Publications by authors named "Christian Devaux"

67 Publications

Spreading of a new SARS-CoV-2 N501Y spike variant in a new lineage.

Clin Microbiol Infect 2021 May 12. Epub 2021 May 12.

IHU Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France; Aix-Marseille Univ., Institut de Recherche pour le Développement (IRD), Assistance Publique - Hôpitaux de Marseille (AP-HM), MEPHI, 27 boulevard Jean Moulin, 13005 Marseille, France. Electronic address:

Objectives: Our surveillance of the SARS-CoV-2 genomic epidemiology led us to detect several variants since summer 2020. We report the recent spread of a new SARS-CoV-2 spike 501Y variant.

Methods: SARS-CoV-2 sequences obtained from human nasopharyngeal samples by Illumina next-generation sequencing were analyzed using Nextclade and an in-house Python script and compared using BLASTn to the GISAID database. Phylogeny was performed using the IQ-TREE software.

Results: We identified that SARS-CoV-2 genomes from four patients diagnosed in our institute harbored a new set of amino acid substitutions including L18F;L452R;N501Y;A653V;H655Y;D796Y;G1219V±Q677H. These spike N501Y genomes are the first of Nextstrain clade 19B. We obtained partial spike gene sequences of this genotype for an additional 43 patients. All patients infected with this genotype were diagnosed since mid-January 2021. We detected 42 other genomes of this genotype in GISAID, which were obtained from samples collected in December 2020 in four cases and in 2021 in 38 cases. The 89 sequences obtained in our institute or other laboratories originated from the Comoros archipelago, Western European countries (mostly metropolitan France), Turkey and Nigeria.

Conclusion: These findings warrant further studies to investigate the spread, epidemiological and clinical features, and sensitivity to immune responses of this variant.
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http://dx.doi.org/10.1016/j.cmi.2021.05.006DOI Listing
May 2021

Current Status of Putative Animal Sources of SARS-CoV-2 Infection in Humans: Wildlife, Domestic Animals and Pets.

Microorganisms 2021 Apr 17;9(4). Epub 2021 Apr 17.

IHU-Méditerranée Infection, 13005 Marseille, France.

SARS-CoV-2 is currently considered to have emerged from a bat coronavirus reservoir. However, the real natural cycle of this virus remains to be elucidated. Moreover, the COVID-19 pandemic has led to novel opportunities for SARS-CoV-2 transmission between humans and susceptible animal species. In silico and in vitro evaluation of the interactions between the SARS-CoV-2 spike protein and eucaryotic angiotensin-converting enzyme 2 (ACE2) receptor have tentatively predicted susceptibility to SARS-CoV-2 infection of several animal species. Although useful, these data do not always correlate with in vivo data obtained in experimental models or during natural infections. Other host biological properties may intervene such as the body temperature, level of receptor expression, co-receptor, restriction factors, and genetic background. The spread of SARS-CoV-2 also depends on the extent and duration of viral shedding in the infected host as well as population density and behaviour (group living and grooming). Overall, current data indicate that the most at-risk interactions between humans and animals for COVID-19 infection are those involving certain mustelids (such as minks and ferrets), rodents (such as hamsters), lagomorphs (especially rabbits), and felines (including cats). Therefore, special attention should be paid to the risk of SARS-CoV-2 infection associated with pets.
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http://dx.doi.org/10.3390/microorganisms9040868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072559PMC
April 2021

Mink, SARS-CoV-2, and the Human-Animal Interface.

Front Microbiol 2021 1;12:663815. Epub 2021 Apr 1.

IHU-Méditerranée Infection, Marseille, France.

Mink are small carnivores of the Mustelidae family. The American mink is the most common and was imported to Europe, Asia, and Latin America for breeding, as its fur is very popular. Denmark, the Netherlands, and China are the biggest producers of mink. Mink farms with a high population density in very small areas and a low level of genetic heterogeneity are places conducive to contagion. The mink's receptor for SARS-CoV-2 is very similar to that of humans. Experimental models have shown the susceptibility of the ferret, another mustelid, to become infected with SARS-CoV-2 and to transmit it to other ferrets. On April 23, 2020, for the first time, an outbreak of SARS-CoV-2 in a mink farm was reported in the Netherlands. Since then, COVID-19 has reached numerous mink farms in the Netherlands, Denmark, United States, France, Greece, Italy, Spain, Sweden, Poland, Lithuania, and Canada. Not only do mink become infected from each other, but also they are capable of infecting humans, including with virus variants that have mutated in mink. Human infection with variant mink viruses with spike mutations led to the culling in Denmark of all mink in the country. Several animals can be infected with SARS-CoV-2. However, anthropo-zoonotic outbreaks have only been reported in mink farms. The rapid spread of SARS-CoV-2 in mink farms raises questions regarding their potential role at the onset of the pandemic and the impact of mutants on viral fitness, contagiousness, pathogenicity, re-infections with different mutants, immunotherapy, and vaccine efficacy.
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http://dx.doi.org/10.3389/fmicb.2021.663815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047314PMC
April 2021

Mouthpiece ventilation in neuromuscular disorders: Narrative review of technical issues important for clinical success.

Respir Med 2021 Mar 24;180:106373. Epub 2021 Mar 24.

