Publications by authors named "Pierre Becquart"

54 Publications

Elevated levels of serum CD5 antigen-like protein distinguish secondary progressive multiple sclerosis from other disease subtypes.

Mult Scler Relat Disord 2021 Sep 20;56:103269. Epub 2021 Sep 20.

Department of Pathology & Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada; International Collaboration on Repair Discoveries (ICORD), Faculty of Medicine, University of British Columbia, Vancouver, Canada. Electronic address:

CD5 antigen-like (CD5L) protein is a macrophage-secreted protein with roles in immunomodulation and lipid homeostasis. We compared serum CD5L levels in healthy controls to individuals diagnosed with clinically isolated syndrome, relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP) multiple sclerosis (MS). CD5L was increased in SPMS relative to controls, RRMS, and PPMS. SPMS CD5L was associated with longer disease duration independent of age, sex, or disease severity. The positive relationship between CD5L and disease duration in SPMS suggests a chronic peripheral inflammatory profile compared to other subtypes, particularly PPMS, warranting investigation of functional roles for CD5L in MS.
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http://dx.doi.org/10.1016/j.msard.2021.103269DOI Listing
September 2021

Herpes Infections in Suspected Cases of Yellow Fever in the Democratic Republic of the Congo.

Medicina (Kaunas) 2021 Aug 25;57(9). Epub 2021 Aug 25.

Unité Mixte de Recherche MIVEGEC, Institut de Recherche pour le Développement, UMR IRD/CNRS/Université de Montpellier, 34394 Montpellier, France.

In the battle to quickly identify potential yellow fever arbovirus outbreaks in the Democratic Republic of the Congo, active syndromic surveillance of acute febrile jaundice patients across the country is a powerful tool. However, patients who test negative for yellow fever virus infection are too often left without a diagnosis. By retroactively screening samples for other potential viral infections, we can both try to find sources of patient disease and gain information on how commonly they may occur and co-occur. Several human arboviruses have previously been identified, but there remain many other viral families that could be responsible for acute febrile jaundice. Here, we assessed the prevalence of human herpes viruses (HHVs) in these acute febrile jaundice disease samples. Total viral DNA was extracted from serum of 451 patients with acute febrile jaundice. We used real-time quantitative PCR to test all specimens for cytomegalovirus (CMV), herpes simplex virus (HSV), human herpes virus type 6 (HHV-6) and varicella-zoster virus (VZV). We found 21.3% had active HHV replication (13.1%, 2.4%, 6.2% and 2.4% were positive for CMV, HSV, HHV-6 and VZV, respectively), and that nearly half (45.8%) of these infections were characterized by co-infection either among HHVs or between HHVs and other viral infection, sometimes associated with acute febrile jaundice previously identified. Our results show that the role of HHV primary infection or reactivation in contributing to acute febrile jaundice disease identified through the yellow fever surveillance program should be routinely considered in diagnosing these patients.
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http://dx.doi.org/10.3390/medicina57090871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468251PMC
August 2021

Detection of Ebola Virus Antibodies in Fecal Samples of Great Apes in Gabon.

Viruses 2020 11 24;12(12). Epub 2020 Nov 24.

Institut de Recherche pour le Développement (IRD), Maladies Infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle (MIVEGEC) (IRD 224-CNRS 5290-Université de Montpellier), BP 64501 Montpellier, France.

Based on a large study conducted on wild great ape fecal samples collected in regions of Gabon where previous human outbreaks of Ebola virus disease have occurred between 1994 and 2002, we provide evidence for prevalence of (EBOV)-specific antibodies of 3.9% (immunoglobulin G (IgG)) and 3.5% (immunoglobulin M (IgM)) in chimpanzees and 8.8% (IgG) and 2.4% (IgM) in gorillas. Importantly, we observed a high local prevalence (31.2%) of anti-EBOV IgG antibodies in gorilla samples. This high local rate of positivity among wild great apes raises the question of a spatially and temporally localized increase in EBOV exposure risk and the role that can be played by these animals as sentinels of the virus's spread or reemergence in a given area.
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http://dx.doi.org/10.3390/v12121347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761173PMC
November 2020

High prevalence of SARS-CoV-2 antibodies in pets from COVID-19+ households.

One Health 2021 Jun 4;11:100192. Epub 2020 Nov 4.

Institut de Recherche pour le Développement (IRD), Maladies Infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle (MIVEGEC) (IRD 224 - CNRS 5290 - Université de Montpellier), Montpellier, France.

In a survey of household cats and dogs of laboratory-confirmed COVID-19 patients, we found a high seroprevalence of SARS-CoV-2 antibodies, ranging from 21% to 53%, depending on the positivity criteria chosen. Seropositivity was significantly greater among pets from COVID-19+ households compared to those with owners of unknown status. Our results highlight the potential role of pets in the spread of the epidemic.
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http://dx.doi.org/10.1016/j.onehlt.2020.100192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641531PMC
June 2021

Enhanced expression of complement and microglial-specific genes prior to clinical progression in the MOG-experimental autoimmune encephalomyelitis model of multiple sclerosis.

Brain Res Bull 2020 12 23;165:63-69. Epub 2020 Sep 23.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Understanding the biological changes responsible for failures in repair and the development of progressive MS is paramount for therapeutic intervention. In a well characterized experimental autoimmune encephalomyelitis (EAE) model of MS the clinical phenotype features an acute attack with partial recovery followed by a chronic or progressive disease phase. Neuropathology-focused gene expression profiles were generated from spinal cord, hindbrain and forebrain of mice 25 days after the induction of EAE, the time when recovery plateaus and transitions to a chronic or worsening phase. Differences in gene expression were most pronounced in the spinal cord of EAE mice compared to sham-immunized animals, with a subset of genes also found to be differentially expressed in the hindbrain and the forebrain, albeit with smaller fold-changes in expression. Our data suggests that changes in complement components, chemoattractant cytokines and especially enrichment in microglial cells may be the primary drivers of processes that limit recovery in EAE.
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http://dx.doi.org/10.1016/j.brainresbull.2020.09.010DOI Listing
December 2020

Oligodendrocyte ARNT2 expression is altered in models of MS.

