, Domenico <br/> <br/>Abstract: Objectives Evaluation of the presence and expression of genes coding for pili in a collection of group B streptococcci (GBS) isolated from newborn infection and pregnant women in the course of the DEVANI (Design of a Vaccine Against Neonatal Infection) project. Methods GBS isolates from pregnant women (PW) and cases of newborn infection (NI) were collected in 8 European countries (Belgium, Bulgaria, Czech Republic, Denmark, Germany, Italy, Spain, United Kingdom) during 2009/10 under the auspices of DEVANI. Total no. of strains examined was 1078 and 192 from PW and NI, respectively. Isolates were screened by multiplex PCR and FACS analysis to evaluate respectively gene presence and surface-exposure of pili. Results The most common gene patterns found were PI-2a alone, PI 1+2a and PI 1+2b, while the PI-2b gene alone was very rare. The most prominent result was that a majority of isolates from NI carried the PI-1+2b gene pattern, while the most common pattern among PW was PI-1+2a. Most of analyzed strains express at least one pilus on their surface. Conclusions All isolates contained at least one gene coding for pili. When present pili 2a and 2b were highly surface exposed. http://hdl.handle.net/2268/147904 Title: Group B streptococci, a European perspective with results of the DEVANI project <br/> <br/>Author, co-author: MELIN, Pierrette <br/> <br/>Abstract: In 2011, neonatal group B streptococcal (GBS) diseases remain a global public health concern. Where consensus guidelines to detect and treat intrapartum women with GBS colonization have been widely adopted, incidence of neonatal early onset disease (EOD) has dramatically declined, however despite preventive strategies cases still occur. The strategy was not expected to prevent all cases and there are challenges and limitations to this preventive approach. The best strategy for European countries is still a matter of debate and intrapartum antimicrobial prophylaxis (IAP) is not widely recommended. To adopt the best preventive strategy, we first need better data assessing more accurately the true burden of GBS diseases in the different countries. Furthermore, as the current screening-based strategy for prevention is highly effective but imperfect, given the challenges, limitations and potential complications of maternal IAP, a new approach is still needed. Maternal immunization against GBS is an attractive alternative for the prevention of not only neonatal diseases but also stillbirths and maternal diseases. Vaccines against GBS may likely become the most effective and sustainable long-term preventive strategy. But the development of vaccines with global relevance has been hampered by changes in the distribution of GBS serotypes of strains causing diseases over time and in different parts of the world. A multivalent vaccine to cover against the more prevalent serotypes suitable for European populations might not be suitable for Asian or African populations. To overcome type-specificity, new developments target vaccines based on conserved surface antigenic proteins, such as Sip protein located at the cell surface of all GBS and on immunogenic proteins from GBS pili. A pilus-based GBS vaccine is appealing and could become a globally relevant reality. The DEVANI (DEsign of a Vaccine Against Neonatal Infections) programme funded through the European Commission Seventh Framework was launched on 1 January 2008 with the key objective being the assessment of European GBS epidemiology to facilitate the design of a new vaccine that will confer neonatal immunity through a durable maternal immune response. A major component was to undertake pan European surveillance of maternal colonisation, maternal GBS antibody responses and neonatal diseases in eight European countries. Through 2009 and 2010, all Belgian laboratories sending any neonatal GBS invasive isolate to the National Reference Centre for GBS were invited to bring their contribution to this project. Belgium, Bulgaria, Czech Republic, Denmark, Germany, Italy, Spain and the United Kingdom established specific GBS screening studies during 2008/10. Maternal vaginal/rectal swabs and sera were taken between 34-37 weeks gestation and processed using a standardised microbiological screening protocol. Samples from neonatal cases were processed using local procedures. For each pregnant woman and each case of GBS neonatal disease, standardized case report forms were filled. GBS isolates were characterised using standardised serological and molecular typing methods for detection of all ten GBS capsular polysaccharide types (Ia to IX). Furthermore all the collected isolates were screened by multiplex PCR and FACS analysis to evaluate respectively gene presence and surface-exposure of pili. And clonal analysis of these isolates was performed using multi-locus sequence typing (MLST). The main microbiological results of this pan European surveillance are following. Carriage rates among pregnant women in all countries ranged from 8% to 26%. The most common GBS capsular types were III (33%), Ia (25%) and V (8%). Among GBS from EOD, the major serotypes were III (43%), V (21%) and Ia (18%). In contrast among GBS isolated from neonatal late onset disease (LOD), serotype III was highly predominant (80.6%) followed mainly by Ia (12.5%). Analysis of the pattern of pili genes showed that all isolates contained at least one gene coding for pili. The most common gene patterns found were PI-2a alone, PI 1+2a and PI 1+2b, while the PI-2b gene alone was very