Norwegian Advisory Unit on Home Mechanical Ventilation, Thoracic Department, Haukeland University Hospital, Bergen, Norway. Electronic address:

In neuromuscular disorders (NMDs), nocturnal non-invasive ventilation (NIV) via a nasal mask is offered when hypercapnic respiratory failure occurs. With disease progression, nocturnal NIV needs to be extended into the daytime. Mouthpiece ventilation (MPV) is an option for daytime NIV. MPV represents a difficult task for home ventilators due to rapidly changing load conditions resulting from intermittent connections and disconnections from MPV circuit. The 252nd ENMC International Expert Workshop, held March 6th to 8th 2020 in Amsterdam, reported general guidelines for management of daytime MPV in NMDs. This report could not present all the detail regarding the technical issues important for clinical success of MPV. Based on the expert workshop discussions and the evidence from existing studies, the current narrative review aims to identify the technical issues of MPV and offers guidance via a decisional algorithm and educational figures providing relevant information that is important for successful implementation of MPV.
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http://dx.doi.org/10.1016/j.rmed.2021.106373DOI Listing
March 2021

Emergence of Bat-Related Betacoronaviruses: Hazard and Risks.

Front Microbiol 2021 15;12:591535. Epub 2021 Mar 15.

Aix Marseille University, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

The current Coronavirus Disease 2019 (COVID-19) pandemic, with more than 111 million reported cases and 2,500,000 deaths worldwide (mortality rate currently estimated at 2.2%), is a stark reminder that coronaviruses (CoV)-induced diseases remain a major threat to humanity. COVID-19 is only the latest case of betacoronavirus (β-CoV) epidemics/pandemics. In the last 20 years, two deadly CoV epidemics, Severe Acute Respiratory Syndrome (SARS; fatality rate 9.6%) and Middle East Respiratory Syndrome (MERS; fatality rate 34.7%), plus the emergence of HCoV-HKU1 which causes the winter common cold (fatality rate 0.5%), were already a source of public health concern. Betacoronaviruses can also be a threat for livestock, as evidenced by the Swine Acute Diarrhea Syndrome (SADS) epizootic in pigs. These repeated outbreaks of β-CoV-induced diseases raise the question of the dynamic of propagation of this group of viruses in wildlife and human ecosystems. SARS-CoV, SARS-CoV-2, and HCoV-HKU1 emerged in Asia, strongly suggesting the existence of a regional hot spot for emergence. However, there might be other regional hot spots, as seen with MERS-CoV, which emerged in the Arabian Peninsula. β-CoVs responsible for human respiratory infections are closely related to bat-borne viruses. Bats are present worldwide and their level of infection with CoVs is very high on all continents. However, there is as yet no evidence of direct bat-to-human coronavirus infection. Transmission of β-CoV to humans is considered to occur accidentally through contact with susceptible intermediate animal species. This zoonotic emergence is a complex process involving not only bats, wildlife and natural ecosystems, but also many anthropogenic and societal aspects. Here, we try to understand why only few hot spots of β-CoV emergence have been identified despite worldwide bats and bat-borne β-CoV distribution. In this work, we analyze and compare the natural and anthropogenic environments associated with the emergence of β-CoV and outline conserved features likely to create favorable conditions for a new epidemic. We suggest monitoring South and East Africa as well as South America as these regions bring together many of the conditions that could make them future hot spots.
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http://dx.doi.org/10.3389/fmicb.2021.591535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005542PMC
March 2021

Emergence and outcomes of the SARS-CoV-2 'Marseille-4' variant.

Int J Infect Dis 2021 Mar 27;106:228-236. Epub 2021 Mar 27.

IHU Méditerranée Infection, Marseille, France; Microbes Evolution Phylogeny and Infections (MEPHI), Aix-Marseille Université, Marseille, France. Electronic address:

Background: In Marseille, France, following a first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in March-May 2020, a second epidemic phase occurred from June, involving 10 new variants. The Marseille-4 variant caused an epidemic that started in August and is still ongoing.

Methods: The 1038 SARS-CoV-2 whole genome sequences obtained in our laboratory by next-generation sequencing with Illumina technology were analysed using Nextclade and nextstrain/ncov pipelines and IQ-TREE. A Marseille-4-specific qPCR assay was implemented. Demographic and clinical features were compared between patients with the Marseille-4 variant and those with earlier strains.

Results: Marseille-4 harbours 13 hallmark mutations. One leads to an S477N substitution in the receptor binding domain of the spike protein targeted by current vaccines. Using a specific qPCR, it was observed that Marseille-4 caused 12-100% of SARS-CoV-2 infections in Marseille from September 2020, being involved in 2106 diagnoses. This variant was more frequently associated with hypoxemia than were clade 20A strains before May 2020. It caused a re-infection in 11 patients diagnosed with different SARS-CoV-2 strains before June 2020, suggesting either short-term protective immunity or a lack of cross-immunity.

Conclusions: Marseille-4 should be considered as a major SARS-CoV-2 variant. Its sudden appearance points towards an animal reservoir, possibly mink. The protective role of past exposure and current vaccines against this variant should be evaluated.
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http://dx.doi.org/10.1016/j.ijid.2021.03.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997945PMC
March 2021

Understanding the origin of COVID-19 requires to change the paradigm on zoonotic emergence from the spillover model to the viral circulation model.

Infect Genet Evol 2021 Mar 17:104812. Epub 2021 Mar 17.

IHU-Méditerranée Infection and CNRS, Marseille, France.

While the COVID-19 pandemic continues to spread with currently more than 117 million cumulated cases and 2.6 million deaths worldwide as per March 2021, its origin is still debated. Although several hypotheses have been proposed, there is still no clear explanation about how its causative agent, SARS-CoV-2, emerged in human populations. Today, scientifically-valid facts that deserve to be debated still coexist with unverified statements blurring thus the knowledge on the origin of COVID-19. Our retrospective analysis of scientific data supports the hypothesis that SARS-CoV-2 is indeed a naturally occurring virus. However, the spillover model considered today as the main explanation to zoonotic emergence does not match the virus dynamics and somehow misguided the way researches were conducted. We conclude this review by proposing a change of paradigm and model and introduce the circulation model for explaining the various aspects of the dynamic of SARS-CoV-2 emergence in humans.
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http://dx.doi.org/10.1016/j.meegid.2021.104812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969828PMC
March 2021

New Insights Into the Physiopathology of COVID-19: SARS-CoV-2-Associated Gastrointestinal Illness.