Neurol Neuroimmunol Neuroinflamm 2020 07 21;7(4). Epub 2020 May 21.

From the Department of Pathology and Laboratory Medicine (P.B., J.J., J.A.Q.), University of British Columbia, Vancouver, BC, Canada; and Department of Medical Genetics (C.V.-G.), University of British Columbia, Vancouver, BC, Canada.

Objective: We examined expression of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), a basic-loop-helix transcription factor implicated in neuronal development and axonal health, in oligodendrocyte (OL) cultures and over the course of chronic experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS).

Methods: We assessed OL ARNT2 expression in EAE compared with sham-immunized controls and also in OL primary cultures and over the course of dibutyryl cyclic adenosine monophosphate (dbcAMP)-mediated maturation of the immortalized Oli-neu cell line. We also tested the functional role of ARNT2 in influencing OL characteristics using small interfering RNA (siRNA).

Results: ARNT2 is localized to Olig2 cells in healthy spinal cord gray and white matter. Despite a significant expansion of Olig2 cells in the white matter at peak disease, ARNT2 is reduced by almost half in OLs, along with a reduction in the percentage of ARNT2/Olig2 cells. Mature OLs in mixed cortical cultures or OLs matured from embryonic progenitors express negligible ARNT2. Similarly, Oli-neu cells express high levels of ARNT2, which are reduced following dbcAMP maturation. siRNA-mediated knockdown of ARNT2 affected OL viability, which led to an enrichment of myelin-producing OLs.

Conclusion: The analysis of ARNT2 expression in OLs demonstrates that OL ARNT2 expression is altered in EAE and during OL maturation. Findings point to ARNT2 as an important mediator of OL viability and differentiation and warrant further characterization as a target for intervention in demyelinating disorders such as MS.
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http://dx.doi.org/10.1212/NXI.0000000000000745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251514PMC
July 2020

Exposure to Ebola Virus and Risk for Infection with Malaria Parasites, Rural Gabon.

Emerg Infect Dis 2020 02 17;26(2):229-237. Epub 2020 Feb 17.

An association between malaria and risk for death among patients with Ebola virus disease has suggested within-host interactions between Plasmodium falciparum parasites and Ebola virus. To determine whether such an interaction might also influence the probability of acquiring either infection, we used a large snapshot surveillance study from rural Gabon to test if past exposure to Ebola virus is associated with current infection with Plasmodium spp. during nonepidemic conditions. We found a strong positive association, on population and individual levels, between seropositivity for antibodies against Ebola virus and the presence of Plasmodium parasites in the blood. According to a multiple regression model accounting for other key variables, antibodies against Ebola virus emerged as the strongest individual-level risk factor for acquiring malaria. Our results suggest that within-host interactions between malaria parasites and Ebola virus may underlie epidemiologic associations.
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http://dx.doi.org/10.3201/eid2602.181120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986822PMC
February 2020

Next-Generation Sequencing on Insectivorous Bat Guano: An Accurate Tool to Identify Arthropod Viruses of Potential Agricultural Concern.

Viruses 2019 11 28;11(12). Epub 2019 Nov 28.

Maladies Infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle- Unité Mixe de Recherche 224 (MIVEGEC), Institut de Recherche pour le Développement (IRD), Centre National de Recherche Scientifique (CNRS), Univ. Montpellier, 34398 Montpellier, France.

Viruses belonging to the family have attracted a great deal of attention from scientists owing to their negative impact on agricultural economics, as well as their recent identification as potential aetiological agents of febrile illness in human patients. On the other hand, some Dicistroviruses are also studied for their potential biopesticide properties. To date, Dicistrovirus characterized in African mainland remain scarce. By using High-Throughput Sequencing technology on insectivorous bat faeces () sampled in a cave used by humans to collect bat guano (bat manure) as fertilizer in Zimbabwe, we characterized the full-length sequences of three belonging to the and genus: (-Like), (), and (). Phylogenetic analyses of ORF-1 and ORF-2 genes showed a complex evolutionary history between and close viruses, as well as for the genus. Herewith, we provide the first evidence of the presence of in Zimbabwe and highlight the need to further document the impact of such viruses on crops, as well as in beekeeping activities in Zimbabwe which represent a crucial source of income for Zimbabwean people.
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http://dx.doi.org/10.3390/v11121102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950063PMC
November 2019

Mucosal Administration of E-selectin Limits Disability in Models of Multiple Sclerosis.

Front Mol Neurosci 2019 27;12:190. Epub 2019 Aug 27.

Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.

