Publications by authors named "Morgane Gourlaouen"

8 Publications

  • Page 1 of 1

Rabies control in Liberia: Joint efforts towards zero by 30.

Acta Trop 2021 Apr 29;216:105787. Epub 2020 Dec 29.

Institut Pasteur, Unit Lyssavirus Epidemiology and Neuropathology, National Reference Center for Rabies and WHO Collaborating center for Reference and Research on Rabies, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France; Swiss Tropical and Public Health Institute, Socinstrasse 57, P.O. Box, CH-4002 Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland. Electronic address:

Despite declaration as a national priority disease, dog rabies remains endemic in Liberia, with surveillance systems and disease control activities still developing. The objective of these initial efforts was to establish animal rabies diagnostics, foster collaboration between all rabies control stakeholders, and develop a short-term action plan with estimated costs for rabies control and elimination in Liberia. Four rabies diagnostic tests, the direct fluorescent antibody (DFA) test, the direct immunohistochemical test (dRIT), the reverse transcriptase polymerase chain reaction (RT-PCR) assay and the rapid immunochromatographic diagnostic test (RIDT), were implemented at the Central Veterinary Laboratory (CVL) in Monrovia between July 2017 and February 2018. Seven samples (n=7) out of eight suspected animals were confirmed positive for rabies lyssavirus, and molecular analyses revealed that all isolates belonged to the Africa 2 lineage, subgroup H. During a comprehensive in-country One Health rabies stakeholder meeting in 2018, a practical workplan, a short-term action plan and an accurately costed mass dog vaccination strategy were developed. Liberia is currently at stage 1.5/5 of the Stepwise Approach towards Rabies Elimination (SARE) tool, which corresponds with countries that are scaling up local-level interventions (e.g. dog vaccination campaigns) to the national level. Overall an estimated 5.3 - 8 million USD invested over 13 years is needed to eliminate rabies in Liberia by 2030. Liberia still has a long road to become free from dog-rabies. However, the dialogue between all relevant stakeholders took place, and disease surveillance considerably improved through implementing rabies diagnosis at the CVL. The joint efforts of diverse national and international stakeholders laid important foundations to achieve the goal of zero dog-mediated human rabies deaths by 2030.
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http://dx.doi.org/10.1016/j.actatropica.2020.105787DOI Listing
April 2021

Field Postmortem Rabies Rapid Immunochromatographic Diagnostic Test for Resource-Limited Settings with Further Molecular Applications.

J Vis Exp 2020 06 29(160). Epub 2020 Jun 29.

Unit Lyssavirus Epidemiology and Neuropathology, National Reference Center for Rabies and WHO Collaborating Center for Reference and Research on Rabies, Institut Pasteur;

Functional rabies surveillance systems are crucial to provide reliable data and increase the political commitment necessary for disease control. To date, animals suspected as rabies-positive must be submitted to a postmortem confirmation using classical or molecular laboratory methods. However, most endemic areas are in low- and middle-income countries where animal rabies diagnosis is restricted to central veterinary laboratories. Poor availability of surveillance infrastructure leads to serious disease underreporting from remote areas. Several diagnostic protocols requiring low technical expertise have been recently developed, providing opportunity to establish rabies diagnosis in decentralized laboratories. We present here a complete protocol for field postmortem diagnosis of animal rabies using a rapid immunochromatographic diagnostic test (RIDT), from brain biopsy sampling to the final interpretation. We complete the protocol by describing a further use of the device for molecular analysis and viral genotyping. RIDT easily detects rabies virus and other lyssaviruses in brain samples. The principle of such tests is simple: brain material is applied on a test strip where gold conjugated antibodies bind specifically to rabies antigens. The antigen-antibody complexes bind further to fixed antibodies on the test line, resulting in a clearly visible purple line. The virus is inactivated in the test strip, but viral RNA can be subsequently extracted. This allows the test strip, rather than the infectious brain sample, to be safely and easily sent to an equipped laboratory for confirmation and molecular typing. Based on a modification of the manufacturer's protocol, we found increased test sensitivity, reaching 98% compared to the gold standard reference method, the direct immunofluorescence antibody test. The advantages of the test are numerous: rapid, easy-to-use, low cost and no requirement for laboratory infrastructure, such as microscopy or cold-chain compliance. RIDTs represent a useful alternative for areas where reference diagnostic methods are not available.
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http://dx.doi.org/10.3791/60008DOI Listing
June 2020

An inter-laboratory trial as a tool to increase rabies diagnostic capabilities of Sub-Saharan African Veterinary laboratories.