Front Med (Lausanne) 2021 18;8:640073. Epub 2021 Feb 18.

Aix-Marseille University, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

Although SARS-CoV-2 is considered a lung-tropic virus that infects the respiratory tract through binding to the ACE2 cell-surface molecules present on alveolar lungs epithelial cells, gastrointestinal symptoms have been frequently reported in COVID-19 patients. What can be considered an apparent paradox is that these symptoms (e.g., diarrhea), sometimes precede the development of respiratory tract illness as if the breathing apparatus was not its first target during viral dissemination. Recently, evidence was reported that the gut is an active site of replication for SARS-CoV-2. This replication mainly occurs in mature enterocytes expressing the ACE2 viral receptor and TMPRSS4 protease. In this review we question how SARS-CoV-2 can cause intestinal disturbances, whether there are pneumocyte-tropic, enterocyte-tropic and/or dual tropic strains of SARS-CoV-2. We examine two major models: first, that of a virus directly causing damage locally (e.g., by inducing apoptosis of infected enterocytes); secondly, that of indirect effect of the virus (e.g., by inducing changes in the composition of the gut microbiota followed by the induction of an inflammatory process), and suggest that both situations probably occur simultaneously in COVID-19 patients. We eventually discuss the consequences of the virus replication in brush border of intestine on long-distance damages affecting other tissues/organs, particularly lungs.
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http://dx.doi.org/10.3389/fmed.2021.640073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930624PMC
February 2021

COVID-19 re-infection.

Eur J Clin Invest 2021 May 17;51(5):e13537. Epub 2021 Mar 17.

IRD, APHM, Aix-Marseille University, MEPHI, Marseille, France.

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http://dx.doi.org/10.1111/eci.13537DOI Listing
May 2021

Can ACE2 Receptor Polymorphism Predict Species Susceptibility to SARS-CoV-2?

Front Public Health 2020;8:608765. Epub 2021 Feb 10.

Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

A novel severe acute respiratory syndrome coronavirus, SARS-CoV-2, emerged in China in December 2019 and spread worldwide, causing more than 1.3 million deaths in 11 months. Similar to the human SARS-CoV, SARS-CoV-2 shares strong sequence homologies with a sarbecovirus circulating in bats. Because bats are expected to be able to transmit their coronaviruses to intermediate animal hosts that in turn are a source of viruses able to cross species barriers and infect humans (so-called spillover model), the identification of an intermediate animal reservoir was the subject of intense researches. It was claimed that a reptile () was the intermediate host. This hypothesis was quickly ruled out and replaced by the pangolin () hypothesis. Yet, pangolin was also recently exonerated from SARS-CoV-2 transmission to humans, leaving other animal species as presumed guilty. Guided by the spillover model, several laboratories investigated the species polymorphism of the angiotensin I converting enzyme 2 (ACE2) to find the best fits with the SARS-CoV-2 spike receptor-binding site. Following the same strategy, we used multi-sequence alignment, 3-D structure analysis, and electrostatic potential surface generation of ACE2 variants to predict their binding capacity to SARS-CoV-2. We report evidence that such simple investigation is a powerful tool to quickly screen which species are potentially susceptible to SARS-CoV-2. However, possible receptor binding does not necessarily lead to successful replication in host. Therefore, we also discuss here the limitations of these approaches in our quest on the origins of COVID-19 pandemic.
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http://dx.doi.org/10.3389/fpubh.2020.608765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902720PMC
March 2021

Can hydroxychloroquine be protective against COVID-19-associated thrombotic events ?

J Microbiol Immunol Infect 2021 Feb 5;54(1):37-45. Epub 2021 Jan 5.

Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

Although SARS-CoV-2 is considered a lung-tropic virus, severe COVID-19 is not just a viral pulmonary infection, clinically it is a multi-organ pathology with major coagulation abnormalities and thromboembolism events. Recently, antiphospholipid (aPL) antibodies were found increased in a large number of COVID-19 patients. Elevated aPL have been well documented in antiphospholipid syndrome (APS), a systemic autoimmune disorder characterized by recurrent venous or arterial thrombosis and/or obstetrical morbidity. Among treatment regimen of APS, hydroxychloroquine (HCQ) is one of the molecules proposed in the primary prevention of thrombosis and obstetrical morbidity in those patients. Due to its antithrombotic properties documented in APS therapy, HCQ could be considered a good candidate for the prevention of thrombotic events in COVID-19 patients in association with anticoagulant and its repurposing deserves further evaluation.
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http://dx.doi.org/10.1016/j.jmii.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783458PMC
February 2021

Natural history of COVID-19 and therapeutic options.

Expert Rev Clin Immunol 2020 12 24;16(12):1159-1184. Epub 2020 Dec 24.

Institut Hospitalo-Universitaire Méditerranée Infection , Marseille, France.