E-selectin plays an important role in mediating the rolling of leukocytes along and thus, the subsequent extravasation across activated endothelial cells comprising the microvasculature of the blood brain barrier (BBB). In multiple sclerosis (MS) and other inflammatory disorders of the central nervous system (CNS), the microvasculature is altered and immune cells infiltrate the brain and spinal cord contributing to damage, demyelination and ultimately disability. While mucosal administration is typically used to affect lymphocyte hyporesponsiveness or tolerance to suspect autoantigens, intranasal administration to E-selectin has previously been shown to protect against CNS inflammatory insults. We characterized the potential for mucosal administration of E-selectin to modulate CNS autoimmunity in the experimental autoimmune encephalomyelitis (EAE) model of MS. Intranasally administered E-selectin reduced swelling by as much as 50% in delayed-type hypersensitivity reactions compared to ovalbumin-tolerized controls. Intranasal E-selectin delivery prior to disease induction with myelin oligodendrocyte glycoprotein (MOG) reduced disease severity and total disease burden by more than 50% compared to PBS-tolerized animals; this protection was not associated with differences in the magnitude of the autoimmune response. Examination after the onset of disease showed that protection was associated with significant reductions in inflammatory infiltrates throughout the spinal cord. Tolerization to E-selectin did not influence encephalitogenic characteristics of autoreactive T cells such as IFN-gamma or IL-17 production. Clinical disease was also significantly reduced when E-selectin was first delivered after the onset of clinical symptoms. Splenic and lymph node (LN) populations from E-selectin-tolerized animals showed E-selectin-specific T cell responses and production of the immunomodulatory cytokine IL-10. Transfer of enriched CD4+ T cells from E-selectin tolerized mice limited disability in the passive SJL model of relapsing remitting MS. These results suggest a role for influencing E-selectin specific responses to limit neuroinflammation that warrants further exploration and characterization to better understand its potential to mitigate neurodegeneration in disorders such as MS.
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http://dx.doi.org/10.3389/fnmol.2019.00190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718462PMC
August 2019

Re-emergence of chikungunya in the Republic of the Congo in 2019 associated with a possible vector-host switch.

Int J Infect Dis 2019 Jul 13;84:99-101. Epub 2019 May 13.

Institut de Recherches et de Développement (IRD), Maladies Infectieuses et vecteurs: Ecologie, génétique, Evolution et Contrôle (MIVEGEC) (IRD 224 - CNRS 5290 - UM), Montpellier, France. Electronic address:

In January 2019, an outbreak of chikungunya virus fever was reported in a rural region near Pointe-Noire, Republic of the Congo. Molecular and phylogenetic analysis of this new CHIKV strain demonstrated the presence of the A226V substitution and a surprisingly close relation with Aedes aegypti-associated Central Africa chikungunya strains. These results, combined with the preponderance of Aedes albopictus in the outbreak area, suggest a recent vector-host switch facilitated by the emergence and spread of the A226V mutation from a related CHIKV strain previously circulating in Aedes aegypti. The proximity of this outbreak to the large city of Pointe-Noire alerts us to a possibly devastating future outbreak in the absence of measures limiting the proliferation of Ae. albopictus mosquitoes.
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http://dx.doi.org/10.1016/j.ijid.2019.05.013DOI Listing
July 2019

Expression of the neuroprotective protein aryl hydrocarbon receptor nuclear translocator 2 correlates with neuronal stress and disability in models of multiple sclerosis.

J Neuroinflammation 2018 Sep 19;15(1):270. Epub 2018 Sep 19.

Department of Pathology and Laboratory Medicine, University of British Columbia, G227-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.

Background: Axonal degeneration and neuronal loss have been described as the major causes of irreversible clinical disability in multiple sclerosis (MS). The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) protein has been associated with neuroprotection in models of ischemia and neuronal responses to stressors.

Methods: To characterize its potential to influence inflammatory neurodegeneration, we examined ARNT2 expression in the experimental autoimmune encephalomyelitis (EAE) model of MS and characterized mediators that influence ARNT2 expression as well as plausible partners and targets.

Results: Arnt2 message and protein levels dropped significantly in EAE spinal cords as disease developed and were lowest at peak disability. ARNT2 expression is prominent in neuronal cell bodies within the gray matter with some staining in glial fibrillary acidic protein (GFAP) astrocytes in healthy animals. At peak disease, ARNT2 expression is reduced by 20-50% in gray matter neurons compared to healthy controls. ARNT2 intensity in neurons throughout the EAE spinal cord correlated inversely with the degree of immune cell infiltration (r = - 0.5085, p < 0.01) and axonal damage identified with SMI32 staining (r = - 0.376, p = 0.032). To understand the relationship between ARNT2 expression and neuronal health, we exposed enriched cortical cultures of neurons to hydrogen peroxide (HO) to mimic oxidative stress. HO at lower doses rapidly increased ARNT2 protein levels which returned to baseline within 3-4 h. Exposure to higher doses of HO) dropped ARNT2 levels below baseline, preceding cytotoxicity measured by morphological changes and lactate dehydrogenase release from cells. Decreases in ARNT2 secondary to staurosporine and HO preceded increases in cleaved caspase 3 and associated apoptosis. We also examined expression of neuronal pas 4 (Npas4), whose heterodimerization with ARNT2 drives expression of the neurotrophic factor brain-derived neurotrophic factor (Bdnf). Like ARNT2, Npas4 levels also decline at the onset of EAE and are linked to decreases in Bdnf. In vitro, HO exposure drives Npas4 expression that is tied to increases in Bdnf.

Conclusion: Our data support ARNT2 as a neuronal transcription factor whose sustained expression is linked to neuronal and axonal health, protection that may primarily be driven through its partnering with Npas4 to influence BDNF expression.
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http://dx.doi.org/10.1186/s12974-018-1290-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145183PMC
September 2018

High prevalence and diversity of hepatitis B and hepatitis delta virus in Gabon.

J Viral Hepat 2019 01 19;26(1):170-182. Epub 2018 Sep 19.

MIVEGEC, IRD/CNRS/Univ. Montpellier, Montpellier, France.