PLoS Negl Trop Dis 2020 02 10;14(2):e0008010. Epub 2020 Feb 10.

FAO and National Reference Centre for Rabies, OIE Collaborating Centre for Diseases at the Animal-Human Interface, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro (PD), Italy.

To achieve the goal of eliminating dog-mediated human rabies deaths by 2030, many African countries have agreed to list rabies as a priority zoonotic disease and to undertake both short and long-term control programs. Within this context, reliable local diagnosis is essential for the success of field surveillance systems. However, a harmonized, sustainable and supportive diagnostic offer has yet to be achieved in the continent. We herewith describe the organization and outcome of a proficiency test (PT) for the post-mortem diagnosis of rabies in animals, involving thirteen veterinary laboratories and one public health laboratory in Africa. Participants were invited to assess both the performance of the Direct Fluorescent Antibody (DFA) test and of a conventional RT-PCR. From the submitted results, while thirteen laboratories proved to be able to test the samples through DFA test, eleven performed the RT-PCR method; ten applied both techniques. Of note, the number of laboratories able to apply rabies RT-PCR had increased from four to ten after the exercise. Importantly, results showed a higher proficiency in applying the molecular test compared to the DFA test (concordance, sensitivity and specificity: 98.2%, 96.97% and 100% for RT-PCR; 87.69%, 89.23% and 86.15% for DFA test), indicating the feasibility of molecular methods to diagnose animal pathogens in Africa. Another positive outcome of this approach was that negative and positive controls were made available for further in-house validation of new techniques; in addition, a detailed questionnaire was provided to collect useful and relevant information on the diagnostic procedures and biosafety measures applied at laboratory level.
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http://dx.doi.org/10.1371/journal.pntd.0008010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010240PMC
February 2020

Further Evidence of Inadequate Quality in Lateral Flow Devices Commercially Offered for the Diagnosis of Rabies.

Trop Med Infect Dis 2020 Jan 18;5(1). Epub 2020 Jan 18.

Friedrich-Loeffler-Institut (FLI), Federal Research Institute for Animal Health, Institute of Molecular Virology and Cell Biology, 17493 Greifswald-Insel Riems, Germany.

As a neglected zoonotic disease, rabies causes approximately 5.9 × 10 human deaths annually, primarily affecting low- and middle-income countries in Asia and Africa. In those regions, insufficient surveillance is hampering adequate medical intervention and is driving the vicious cycle of neglect. Where resources to provide laboratory disease confirmation are limited, there is a need for user-friendly and low-cost reliable diagnostic tools that do not rely on specialized laboratory facilities. Lateral flow devices (LFD) offer an alternative to conventional diagnostic methods and may strengthen control efforts in low-resource settings. Five different commercially available LFDs were compared in a multi-centered study with respect to their diagnostic sensitivity and their agreement with standard rabies diagnostic techniques. Our evaluation was conducted by several international reference laboratories using a broad panel of samples. The overall sensitivities ranged from 0% up to 62%, depending on the LFD manufacturer, with substantial variation between the different laboratories. Samples with high antigen content and high relative viral load tended to test positive more often in the Anigen/Bionote test, the latter being the one with the best performance. Still, the overall unsatisfactory findings corroborate a previous study and indicate a persistent lack of appropriate test validation and quality control. At present, the tested kits are not suitable for in-field use for rabies diagnosis, especially not for suspect animals where human contact has been identified, as an incorrect negative diagnosis may result in human casualties. This study points out the discrepancy between the enormous need for such a diagnostic tool on the one hand, and on the other hand, a number of already existing tests that are not yet ready for use.
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http://dx.doi.org/10.3390/tropicalmed5010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157750PMC
January 2020

Essential role for endocytosis in the growth factor-stimulated activation of ERK1/2 in endothelial cells.

J Biol Chem 2013 Mar 22;288(11):7467-80. Epub 2013 Jan 22.

Tumour Biology Team, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, United Kingdom.