: COVID-19 presents benign forms in young patients who frequently present with anosmia. Infants are rarely infected, while severe forms occur in patients over 65 years of age with comorbidities, including hypertension and diabetes. Lymphopenia, eosinopenia, thrombopenia, increased lactate dehydrogenase, troponin, C-reactive protein, D-dimers and low zinc levels are associated with severity.: The authors review the literature and provide an overview of the current state of knowledge regarding the natural history of and therapeutic options for COVID-19. : Diagnosis should rely on PCR and not on clinical presumption. Because of discrepancies between clinical symptoms, oxygen saturation or radiological signs on CT scans, pulse oximetry, and radiological investigation should be systematic. The disease evolves in successive phases: an acute virological phase, and, in some patients, a cytokine storm phase; an uncontrolled coagulopathy; and an acute respiratory distress syndrome. Therapeutic options include antivirals, oxygen therapy, immunomodulators, anticoagulants and prolonged mechanical treatment. Early diagnosis, care, and implementation of an antiviral treatment; the use of immunomodulators at a later stage; and the quality of intensive care are critical regarding mortality rates. The higher mortality observed in Western countries remains unexplained. Pulmonary fibrosis may occur in some patients. Its future is unpredictable.
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http://dx.doi.org/10.1080/1744666X.2021.1847640DOI Listing
December 2020

in Dromedary Camels (): A Possible Threat for Humans and Livestock in North Africa and the Near and Middle East?

Front Vet Sci 2020 5;7:558481. Epub 2020 Nov 5.

Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

The "One Health" concept recognizes that human health is connected to animal health and to the ecosystems. -induced human Q fever is one of the most widespread neglected zoonosis. The main animal reservoirs responsible for transmission to humans are domesticated ruminants, primarily goats, sheep, and cattle. Although studies are still too sparse to draw definitive conclusions, the most recent serosurvey studies conducted in herds and farms in Africa, North Africa, Arabian Peninsula, and Asia highlighted that seroprevalence was strikingly higher in dromedary camels () than in other ruminants. The seroprevalence in camel herds can reach more than 60% in Egypt, Saudi Arabia, and Sudan, and 70 to 80% in Algeria and Chad, respectively. The highest seroprevalence was in female camels with a previous history of abortion. Moreover, infection was reported in ticks of the and species collected on camels. Even if dromedary camels represent <3% of the domesticated ruminants in the countries of the Mediterranean basin Southern coast, these animals play a major socioeconomic role for millions of people who live in the arid zones of Africa, Middle East, and Asia. In Chad and Somalia, camels account for about 7 and 21% of domesticated ruminants, respectively. To meet the growing consumers demand of camel meat and milk (>5 million tons/year of both raw and pasteurized milk according to the Food and Agriculture Organization) sustained by a rapid increase of population (growth rate: 2.26-3.76 per year in North Africa), dromedary camel breeding tends to increase from the Maghreb to the Arabic countries. Because of possible long-term persistence of in camel hump adipocytes, this pathogen could represent a threat for herds and breeding farms and ultimately for public health. Because this review highlights a hyperendemia of in dromedary camels, a proper screening of herds and breeding farms for is urgently needed in countries where camel breeding is on the rise. Moreover, the risk of transmission from camel to human should be further evaluated.
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http://dx.doi.org/10.3389/fvets.2020.558481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674558PMC
November 2020

Resistance to human immunodeficiency virus infection: a rare but neglected state.

Ann N Y Acad Sci 2021 02 2;1485(1):22-42. Epub 2020 Oct 2.

IHU Méditerranée Infection and Aix-Marseille University, Institut de Recherche pour le Développement (IRD), Assistance Publique-Hôpitaux de Marseille (AP-HM), Microbes Evolution Phylogeny and Infections (MEPHI), Marseille, France.

The natural history of human immunodeficiency virus (HIV) infection is well understood. In most individuals sexually exposed to HIV, the risk of becoming infected depends on the viral load and on sexual practices and gender. However, a low percentage of individuals who practice frequent unprotected sexual intercourse with HIV-infected partners remain uninfected. Although the systematic study of these individuals has made it possible to identify HIV resistance factors including protective genetic patterns, such epidemiological situations remain paradoxical and not fully understood. In vitro experiments have demonstrated that peripheral blood mononuclear cells (PBMCs) from HIV-free, unexposed blood donors are not equally susceptible to HIV infection; in addition, PBMCs from highly exposed seronegative individuals are generally resistant to infection by primary HIV clinical isolates. We review the literature on permissiveness of PBMCs from healthy blood donors and uninfected hyperexposed individuals to sustained infection and replication of HIV-1 in vitro. In addition, we focus on recent evidence indicating that the gut microbiota may either contribute to natural resistance to or delay replication of HIV infected individuals.
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http://dx.doi.org/10.1111/nyas.14452DOI Listing
February 2021

Impact of Mechanical Ventilation Methods on the Life Perception of Subjects With Duchenne Muscular Dystrophy: French Cross-Sectional Survey.

Respir Care 2020 Nov 18;65(11):1712-1720. Epub 2020 Aug 18.

Direction des Actions Médicales, AFM-Téléthon, Evry, France.

Background: The life expectancy of individuals with Duchenne muscular dystrophy has improved considerably with the use of mechanical ventilation to manage respiratory insufficiency. The choice between continuous noninvasive ventilation (NIV) and invasive ventilation is guided both by local logistical considerations and by clinical considerations, but the choice depends largely on patient preference. It is important to know the effects of ventilatory dependence and the method used (ie, continuous NIV or invasive ventilation) on subjects' quality of life.

Methods: This was a cross-sectional prospective survey of 192 subjects with Duchenne muscular dystrophy using mechanical ventilation in France. Subjects were grouped and compared according to dependence on mechanical ventilation and the ventilation methods used.