Although central Africa is classified as having a high endemicity of hepatitis B virus (HBV) and hepatitis D virus (HDV) infection, there is paucity of prevalence studies. For the first time on a country-wide level in Central Africa, we show in Gabon an overall 7.4% prevalence of Hepatitis B surface antigen (HBsAg) and that more than 25% of the HBsAg-positive population are infected by HDV. Although HBV prevalence did not differ significantly between provinces, there is a north-south split in the distribution of HDV seroprevalence, with the highest rates (>66.0%) correlating with the presence of specific ethnic groups in the northeastern provinces. Genotyping revealed high genetic diversity of the HBV and HDV strains circulating in Gabon, including many restricted to this region of the globe. This work confirmed that high exposure to HBV and HDV infection reported in selected regions of Gabon holds true across the whole country.
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http://dx.doi.org/10.1111/jvh.12991DOI Listing
January 2019

Identification of Dengue and Chikungunya Cases Among Suspected Cases of Yellow Fever in the Democratic Republic of the Congo.

Vector Borne Zoonotic Dis 2018 07 16;18(7):364-370. Epub 2018 May 16.

2 Département de Microbiologie, Cliniques Universitaires de Kinshasa (CUK) , Kinshasa, République Démocratique du Congo.

For more than 95% of acute febrile jaundice cases identified through surveillance for yellow fever, a reemerging arthropod-borne viral disease, no etiological exploration is ever done. The aim of this study was to test for other arthropod-borne viruses that can induce the same symptoms in patients enrolled in the yellow fever surveillance in the Democratic Republic of the Congo (DRC). Of 652 patients included in the surveillance of yellow fever in DRC from January 2003 to January 2012, 453 patients that tested negative for yellow fever virus (YFV) immunoglobulin M (IgM) antibodies were selected for the study. Real-time polymerase chain reaction was performed for the detection of dengue, West Nile, Chikungunya, O'nyong-nyong, Rift Valley fever, Zika, and YFV. The average age of patients was 22.1 years. We reported 16 cases (3.5%; confidence interval [CI]: 0.8-5.2) of dengue (serotypes 1 and 2) and 2 cases (0.4%; CI: 0.0-1.0) of Chikungunya. Three patients were co-infected with the two serotypes of dengue virus. Three cases of dengue were found in early July 2010 from the city of Titule (Oriental province) during a laboratory-confirmed outbreak of yellow fever, suggesting simultaneous circulation of dengue and yellow fever viruses. This study showed that dengue and Chikungunya viruses are potential causes of acute febrile jaundice in the DRC and highlights the need to consider dengue and Chikungunya diagnosis in the integrated disease surveillance and response program in the DRC. A prospective study is necessary to establish the epidemiology of these diseases.
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http://dx.doi.org/10.1089/vbz.2017.2176DOI Listing
July 2018

Evolution in fecal bacterial/viral composition in infants of two central African countries (Gabon and Republic of the Congo) during their first month of life.

PLoS One 2017 2;12(10):e0185569. Epub 2017 Oct 2.

UMR 5290 MIVEGEC, Institut de Recherche pour le Développement (IRD), Montpellier, France.

Few studies have analyzed the gut microbiota of child in unindustrialized countries, but none during the first month of life. Stool samples were collected from healthy newborns in hospitals of Gabon (n = 6) and Republic of the Congo (n = 9) at different time points during the first month of life: meconium, day 2 (D02), day 7 (D07) and day 28 (D28). In addition, one fecal sample was collected from each mother after delivery. Metagenomic sequencing was performed to determine the bacterial communities, and multiplex real-time PCR was used to detect the presence of seven enteric viruses (rotavirus a, adenovirus, norovirus I and II, sapovirus, astrovirus, enterovirus) in these samples. Bacterial diversity was high in the first days of life, and was dominated by the genus Prevotella. Then, it rapidly decreased and remained low up to D28 when the gut flora was composed almost exclusively of strictly anaerobic bacteria. Each infant's fecal bacterial microbiota composition was significantly closer to that of their mother than to that of any other woman in the mothers' group, suggesting an intrauterine, placental or amniotic fluid origin of such bacteria. Moreover, bacterial communities differed according to the delivery mode. Overall, the bacterial microbiota communities displayed a similar diversification and expansion in newborns within and between countries during the first four weeks of life. Moreover, six of the fifteen infants of this study harbored enteric viruses (rotavirus, enterovirus and adenovirus) in fecal samples, but never in the meconium. A maternal source for the viruses detected at D02 and D07 can be excluded because none of them was found also in the child's mother. These findings improve our knowledge on the gut bacterial and viral communities of infants from two Sub-Saharan countries during their first month of life.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185569PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624699PMC
October 2017

High Prevalence and Diversity of Hepatitis Viruses in Suspected Cases of Yellow Fever in the Democratic Republic of Congo.

J Clin Microbiol 2017 05 15;55(5):1299-1312. Epub 2017 Feb 15.