rare. The most prominent result was that a majority of isolates from neonatal infections carried the PI-1+2b gene pattern, while the most common pattern among pregnant women was PI-1+2a. Most of analyzed strains express at least one pilus on their surface. The clonal analysis showed that 66 sequence types were found to belong to nine clonal complexes (CC). Among these nine CCs, five were prevailing and covered 92 % of GBS isolates tested. The GBS population in pregnant women was found to be more heterogeneous than the GBS isolated from neonatal infection cases. Among neonatal isolates, the most frequent CC was CC17 (43 %) known as a highly virulent clone. Among participating countries, there were no significant differences in the occurrence of clonal complexes. The analysis of the levels of specific antibodies as surrogate markers of protection is still ongoing. More detailed and additional results as the main conclusions will be presented. http://hdl.handle.net/2268/147903 Title: GBS colonization and screening in pregnancy: how does it work in Europe? <br/> <br/>Author, co-author: MELIN, Pierrette <br/> <br/>Abstract: In Europe, as in North America, GBS infections among infants are associated to high morbidity and mortality even if some differences exist between different European countries. During the past two decades, major initiatives have been proposed to prevent early onset GBS disease (EOD) and they are still subject of controversy. Several European countries have issued guidelines for the prevention of neonatal GBS diseases, either universal screening-based or risk-based strategy, others have no official guidelines at all. In countries having guidelines, despite considerable efforts and economic resources spent on intrapartum antimicrobial prophylaxis for GBS EOD, cases continue to occur. Among these cases there are a lot of missed opportunities to administer IAP but there are also false negative screening. Therefore in the setting of a maternal GBS-screening program and successful implementation of the strategy, efforts to improve screening for GBS status remain important. The natural reservoir for GBS is the gastrointestinal tract and is likely the source for vaginal colonization. Among pregnant women, GBS carriage rate in the vaginal and rectal flora ranges from 10% up to 30%. Critical factors that influence the accuracy of detecting GBS maternal colonization are the choice of the body sites sampled, the timing of sampling and the use of selective culture media. The evolution of the different culture options to improve the GBS-screening strategy will be reviewed. If the optimal time for performing antenatal cultures is between 35 to 37 weeks’ gestation, as GBS carriage is highly variable, the predictive values of GBS antenatal cultures are not always as good predictors of the maternal GBS status at presentation for delivery as expected. Potential alternative to antenatal GBS-screening culture is the identification of GBS colonization at presentation for delivery. Use of a reliable, sensitive, easy to use rapid test should be cost effective leading to the prevention of more EOGBS cases while reducing the number of unnecessarily IAP. Advances of polymerase chain reaction (PCR) and fluorescence labeling technologies has provided new detection tools for bacterial identification. Therefore, commercialization of rapid detection of GBS through real-time PCR offers the potential for GBS detection among women without prenatal care or those in whom no antenatal culture was collected. However questions of costs and logistics remain unanswered. Could such rapid intrapartum test replace existing screening strategies or could it be used in conjunction with them? Colonizing rates and recommended screening procedures existing through Europe will be reviewed. http://hdl.handle.net/2268/147897 Title: GBS AND THE NEONATE: PREVENTION STRATEGIES <br/> <br/>Author, co-author: MELIN, Pierrette <br/> <br/>Abstract: Streptococcus agalactiae, or group B streptococcus (GBS), remains the leading cause of neonatal sepsis and meningitis, early onset and late onset diseases (EOD, LOD). Where consensus guidelines to detect and treat intrapartum women with GBS colonization have been widely adopted, incidence of neonatal EOD has dramatically declined. In response to both successful impacts on the incidence of GBS-EOD and analyses of missed opportunities, the first American guidelines for prevention issued in the 90s have since been adapted in several stages to improve their efficacy. In some countries in Europe, nationwide guidelines, whether screening-based or risk-based, for the prevention of neonatal GBS diseases have also been issued and adopted, with the expected impact on incidence of GBS-EOD. In spite of universal screening, in spite of the great progress that has been made, GBS-EOD continues to occur and the GBS burden remains a significant public health issue. Continuous efforts to improve screening for GBS status continue to be important and may be able to take advantage of new rapid diagnostic technologies. The current screening-based strategy for prevention is highly effective but imperfect. Given the challenges, limitations and potential complications of maternal intrapartum prophylaxis, a new approach is still needed. Maternal immunization against GBS is an attractive alternative for the prevention of not only neonatal diseases but also stillbirths and maternal diseases. Vaccines against GBS may likely become the most effective and sustainable long-term preventive strategy.