Results: Regardless of the mechanical ventilation method, subjects with gastrostomy tubes reported more frequent emergency consultations for digestive problems (22.5% vs 4.6%, = .001). Subjects with invasive ventilation reported more insomnia than those with continuous NIV (23.8% vs 8.5%, = .04). The latter reported more ineffective cough than the invasive ventilation group (72.3% vs 49.2%, = .02). Overall, the subjects in our sample were satisfied with their medical care, regardless of dependence level or ventilation type. More specifically, 86.1% of subjects with intermittent NIV and 83.6% of ventilator-dependent subjects were satisfied.

Conclusions: Continuous and invasive mechanical ventilation did not affect the perception of quality of life for our subjects with Duchenne muscular dystrophy, apart from more insomnia, which can be explained by the fact that they required frequent repositioning in bed. Different pressure-relief mattresses should be tested and compared to prevent the development of pressure ulcers, which may improve the sleep patterns of these patients.
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http://dx.doi.org/10.4187/respcare.07131DOI Listing
November 2020

The Butyrogenic and Lactic Bacteria of the Gut Microbiota Determine the Outcome of Allogenic Hematopoietic Cell Transplant.

Front Microbiol 2020 22;11:1642. Epub 2020 Jul 22.

Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

Graft versus host disease (GVHD) is a post-transplant pathology in which donor-derived T cells present in the Peyer's patches target the cell-surface alloantigens of the recipient, causing host tissue damages. Therefore, the GVHD has long been considered only a purely immunological process whose prevention requires an immunosuppressive treatment. However, since the early 2010s, the impact of gut microbiota on GVHD has received increased attention. Both a surprising fall in gut microbiota diversity and a shift toward Enterobacteriaceae were described in this disease. Recently, unexpected results were reported that further link GVHD with changes in bacterial composition in the gut and disruption of intestinal epithelial tight junctions leading to abnormal intestinal barrier permeability. Patients receiving allogenic hematopoietic stem cell transplant (allo-HCT) as treatment of hematologic malignancies showed a decrease of the overall diversity of the gut microbiota that affects and spp. and a predominance of lactic acid bacteria (LAB) of the genus, in particular the lactose auxotroph . The reduced microbiota diversity (likely including Actinobacteria, such as that cross feed butyrogenic bacteria) deprives the butyrogenic bacteria (such as or ) of their capacity to metabolize acetate to butyrate. Indeed, administration of butyrate protects against the GVHD. Here, we review the data highlighting the possible link between GVHD and lactase defect, accumulation of lactose in the gut lumen, reduction of Reg3 antimicrobial peptides, narrower enzyme equipment of bacteria that predominate post-transplant, proliferation of that use lactose as metabolic fuels, induction of innate and adaptive immune response against these bacteria which maintains an inflammatory process, elevated expression of myosin light chain kinase 210 (MLCK210) and subsequent disruption of intestinal barrier, and translocation of microbial products (lactate) or transmigration of LAB within the liver. The analysis of data from the literature confirms that the gut microbiota plays a major role in the GVHD. Moreover, the most recent publications uncover that the LAB, butyrogenic bacteria and bacterial cross feeding were the missing pieces in the puzzle. This opens new bacteria-based strategies in the treatment of GVHD.
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http://dx.doi.org/10.3389/fmicb.2020.01642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387665PMC
July 2020

COVID-19: Time to exonerate the pangolin from the transmission of SARS-CoV-2 to humans.

Infect Genet Evol 2020 10 5;84:104493. Epub 2020 Aug 5.

IHU-Méditerranée Infection and CNRS, Marseille, France.

The emergence of COVID-19 has triggered many works aiming at identifying the animal intermediate potentially involved in the transmission of SARS-CoV-2 to humans. The presence of SARS-CoV-2-related viruses in Malayan pangolins, in silico analysis of the ACE2 receptor polymorphism and sequence similarities between the Receptor Binding Domain (RBD) of the spike proteins of pangolin and human Sarbecoviruses led to the proposal of pangolin as intermediary. However, the binding affinity of the pangolin ACE2 receptor for SARS-CoV-2 RBD was later on reported to be low. Here, we provide evidence that the pangolin is not the intermediate animal at the origin of the human pandemic. Moreover, data available do not fit with the spillover model currently proposed for zoonotic emergence which is thus unlikely to account for this outbreak. We propose a different model to explain how SARS-CoV-2 related coronaviruses could have circulated in different species, including humans, before the emergence of COVID-19.
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http://dx.doi.org/10.1016/j.meegid.2020.104493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405773PMC
October 2020

ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome.

J Microbiol Immunol Infect 2020 Jun 6;53(3):425-435. Epub 2020 May 6.

Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; IHU-Méditerranée Infection, 19-21 Boulevard Jean Moulin, 13005, Marseille, France.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged in Chinese people in December 2019 and has currently spread worldwide causing the COVID-19 pandemic with more than 150,000 deaths. In order for a SARS-CoV like virus circulating in wild life for a very long time to infect the index case-patient, a number of conditions must be met, foremost among which is the encounter with humans and the presence in homo sapiens of a cellular receptor allowing the virus to bind. Recently it was shown that the SARS-CoV-2 spike protein, binds to the human angiotensin I converting enzyme 2 (ACE2). This molecule is a peptidase expressed at the surface of lung epithelial cells and other tissues, that regulates the renin-angiotensin-aldosterone system. Humans are not equal with respect to the expression levels of the cellular ACE2. Moreover, ACE2 polymorphisms were recently described in human populations. Here we review the most recent evidence that ACE2 expression and/or polymorphism could influence both the susceptibility of people to SARS-CoV-2 infection and the outcome of the COVID-19 disease. Further exploration of the relationship between the virus, the peptidase function of ACE2 and the levels of angiotensin II in SARS-CoV-2 infected patients should help to better understand the pathophysiology of the disease and the multi-organ failures observed in severe COVID-19 cases, particularly heart failure.
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http://dx.doi.org/10.1016/j.jmii.2020.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201239PMC
June 2020

Teicoplanin: an alternative drug for the treatment of COVID-19?