Institut de recherche pour le développement (IRD), Montpellier, France

The majority of patients with acute febrile jaundice (>95%) identified through a yellow fever surveillance program in the Democratic Republic of Congo (DRC) test negative for antibodies against yellow fever virus. However, no etiological investigation has ever been carried out on these patients. Here, we tested for hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV) viruses, all of which can cause acute febrile jaundice, in patients included in the yellow fever surveillance program in the DRC. On a total of 498 serum samples collected from suspected cases of yellow fever from January 2003 to January 2012, enzyme-linked immunosorbent assay (ELISA) techniques were used to screen for antibodies against HAV (IgM) and HEV (IgM) and for antigens and antibodies against HBV (HBsAg and anti-hepatitis B core protein [HBc] IgM, respectively), HCV, and HDV. Viral loads and genotypes were determined for HBV and HVD. Viral hepatitis serological markers were diagnosed in 218 (43.7%) patients. The seroprevalences were 16.7% for HAV, 24.6% for HBV, 2.3% for HCV, and 10.4% for HEV, and 26.1% of HBV-positive patients were also infected with HDV. Median viral loads were 4.19 × 10 IU/ml for HBV (range, 769 to 9.82 × 10 IU/ml) and 1.4 × 10 IU/ml for HDV (range, 3.1 × 10 to 2.9 × 10 IU/ml). Genotypes A, E, and D of HBV and genotype 1 of HDV were detected. These high hepatitis prevalence rates highlight the necessity to include screening for hepatitis viruses in the yellow fever surveillance program in the DRC.
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http://dx.doi.org/10.1128/JCM.01847-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405249PMC
May 2017

Malaria continues to select for sickle cell trait in Central Africa.

Proc Natl Acad Sci U S A 2015 Jun 4;112(22):7051-4. Epub 2015 May 4.

Maladies Infectieuses et Vecteurs, Ecologie, Génétique, Evolution et Contrôle (Unité Mixte de Recherche 5290, Centre National de la Recherche Scientifique, Institut de Recherche pour le Développement, Université de Montpellier), 34295 Montpellier, France; Evolutionary Parasitology Departement, Centre International de Recherches Médicales de Franceville, BP 769 Franceville, Gabon;

Sickle cell disease (SCD) is a genetic disorder that poses a serious health threat in tropical Africa, which the World Health Organization has declared a public health priority. Its persistence in human populations has been attributed to the resistance it provides to Plasmodium falciparum malaria in its heterozygous state, called sickle cell trait (SCT). Because of migration, SCT is becoming common outside tropical countries: It is now the most important genetic disorder in France, affecting one birth for every 2,400, and one of the most common in the United States. We assess the strength of the association between SCT and malaria, using current data for both SCT and malaria infections. A total of 3,959 blood samples from 195 villages distributed over the entire Republic of Gabon were analyzed. Hemoglobin variants were identified by using HPLCy (HPLC). Infections by three species of Plasmodium were detected by PCR followed by sequencing of a 201-bp fragment of cytochrome b. An increase of 10% in P. falciparum malaria prevalence is associated with an increase by 4.3% of SCT carriers. An increase of 10 y of age is associated with an increase by 5.5% of SCT carriers. Sex is not associated with SCT. These strong associations show that malaria remains a selective factor in current human populations, despite the progress of medicine and the actions undertaken to fight this disease. Our results provide evidence that evolution is still present in humans, although this is sometimes questioned by scientific, political, or religious personalities.
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http://dx.doi.org/10.1073/pnas.1505665112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460506PMC
June 2015

Numerical Study of Granular Scaffold Efficiency to Convert Fluid Flow into Mechanical Stimulation in Bone Tissue Engineering.

Tissue Eng Part C Methods 2015 Sep 6;21(9):863-71. Epub 2015 Apr 6.

1 Laboratoire de Tribologie et Dynamique des Systèmes (LTDS, UMR CNRS 5513) , Ecole Centrale de Lyon, Ecully Cedex, France .

Controlling the mechanical environment in bioreactors represents a key element in the reactors' optimization. Positive effects of fluid flow in three-dimensional bioreactors have been observed, but local stresses at cell scale remain unknown. These effects led to the development of numerical tools to assess the micromechanical environment of cells in bioreactors. Recently, new possible scaffold geometry has emerged: granular packings. In the present study, the primary goal was to compare the efficiency of such a scaffold to the other ones from literature in terms of wall shear stress levels and distributions. To that aim, three different types of granular packings were generated through discrete element method, and computational fluid dynamics was used to simulate the flow within these packings. Shear stress levels and distributions were determined. A linear relationship between shear stress and inlet velocity was observed, and its slope was similar to published data. The distributions of normalized stress were independent of the inlet velocity and were highly comparable to those of widely used porous scaffolds. Granular packings present similar features to more classical porous scaffolds and have the advantage of being easy to manipulate and seed. The methods of this work are generalizable to the study of other granular packing configurations.
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http://dx.doi.org/10.1089/ten.TEC.2014.0648DOI Listing
September 2015

Identification of continuous human B-cell epitopes in the VP35, VP40, nucleoprotein and glycoprotein of Ebola virus.

PLoS One 2014 10;9(6):e96360. Epub 2014 Jun 10.

UMR 264 MIVEGEC, Institut de Recherche pour le Développement (IRD). Montpellier, France; Centre International de Recherches Médicales de Franceville, Franceville, Gabon.

Ebola virus (EBOV) is a highly virulent human pathogen. Recovery of infected patients is associated with efficient EBOV-specific immunoglobulin G (IgG) responses, whereas fatal outcome is associated with defective humoral immunity. As B-cell epitopes on EBOV are poorly defined, we sought to identify specific epitopes in four EBOV proteins (Glycoprotein (GP), Nucleoprotein (NP), and matrix Viral Protein (VP)40 and VP35). For the first time, we tested EBOV IgG+ sera from asymptomatic individuals and symptomatic Gabonese survivors, collected during the early humoral response (seven days after the end of symptoms) and the late memory phase (7-12 years post-infection). We also tested sera from EBOV-seropositive patients who had never had clinical signs of hemorrhagic fever or who lived in non-epidemic areas (asymptomatic subjects). We found that serum from asymptomatic individuals was more strongly reactive to VP40 peptides than to GP, NP or VP35. Interestingly, anti-EBOV IgG from asymptomatic patients targeted three immunodominant regions of VP40 reported to play a crucial role in virus assembly and budding. In contrast, serum from most survivors of the three outbreaks, collected a few days after the end of symptoms, reacted mainly with GP peptides. However, in asymptomatic subjects the longest immunodominant domains were identified in GP, and analysis of the GP crystal structure revealed that these domains covered a larger surface area of the chalice bowl formed by three GP1 subunits. The B-cell epitopes we identified in the EBOV VP35, VP40, NP and GP proteins may represent important tools for understanding the humoral response to this virus and for developing new antibody-based therapeutics or detection methods.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096360PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051576PMC
October 2015

Patterns of selection on Plasmodium falciparum erythrocyte-binding antigens after the colonization of the New World.