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by binding to VEGF receptor 2 (VEGFR2) on endothelial cells (ECs). Downstream activation of the extracellular related kinases 1/2 (ERK1/2) is important for angiogenesis to proceed. Receptor internalization has been implicated in VEGFR2 signaling, but its role in the activation of ERK1/2 is unclear. To explore this question we utilized pitstop and dynasore, two small molecule inhibitors of endocytosis. First, we confirmed that both inhibitors block the internalization of VEGFR2 in ECs. We then stimulated ECs with VEGF in the presence and absence of the inhibitors and examined VEGFR2 signaling to ERK1/2. Activation of VEGFR2 and C-Raf still occurred in the presence of the inhibitors, whereas the activation of MEK1/2 and ERK1/2 was abrogated. Therefore, although internalization is not required for activation of either VEGFR2 or C-Raf in ECs stimulated with VEGF, internalization is necessary to activate the more distal kinases in the cascade. Importantly, inhibition of internalization also prevented activation of ERK1/2 when ECs were stimulated with other pro-angiogenic growth factors, namely fibroblast growth factor 2 and hepatocyte growth factor. In contrast, the same inhibitors did not block ERK1/2 activation in fibroblasts or cancer cells stimulated with growth factors. Finally, we show that these small molecule inhibitors of endocytosis block angiogenesis in vitro and in vivo. Therefore, receptor internalization may be a generic requirement for pro-angiogenic growth factors to activate ERK1/2 signaling in human ECs, and targeting receptor trafficking may present a therapeutic opportunity to block tumor angiogenesis.
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http://dx.doi.org/10.1074/jbc.M112.446401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597788PMC
March 2013

Lysyl oxidase plays a critical role in endothelial cell stimulation to drive tumor angiogenesis.

Cancer Res 2013 Jan 27;73(2):583-94. Epub 2012 Nov 27.

Hypoxia and Metastasis Team, The Institute of Cancer Research, London, UK.

Identification of key molecules that drive angiogenesis is critical for the development of new modalities for the prevention of solid tumor progression. Using multiple models of colorectal cancer, we show that activity of the extracellular matrix-modifying enzyme lysyl oxidase (LOX) is essential for stimulating endothelial cells in vitro and angiogenesis in vivo. We show that LOX activates Akt through platelet-derived growth factor receptor β (PDGFRβ) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRβ, Akt, and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient samples. Finally, we validate our findings in a breast cancer model, showing the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-2447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548904PMC
January 2013

Contrasting effects of sunitinib within in vivo models of metastasis.

Angiogenesis 2012 Dec 28;15(4):623-41. Epub 2012 Jul 28.

Tumour Biology Team, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK.

Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastases in Balb/c mice, to re-address the effects of sunitinib on the progression of metastatic disease in mice. We show that treatment of mice with sunitinib prior to intravenous injection of tumour cells can promote the seeding and growth of 4T1 lung metastases, but not RENCA lung metastases, showing that this effect is cell line dependent. However, increased metastasis occurred only upon administration of a very high sunitinib dose, but not when lower, clinically relevant doses were used. Mechanistically, high dose sunitinib led to a pericyte depletion effect in the lung vasculature that correlated with increased seeding of metastasis. By administering sunitinib to mice after intravenous injection of tumour cells, we demonstrate that while sunitinib does not inhibit the growth of 4T1 lung tumour nodules, it does block the growth of RENCA lung tumour nodules. This contrasting response was correlated with increased myeloid cell recruitment and persistent vascularisation in 4T1 tumours, whereas RENCA tumours recruited less myeloid cells and were more profoundly devascularised upon sunitinib treatment. Finally, we show that progression of 4T1 tumours in sunitinib treated mice results in increased hypoxia and increased glucose metabolism in these tumours and that this is associated with a poor outcome. Taken together, these data suggest that the effects of sunitinib on tumour progression are dose-dependent and tumour model-dependent. These findings have relevance for understanding how anti-angiogenic agents may influence disease progression when used in the adjuvant or metastatic setting in cancer patients.
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http://dx.doi.org/10.1007/s10456-012-9291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496518PMC
December 2012

Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors.

Nat Med 2009 Apr 22;15(4):392-400. Epub 2009 Mar 22.

Tumour Angiogenesis Group, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.

Inhibitors of alpha(v)beta(3) and alpha(v)beta(5) integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(3) integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.
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http://dx.doi.org/10.1038/nm.1941DOI Listing
April 2009