Int J Antimicrob Agents 2020 Apr 13;55(4):105944. Epub 2020 Mar 13.

Aix-Marseille Université, IRD, APHM, MEPHI, Faculté de Médecine et de Pharmacie, 19-21 boulevard Jean Moulin, 13385 Marseille Cedex 05, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13385 Marseille Cedex 05, France. Electronic address:

In December 2019, a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged from China causing pneumonia outbreaks, first in the Wuhan region of China and then spread worldwide because of its probable high transmission efficiency. Owing to the lack of efficient and specific treatments and the need to contain the epidemic, drug repurposing appears to be the best tool to find a therapeutic solution. Chloroquine, remdesivir, lopinavir, ribavirin and ritonavir have shown efficacy to inhibit coronavirus in vitro. Teicoplanin, an antibiotic used to treat staphylococcal infections, previously showed efficacy to inhibit the first stage of the Middle East respiratory syndrome coronavirus (MERS-CoV) viral life cycle in human cells. This activity is conserved against SARS-Cov-2, thus placing teicoplanin as a potential treatment for patients with this virus.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.105944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102624PMC
April 2020

New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?

Int J Antimicrob Agents 2020 May 12;55(5):105938. Epub 2020 Mar 12.

Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France.

Recently, a novel coronavirus (2019-nCoV), officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Despite drastic containment measures, the spread of this virus is ongoing. SARS-CoV-2 is the aetiological agent of coronavirus disease 2019 (COVID-19) characterised by pulmonary infection in humans. The efforts of international health authorities have since focused on rapid diagnosis and isolation of patients as well as the search for therapies able to counter the most severe effects of the disease. In the absence of a known efficient therapy and because of the situation of a public-health emergency, it made sense to investigate the possible effect of chloroquine/hydroxychloroquine against SARS-CoV-2 since this molecule was previously described as a potent inhibitor of most coronaviruses, including SARS-CoV-1. Preliminary trials of chloroquine repurposing in the treatment of COVID-19 in China have been encouraging, leading to several new trials. Here we discuss the possible mechanisms of chloroquine interference with the SARS-CoV-2 replication cycle.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.105938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118659PMC
May 2020

Infectious Disease Risk Across the Growing Human-Non Human Primate Interface: A Review of the Evidence.

Front Public Health 2019 5;7:305. Epub 2019 Nov 5.

Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

Most of the human pandemics reported to date can be classified as zoonoses. Among these, there is a long history of infectious diseases that have spread from non-human primates (NHP) to humans. For millennia, indigenous groups that depend on wildlife for their survival were exposed to the risk of NHP pathogens' transmission through animal hunting and wild meat consumption. Usually, exposure is of no consequence or is limited to mild infections. In rare situations, it can be more severe or even become a real public health concern. Since the emergence of acquired immune deficiency syndrome (AIDS), nobody can ignore that an emerging infectious diseases (EID) might spread from NHP into the human population. In large parts of Central Africa and Asia, wildlife remains the primary source of meat and income for millions of people living in rural areas. However, in the past few decades the risk of exposure to an NHP pathogen has taken on a new dimension. Unprecedented breaking down of natural barriers between NHP and humans has increased exposure to health risks for a much larger population, including people living in urban areas. There are several reasons for this: (i) due to road development and massive destruction of ecosystems for agricultural needs, wildlife and humans come into contact more frequently; (ii) due to ecological awareness, many long distance travelers are in search of wildlife discovery, with a particular fascination for African great apes; (iii) due to the attraction for ancient temples and mystical practices, others travelers visit Asian places colonized by NHP. In each case, there is a risk of pathogen transmission through a bite or another route of infection. Beside the individual risk of contracting a pathogen, there is also the possibility of starting a new pandemic. This article reviews the known cases of NHP pathogens' transmission to humans whether they are hunters, travelers, ecotourists, veterinarians, or scientists working on NHP. Although pathogen transmission is supposed to be a rare outcome, Rabies virus, Herpes B virus, Monkeypox virus, Ebola virus, or Yellow fever virus infections are of greater concern and require quick countermeasures from public health professionals.
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http://dx.doi.org/10.3389/fpubh.2019.00305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849485PMC
November 2019

The E-Cadherin Cleavage Associated to Pathogenic Bacteria Infections Can Favor Bacterial Invasion and Transmigration, Dysregulation of the Immune Response and Cancer Induction in Humans.

Front Microbiol 2019 8;10:2598. Epub 2019 Nov 8.

IRD, MEPHI, APHM, Aix-Marseille University, Marseille, France.