Mol Ecol 2014 Apr;23(8):1979-93

Pathogens, which have recently colonized a new host species or new populations of the same host, are interesting models for understanding how populations may evolve in response to novel environments. During its colonization of South America from Africa, Plasmodium falciparum, the main agent of malaria, has been exposed to new conditions in distinctive new human populations (Amerindian and populations of mixed origins) that likely exerted new selective pressures on the parasite's genome. Among the genes that might have experienced strong selective pressures in response to these environmental changes, the eba genes (erythrocyte-binding antigens genes), which are involved in the invasion of the human red blood cells, constitute good candidates. In this study, we analysed, in South America, the polymorphism of three eba genes (eba-140, eba-175, eba-181) and compared it to the polymorphism observed in African populations. The aim was to determine whether these genes faced selective pressures in South America distinct from what they experienced in Africa. Patterns of genetic variability of these genes were compared to the patterns observed at two housekeeping genes (adsl and serca) and 272 SNPs to separate adaptive effects from demographic effects. We show that, conversely to Africa, eba-140 seemed to be under stronger diversifying selection in South America than eba-175. In contrast, eba-181 did not show any sign of departure from neutrality. These changes in the patterns of selection on the eba genes could be the consequence of changes in the host immune response, the host receptor polymorphisms and/or the ability of the parasite to silence or express differentially its invasion proteins.
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http://dx.doi.org/10.1111/mec.12696DOI Listing
April 2014

Prevalence of the sickle cell trait in Gabon: a nationwide study.

Infect Genet Evol 2014 Jul 13;25:52-6. Epub 2014 Apr 13.

Centre International de Recherches Médicales de Franceville, CIRMF, BP 769 Franceville, Gabon; MIVEGEC (UMR CNRS/IRD/UM1/UM2 5290) CHRU de Montpellier, 39 Av. C. Flahault, 34295 Montpellier, France.

Sickle Cell Disease (SCD) is an important cause of death in young children in Africa, which the World Health Organization has declared a public health priority. Although SCD has been studied at the continental scale and at the local scale, a picture of its distribution at the scale of an African country has never been given. The aim of this study is to provide such a picture for the Republic of Gabon, a country where precisely the epidemiology of SCD has been poorly investigated. To this effect, 4250 blood samples from persons older than 15 were collected between June 2005 and September 2008 in 210 randomly selected villages from the nine administrative provinces of Gabon. Two methods were used to screen Sickle Cell Trait (SCT) carriers: isoelectric focusing (IEF) and high-performance liquid chromatography (HPLC). SCT prevalence in Gabon was 21.1% (895/4249). SCT prevalence was significantly larger for the Bantu population (21.7%, n=860/3959) than for the Pygmy population (12.1%, n=35/290), (p=0.00013). In addition, the presence of Plasmodium sp. was assessed via thick blood examination. Age was positively associated with SCT prevalence (odds-ratio for an increase of 10 years in age=1.063, p=0.020). Sex was not associated with SCT prevalence. The study reveals the absence of homozygous sickle-cell patients, and marked differences in SCT prevalence between the Gabonese provinces, and also between population groups (Bantu vs Pygmy). These findings could be used by the public health authorities to allocate medical resources and target prevention campaigns.
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http://dx.doi.org/10.1016/j.meegid.2014.04.003DOI Listing
July 2014

The pH in the microenvironment of human mesenchymal stem cells is a critical factor for optimal osteogenesis in tissue-engineered constructs.

Tissue Eng Part A 2014 Jul 24;20(13-14):1827-40. Epub 2014 Feb 24.

1 Laboratory of Bioengineering and Bioimaging for Osteo-Articular Tissues, UMR 7052 CNRS, Université Paris Diderot , Sorbonne Paris Cité, Paris, France .

The present study aimed at elucidating the effect of local pH in the extracellular microenvironment of tissue-engineered (TE) constructs on bone cell functions pertinent to new tissue formation. To this aim, we evaluated the osteogenicity process associated with bone constructs prepared from human Bone marrow-derived mesenchymal stem cells (hBMSC) combined with 45S5 bioactive glass (BG), a material that induces alkalinization of the external medium. The pH measured in cell-containing BG constructs was around 8.0, that is, 0.5 U more alkaline than that in two other cell-containing materials (hydroxyapatite/tricalcium phosphate [HA/TCP] and coral) constructs tested. When implanted ectopically in mice, there was no de novo bone tissue in the BG cell-containing constructs, in contrast to results obtained with either HA/TCP or coral ceramics, which consistently promoted the formation of ectopic bone. In addition, the implanted 50:50 composites of both HA/TCP:BG and coral:BG constructs, which displayed a pH of around 7.8, promoted 20-30-fold less amount of bone tissue. Interestingly, hBMSC viability in BG constructs was not affected compared with the other two types of material constructs tested both in vitro and in vivo. Osteogenic differentiation (specifically, the alkaline phosphatase [ALP] activity and gene expression of RUNX2, ALP, and BSP) was not affected when hBMSC were maintained in moderate alkaline pH (≤7.90) external milieu in vitro, but was dramatically inhibited at higher pH values. The formation of mineralized nodules in the extracellular matrix of hBMSC was fully inhibited at alkaline (>7.54) pH values. Most importantly, there is a pH range (specifically, 7.9-8.27) at which hBMSC proliferation was not affected, but the osteogenic differentiation of these cells was inhibited. Altogether, these findings provided evidence that excessive alkalinization in the microenvironment of TE constructs (resulting, for example, from material degradation) affects adversely the osteogenic differentiation of osteoprogenitor cells.
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http://dx.doi.org/10.1089/ten.TEA.2013.0500DOI Listing
July 2014

The stability of BMP loaded polyelectrolyte multilayer coatings on titanium.