Once bound to the epithelium, pathogenic bacteria have to cross epithelial barriers to invade their human host. In order to achieve this goal, they have to destroy the adherens junctions insured by cell adhesion molecules (CAM), such as E-cadherin (E-cad). The invasive bacteria use more or less sophisticated mechanisms aimed to deregulate CAM genes expression or to modulate the cell-surface expression of CAM proteins, which are otherwise rigorously regulated by a molecular crosstalk essential for homeostasis. Apart from the repression of CAM genes, a drastic decrease in adhesion molecules on human epithelial cells can be obtained by induction of eukaryotic endoproteases named sheddases or through synthesis of their own (prokaryotic) sheddases. Cleavage of CAM by sheddases results in the release of soluble forms of CAM. The overexpression of soluble CAM in body fluids can trigger inflammation and pro-carcinogenic programming leading to tumor induction and metastasis. In addition, the reduction of the surface expression of E-cad on epithelia could be accompanied by an alteration of the anti-bacterial and anti-tumoral immune responses. This immune response dysfunction is likely to occur through the deregulation of immune cells homing, which is controlled at the level of E-cad interaction by surface molecules α integrin (CD103) and lectin receptor KLRG1. In this review, we highlight the central role of CAM cell-surface expression during pathogenic microbial invasion, with a particular focus on bacterial-induced cleavage of E-cad. We revisit herein the rapidly growing body of evidence indicating that high levels of soluble E-cad (sE-cad) in patients' sera could serve as biomarker of bacterial-induced diseases.
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http://dx.doi.org/10.3389/fmicb.2019.02598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857109PMC
November 2019

High Concentrations of Serum Soluble E-Cadherin in Patients With Q Fever.

Front Cell Infect Microbiol 2019 21;9:219. Epub 2019 Jun 21.

Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

Cadherins switching is a hallmark of neoplasic processes. The E-cadherin (E-cad) subtype is one of the surface molecules regulating cell-to-cell adhesion. After its cleavage by sheddases, a soluble fragment (sE-cad) is released that has been identified as a pro-carcinogenic inflammatory signal in several bacteria-induced cancers. Recently we reported that Q fever, a disease due to infection, can be complicated by occurrence of non-Hodgkin lymphoma (NHL). Therefore, we studied E-cad switching in Q fever. The sE-cad levels were found increased in the sera of acute and persistent Q fever patients, whereas they remained at the baseline in controls groups of healthy donors, people cured of Q fever, patients suffering from unrelated inflammatory diseases, and past Q fever patients who developed NHL. These results indicate that sE-cad can be considered as a new biomarker of infection rather than a marker of NHL-associated to Q fever. We wondered if changes in sE-cad reflected variations in the gene transcription. The expression of E-cad mRNA and its intracellular ligand β-catenin was down-regulated in peripheral blood mononuclear cells (PBMCs) of patients with either acute or persistent forms of Q fever. Indeed, a lower cell-surface expression of E-cad was measured in a minority (<5%) subpopulation of HLADR/CD16 monocytes from patients with acute Q fever. However, a very strong increase in E-cad expression was observed on more than 30% of the HLADR/CD16 monocytes of persistent Q fever patients, a cell subpopulation known to be a target for in humans. An experimental infection of healthy donors' PBMCs with , was performed to directly evaluate the link between interaction with PBMCs and their E-cad expression. A significant increase in the percentage of HLADR/CD16 monocytes expressing E-cad was measured after PBMCs had been incubated for 8 h with Nine Mile strain. Altogether, these data demonstrate that severely impairs the E-cad expression in circulating cells of Q fever patients.
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http://dx.doi.org/10.3389/fcimb.2019.00219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598114PMC
February 2020

A transcriptional signature associated with non-Hodgkin lymphoma in the blood of patients with Q fever.

PLoS One 2019 10;14(6):e0217542. Epub 2019 Jun 10.

Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

Coxiella burnetii, the agent causing Q fever, has been associated with B-cell non-Hodgkin lymphoma (NHL). To better clarify this link, we analysed the genetic transcriptomic profile of peripheral blood leukocytes from patients with C. burnetii infection to identify possible links to lymphoma. Microarray analyses revealed that 1189 genes were expressed differently (p <.001 and fold change ≥4) in whole blood of patients with C. burnetii infection compared to controls. In addition, 95 genes expressed in patients with non-Hodgkin lymphoma (NHL) and in patients with C. burnetii persistent infection have allowed us to establish the 'C. burnetii-associated NHL signature'. Among these, 33 genes previously found modulated in C. burnetii-associated -NHL by the microarray analysis were selected and their mRNA expression levels were measured in distinct C. burnetii-induced pathologies, namely, acute Q fever, focalized persistent infection, lymphadenitis and C.burnetii-associated NHL. Specific genes involved in anti-apoptotic process were found highly expressed in leukocytes from patients with C. burnetii associated-NHL: MIR17HG, REL and SP100. This signature differed from that found for NHL-control group. Patients with C. burnetii lymphadenitis presented significant elevated levels of BCL2 and ETS1 mRNAs. Altogether, we identified a specific transcriptionnal signature for NHL during C. burnetii infection reflecting the up-regulation of anti-apoptotic processes and the fact that lymphadenitis might constitute a critical step towards lymphomagenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217542PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557487PMC
March 2020

Malaria, tuberculosis and HIV: what's new? Contribution of the Institut Hospitalo-Universitaire Méditerranée Infection in updated data.

New Microbes New Infect 2018 Nov 4;26:S23-S30. Epub 2018 Jul 4.

Unité Parasitologie et entomologie, Département des maladies infectieuses, Institut de recherche biomédicale des armées, Institut Hospitalo-Universitaire (IHU)-Méditerranée Infection, Marseille, France.

The Institut Hospitalo-Universitaire Méditerranée Infection is positioned for the diagnosis, prevention and treatment of the 'big three' killer diseases: malaria, tuberculosis and HIV. We implemented the use of new diagnostic samples such as stools and new diagnostic tests such as mass spectrometry for the dual identification of vectors and pathogens. Furthermore, advances in the prevention and treatment of malaria and tuberculosis are reviewed, along with advances in the understanding of the role of microbiota in the resistance to HIV infection. These achievements represent a major step towards a better management of the 'big three' diseases worldwide.
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http://dx.doi.org/10.1016/j.nmni.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205578PMC
November 2018

The Microbiological Memory, an Epigenetic Regulator Governing the Balance Between Good Health and Metabolic Disorders.

Front Microbiol 2018 26;9:1379. Epub 2018 Jun 26.

IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix-Marseille University, Marseille, France.

If the transmission of biological information from one generation to the next is based on DNA, most heritable phenotypic traits such as chronic metabolic diseases, are not linked to genetic variation in DNA sequences. Non-genetic heritability might have several causes including epigenetic, parental effect, adaptive social learning, and influence of the ecological environment. Distinguishing among these causes is crucial to resolve major phenotypic enigmas. Strong evidence indicates that changes in DNA expression through various epigenetic mechanisms can be linked to parent-offspring resemblance in terms of sensitivity to metabolic diseases. Among non-genetic heritable traits, early nutrition could account for a long term deviant programming of genes expression responsible for metabolic diseases in adulthood. Nutrition could shape an inadequate gut microbiota (dysbiosis), triggering epigenetic deregulation of transcription which can be observed in chronic metabolic diseases. We review herein the evidence that dysbiosis might be a major cause of heritable epigenetic patterns found to be associated with metabolic diseases. By taking into account the recent advances on the gut microbiome, we have aggregated together different observations supporting the hypothesis that the gut microbiota could promote the molecular crosstalk between bacteria and surrounding host cells which controls the pathological epigenetic signature. We introduce for the first time the concept of "microbiological memory" as the main regulator of the epigenetic signatures, thereby indicating that different causes of non-genetic heritability can interact in complex pathways to produce inheritance.
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http://dx.doi.org/10.3389/fmicb.2018.01379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028609PMC
June 2018

Bats, Coronaviruses, and Deforestation: Toward the Emergence of Novel Infectious Diseases?

Front Microbiol 2018 11;9:702. Epub 2018 Apr 11.

Aix Marseille Université, Centre National de la Recherche Scientifique, IRD, Institut National de la Santé et de la Recherche Médicale, AP-HM, URMITE, IHU-Méditerranée Infection, Marseille, France.

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http://dx.doi.org/10.3389/fmicb.2018.00702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904276PMC
April 2018

Airway clearance techniques in neuromuscular disorders: A state of the art review.

Respir Med 2018 03 6;136:98-110. Epub 2018 Feb 6.

Department of Paediatrics and Child Health, University of Cape Town, Klipfontein Rd, Rondebosch, Cape Town, South Africa.

This is a unique state of the art review written by a group of 21 international recognized experts in the field that gathered during a meeting organized by the European Neuromuscular Centre (ENMC) in Naarden, March 2017. It systematically reports the entire evidence base for airway clearance techniques (ACTs) in both adults and children with neuromuscular disorders (NMD). We not only report randomised controlled trials, which in other systematic reviews conclude that there is a lack of evidence base to give an opinion, but also include case series and retrospective reviews of practice. For this review, we have classified ACTs as either proximal (cough augmentation) or peripheral (secretion mobilization). The review presents descriptions; standard definitions; the supporting evidence for and limitations of proximal and peripheral ACTs that are used in patients with NMD; as well as providing recommendations for objective measurements of efficacy, specifically for proximal ACTs. This state of the art review also highlights how ACTs may be adapted or modified for specific contexts (e.g. in people with bulbar insufficiency; children and infants) and recommends when and how each technique should be applied.
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http://dx.doi.org/10.1016/j.rmed.2018.01.012DOI Listing
March 2018

Incidence of dengue and chikungunya viruses in mosquitoes and human patients in border provinces of Vietnam.

Parasit Vectors 2017 Nov 9;10(1):556. Epub 2017 Nov 9.

Cirad, Intertryp, UMR 17, TA-A17/G, Campus International de Baillarguet, 34398 Cedex 5, Montpellier, France.

Background: Dengue virus remains a major threat in Vietnam, while chikungunya virus is expected to become one. Surveillance was conducted from 2012 to 2014 in Vietnam to assess the presence of dengue and chikungunya viruses in patients hospitalized with acute fever in five Vietnam provinces neighboring Lao PDR and Cambodia. Surveillance was extended to mosquitoes present in the vicinity of the patients' households.

Results: A total 558 human serum samples were collected along with 1104 adult mosquitoes and 12,041 larvae from 2250 households. Dengue virus was found in 17 (3%) human serum samples and in 9 (0.8%) adult mosquitoes. Chikungunya virus was detected in 2 adult mosquitoes (0.18%) while no chikungunya virus was detected in humans. Differing densities of mosquito populations were found, with the highest in the Long An Province border with Cambodia. Long An Province also displayed the lowest rate of infection, despite a very high Breteau Index, high human population density and presence of the main cross border road system. The highest incidence was found in Dac Nong Province, where the Breteau and Container indices were the second lowest. Dengue virus was detected in five Aedes albopictus, three Aedes aegypti and one Culex vishnui. Chikungunya virus was detected in two Ae. aegypti. All infected mosquitoes belonged to haplotypes described in other parts of the world and a number of novel haplotypes were found among uninfected mosquitoes.

Conclusions: Dengue is considered to be regularly introduced to Vietnam from Cambodia, mostly through human movement. The data reported here provides a complementary picture. Due to intensive international trade, long-distance transportation of mosquito populations may play a role in the regular importation of dengue in Vietnam through Ho Chi Minh City. It is important to decipher the movement of mosquitoes in Vietnam, not only at the Lao PDR and Cambodia borders but also through international trade routes. Mosquito surveillance programs should address and follow mosquito populations instead of mosquito species.
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http://dx.doi.org/10.1186/s13071-017-2422-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680899PMC
November 2017