Biomaterials 2013 Jul 2;34(23):5737-46. Epub 2013 May 2.

UMR 5628 (LMGP), Grenoble Institute of Technology and CNRS, 3 Parvis Louis Néel, F-38016 Grenoble Cedex, France.

Immobilization of bone morphogenetic proteins (BMP) onto material surfaces is a promising, but still challenging, strategy for achieving dependable and consistent osseointegration of long-term metal implants. In the present study, we have developed an osteoinductive coating of a porous titanium implant using biomimetic polyelectrolyte multilayer (PEM) films loaded with BMP-2. The amount of BMP-2 loaded in these films was tuned - over a large range - depending on the cross-linking extent of the film and of the BMP-2 initial concentration. The air-dried PEM films were stable for at least one year of storage at 4 °C. In addition, they resisted exposure to γ-irradiation at clinically approved doses. The preservation of the growth factor bioactivity upon long-term storage and sterilization were evaluated both in vitro (using C2C12 cells) and in vivo (in a rat ectopic model) for the perspective of industrial and clinical development. BMP-2 loaded in dried PEM films exhibited shelf-life stability over one year. However, their bioactivity in vitro decreased from 50 to 80% after irradiation depending on the γ-irradiation dose. Remarkably, the in vivo studies showed that the osteoinductive potential of BMP-2 contained in PEM-coated Ti implants was fully preserved after air-drying of the implants and sterilization at 25 kGy. Film drying or irradiation did not affect the amount of new bone tissue formation. This "off-the-shelf" novel technology of functionalized implants opens promising applications in prosthetic and tissue engineering fields.
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http://dx.doi.org/10.1016/j.biomaterials.2013.03.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119881PMC
July 2013

Diversity, host switching and evolution of Plasmodium vivax infecting African great apes.

Proc Natl Acad Sci U S A 2013 May 1;110(20):8123-8. Epub 2013 May 1.

Laboratoire Maladies Infectieuses et Vecteur: Ecologie, Génétique, Evolution et Contrôle, Unité Mixte de Recherche 224-5290 Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Université de Montpellier 1 (UM1)-UM2, Centre IRD de Montpellier, 34394 Montpellier Cedex 5, France.

Plasmodium vivax is considered to be absent from Central and West Africa because of the protective effect of Duffy negativity. However, there are reports of persons returning from these areas infected with this parasite and observations suggesting the existence of transmission. Among the possible explanations for this apparent paradox, the existence of a zoonotic reservoir has been proposed. May great apes be this reservoir? We analyze the mitochondrial and nuclear genetic diversity of P. vivax parasites isolated from great apes in Africa and compare it to parasites isolated from travelers returning from these regions of Africa, as well as to human isolates distributed all over the world. We show that the P. vivax sequences from parasites of great apes form a clade genetically distinct from the parasites circulating in humans. We show that this clade's parasites can be infectious to humans by describing the case of a traveler returning from the Central African Republic infected with one of them. The relationship between this P. vivax clade in great apes and the human isolates is discussed.
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http://dx.doi.org/10.1073/pnas.1306004110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657773PMC
May 2013

Recent introduction and rapid dissemination of Chikungunya virus and Dengue virus serotype 2 associated with human and mosquito coinfections in Gabon, central Africa.

Clin Infect Dis 2012 Sep 5;55(6):e45-53. Epub 2012 Jun 5.

Unité des Maladies Virales Emergentes, Centre International de Recherches Médicales de Franceville, Gabon.

Background: Chikungunya virus (CHIKV) and Dengue virus serotype 2 (DENV-2) were recently introduced in central Africa, along with Aedes albopictus. Simultaneous outbreaks of CHIKV and DENV-2 have subsequently occurred, in Cameroon in 2006 and Gabon in 2007.

Methods: To study the spread of the 2 viruses, we conducted active surveillance of acute febrile syndromes throughout Gabon between 2007 and 2010. Diagnostic methods included quantitative real-time reverse-transcription polymerase chain reaction, and molecular characterization was based on partial envelope gene sequences.

Results: Between 2007 and 2010, 4287 acutely febrile patients were investigated for CHIKV and DENV-2 infections, of whom 1567 were CHIKV-positive, 376 DENV-2-positive, and 37 coinfected. We diagnosed 153 CHIKV and 11 DENV-2 cases in 2008, and 5 CHIKV and 9 DENV-2 cases in 2009. In 2010, CHIKV and DENV-2 caused a second large simultaneous outbreak. Among 2826 acutely febrile patients examined during this outbreak, 1112 were CHIKV-positive, 288 DENV-2-positive, and 28 coinfected. Mosquitoes were collected near the homes of coinfected patients, and 1 Aedes albopictus specimen was found to be positive for both CHIKV and DENV-2.

Conclusions: These findings show the rapid dissemination of CHIKV and DENV-2 within a nonimmune population in a tropical African country, probably facilitated by the spread of Aedes albopictus. This has resulted in major simultaneous outbreaks with numerous coinfections in both human and mosquito.
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http://dx.doi.org/10.1093/cid/cis530DOI Listing
September 2012

Ischemia is the prime but not the only cause of human multipotent stromal cell death in tissue-engineered constructs in vivo.

Tissue Eng Part A 2012 Oct 25;18(19-20):2084-94. Epub 2012 Jun 25.

Laboratory of Bioengineering and Biomechanics for Bone and Articulations, UMR 7052 CNRS, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Local tissue ischemia is a prime cause responsible for the massive cell death in tissue-engineered (TE) constructs observed postimplantation. To assess the impact of ischemia on the death of implanted human multipotent stromal cells (hMSCs), which have great potential for repairing damaged tissues, we hereby investigated the in vivo temporal and spatial fate of human Luc-GFP-labeled MSCs within fibrin gel/coral scaffolds subcutaneously implanted in nude mice. In vivo bioluminescence imaging monitoring and histological analyses of the constructs tested confirmed the irremediable death of hMSCs over 30 days postimplantation. The kinetics of expression of three hypoxic/ischemic markers (HIF-1α, LDH-A, and BNIP3) was also monitored. Our results provided evidence that hMSCs located within the core of implanted constructs died faster and predominantly and strongly expressed the aforementioned ischemic markers. In contrast, cells located in the outer regions of TE constructs were reperfused by neovascularization and were still viable (as evidenced by their ex-vivo proliferative potential) at day 15 postimplantation. These results support the explanation that in the central part of the constructs tested, death of hMSCs was due to ischemia, whereas in the periphery of these constructs, cell death was due to another mechanism that needs to be elucidated.
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http://dx.doi.org/10.1089/ten.TEA.2011.0690DOI Listing
October 2012

Clinical forms of chikungunya in Gabon, 2010.

PLoS Negl Trop Dis 2012 14;6(2):e1517. Epub 2012 Feb 14.

Unité des Maladies Virales Emergentes, Centre International de Recherches Médicales de Franceville-CIRMF, Franceville, Gabon.

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.
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http://dx.doi.org/10.1371/journal.pntd.0001517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279511PMC
June 2012

Risk factors for Zaire ebolavirus--specific IgG in rural Gabonese populations.

J Infect Dis 2011 Nov;204 Suppl 3:S768-75

Centre International de Recherches Médicales de Franceville, Franceville, Gabon.

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.
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http://dx.doi.org/10.1093/infdis/jir344DOI Listing
November 2011

Unconventional repertoire profile is imprinted during acute chikungunya infection for natural killer cells polarization toward cytotoxicity.

PLoS Pathog 2011 Sep 22;7(9):e1002268. Epub 2011 Sep 22.

INSERM UMR-S 945, Immunité et Infection, Hôpital Pitié-Salpêtrière, Paris, France.

Chikungunya virus (CHIKV) is a worldwide emerging pathogen. In humans it causes a syndrome characterized by high fever, polyarthritis, and in some cases lethal encephalitis. Growing evidence indicates that the innate immune response plays a role in controlling CHIKV infection. We show here that CHIKV induces major but transient modifications in NK-cell phenotype and function soon after the onset of acute infection. We report a transient clonal expansion of NK cells that coexpress CD94/NKG2C and inhibitory receptors for HLA-C1 alleles and are correlated with the viral load. Functional tests reveal cytolytic capacity driven by NK cells in the absence of exogenous signals and severely impaired IFN-γ production. Collectively these data provide insight into the role of this unique subset of NK cells in controlling CHIKV infection by subset-specific expansion in response to acute infection, followed by a contraction phase after viral clearance.
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http://dx.doi.org/10.1371/journal.ppat.1002268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178577PMC
September 2011

The performance of BMP-2 loaded TCP/HAP porous ceramics with a polyelectrolyte multilayer film coating.

Biomaterials 2011 Oct 23;32(30):7543-54. Epub 2011 Jul 23.

LMGP, UMR 5628 CNRS/INPG, 3 parvis Louis Néel, 38016 Grenoble, France.

Delivering rhBMP-2 (recombinant Bone Morphogenic Protein-2) at low but therapeutically efficient dose is one of the current challenges for bone tissue repair. In this context, Polyelectrolyte Multilayer films (PEM) represent an attractive rhBMP-2 carrier due to their ability to protect proteins from denaturation and to coat a wide variety of materials with complex geometry. Herein, we coated macroporous TCP/HAP granules with a biopolymeric PEM film to deliver rhBMP-2 in a "matrix-bound" manner. In vitro release kinetics indicated that the PEM-coated granules sequestered significant amounts of rhBMP-2. The degree of film cross-linking influenced the quantity of rhBMP-2 trapped within the films. Bare (uncoated) TCP/HAP scaffolds were also able to retain rhBMP-2. Bioactivity of rhBMP-2 in the PEM-coated granules was confirmed on two cell markers: luciferase expression on BMP-responsive-element/Luc C2C12 cells and alkaline phosphatase activity induction on C2C12 cells. Promisingly, rhBMP-2 adsorbed onto PEM-coated and on bare granules in a lesser extent, could be stored and remained bioactive over at least 3 weeks. In vivo, both uncoated and PEM-coated TCP/HAP granules loaded with rhBMP-2 exhibited both osteoconductive and osteoinductive properties. This opens perspective for coating these bioactive PEM on other types of implantable materials, including metal alloy that do not exhibit any affinity for rhBMP-2.
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http://dx.doi.org/10.1016/j.biomaterials.2011.06.062DOI Listing
October 2011
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