* Service de Santé des Armées
** Soutenance Septembre 2010
The past decades have seen a dramatic change in the geographic and host ranges of many vector-borne pathogens, and their diseases. This research team comes from the past Team n°5 from URMITE. Beside recognition in the field of rickettsiology and tick-, flea- and louse - borne bacterial diseases (WHO coll. Center FRA 75), we have significantly contributed in the recent years to study clinical, virological and entomological aspects of the Chikungunya global and ongoing outbreak, as well as to other vector borne imported emerging disease. Research in travel mecidicine and in military medicine has also been developed. Therefore, our research team has been enriched by mosquito/sand fly entomologists, military infectious diseases physician and microbiologists, in addition to infectious diseases researchers, ticks/fleas/lice entomologists and rickettsiologists. Several thematic projects will be conducted. The first consists in the detection and surveillance of imported vector-borne diseases, with help of international network that we coordinate and the laboratory tools connected to our unit. A particular interest will be paid to specific populations including Comorians from Marseille, soldiers deployed overseas, hajj pilgrims and travelers to Senegal. Screening arthropods (collected in Southern France and tropical countries) by molecular biology using broad range primers and culture the detected agent, particularly if it is a new microorganism, will be used for detecting new infectious agent from ticks, fleas, lice, bed bugs, sand flies and mosquitoes. Experimental models will be developed to understand arthropods – microorganisms relations ships, as well as the role of saliva in the transmission of agents and specific immunity. New tools including Mass spectrometry will be included in most of the projects as well as to develop new approach for the identification and taxonomy of arthropods.
Ticks are currently considered to be second only to mosquitoes as vectors of infectious diseases in the world. The impact of ticks on human public health was recognised with the emergence of Lyme disease 25 years ago (1). Since then, around 15 emerging tick-borne rickettsioses have emerged (2). Flea-borne infections are emerging or re-emerging throughout the world, and their incidence is on the rise (3). Also, because of poor living conditions and limited access to healthcare systems, homeless persons are exposed to many communicable infections including body lice transmitted diseases (4).
Currently, intense international traffic between Europe and the rest of the world (tourists, soldiers, business, migrants), along with significant intra-European migration, results in greater vulnerability to the transmission of old, new and re-emerging infectious diseases, with travellers as a key element in disease dissemination (5). Numerous outbreaks and case reports serve as reminders that infections can be imported and /or transmitted inEuropeby visiting or returning travellers. This was illustrated by severe acute respiratory syndrome (SARS) in 2003 (6), chikungunya virus (CHIKV) in Italy 2007 (7) and most recently by the rapid spread of influenza A (H1N1) in 2009 (8).
From time immemorial, infectious diseases and particularly vector-borne diseases have severely reduced the fighting capacity of armies and caused suspension or cancellation of military operations (9). Most recent conflicts involving Western armies have occurred overseas, increasing the risk of vector-borne disease for the soldiers and for the displaced populations. New potential threats have appeared (9;10).
Recognizing and tracking such health threats clearly requires accurate surveillance as well as field investigations and arthropod-microorganisms relationships research programs. Active collaboration allows surveillance networks to successfully follow regional trends and detect international outbreaks of concern and provide accurate data on which evidence-based travel health policies and recommendations can be made.
This team comes from the past Team n°5 from URMITE. Beside recognition in the field of rickettsiology and arthropod bacterial diseases (WHO coll. Center FRA 75) (2;4), we have significantly contributed in the recent years to study clinical (11-13), virological (14;15) and entomological (16-18) aspects of the Chikungunya global outbreak that started in 2004-2005 inIndian Ocean islands (19), as well as to other vector borne emerging diseases (20). Research in travel medicine and military medicine has also been developed (9;21). Therefore, to develop these new research areas our research team has been enriched by mosquito/sand fly entomologists, military infectious diseases physician, microbiologists, in addition to infectious diseases researchers, ticks/fleas/lice entomologists and rickettsiologists (see the results of the 2008-2011 research program joined to the global application as well as individual activity summary).
1-1. Detection and surveillance of imported diseases focusing on Indian Ocean islands
Our Unit is the coordinating center of EuroTravNet (www.eurotravnet.eu) network, the European CDC collaborative network for travel and tropical medicine (5). EuroTravNet core sites also participate in surveillance and monitoring of travel-related illnesses by collecting epidemiologic data, linking diagnoses with exposure information, of returned ill travellers. Data collected using a standardised format, are entered into the international Geosentinel (www.geosentinel.org) database and analysed periodically (21). The EuroTravNet/Geosentinel database analysis has been identified as a main source of data on the epidemiology of travel-related illness (21-26). One objective of this project is to describe the spectrum of infectious diseases in European travellers every year, grouped by specified clinical syndrome categories with focused sub-analyses of specific conditions, and emerging diseases. Also, when facing a case of emerging imported infectious diseases we will work in connection with microbiologists from our team, as well as with other team within the network to investigate clinical, microbiological and epidemiological aspects of importance, including the risk of spread in Europe.
1.1.1. Focus on diseases imported from Indian Ocean islands
In Marseille, France, there are approximately 50,000–70,000 immigrants from theComorosIslands. Persons originating from theseIndian Oceanislands represent most patients in Marseille diagnosed with imported malaria (27). We also highlighted Marseille as a reference place for the diagnosis of infectious diseases emerging in Comoros and Indian Ocean islands, when we isolated and characterized the chikungunya virus variant that was responsible of the 2005-2006 giant outbreaks in Reunion and Comoros (14), and described new clinical aspects of the diseases(12;13). Our objective is to be aware of any case of fever in travellers returning fromComorosandIndian OceanIslandand conduct rapid survey to identify the agent, with a particular interest for arboviral diseases.
1.1.2. Illness in French travelers to Senegal: Prospective cohort follow-up and sentinel surveillance data
With around 900.000 foreign visitors per year (http://www.afrik.com/article15065.html) Senegal represents a very popular destination for tourists and is the most popular destination in sub-Saharan Africa for French travelers(28). Preliminary cohort study showed that travelers departing from Marseille (around 1000 per year), frequently report arthropod bites (75%) and diarrhea (46%). Several vector-borne diseases of interests will be surveyed prospectively in such cohorts, including malaria, dengue, rickettsiosis, leishmaniasis, filiariasis, chikungunya and Crimean-Congo fever. Detection of viruses in potential vectors will be conducted in collaboration with local researchers. Travelers will be included at pre-travel consultation over one year and administer a questionnaire before and after travel. Stool and blood samples will be collected for the purpose of detecting infectious agents and/or antibodies before and after travel. In addition, detection of infectious agents in potential vectors will be conducted in collaboration with local researchers.
1-2. Survey of emerging vector borne diseases in specific populations
1.2.1. Hajj pilgrims
Each year, approximately 2000 Muslims travel from Marseille to participate in the Hajj, gathering with over two million pilgrims from all over the world. Health risks during the Hajj are a critical issue due to the extreme congestion of people. Infectious diseases represent a major problem during the pilgrimage (29). Around 600 pilgrims in preparation for the Hajj pilgrimage seek advice from the Travel Clinic in the Infectious Disease Unit to satisfy compulsory vaccination requirements.. Several cohorts have been enrolled over last years for the purpose of evaluating vaccination coverage and its determinant (30;31), or to study the spectrum of diseases that face in the management of cohort pilgrims during their stay in Saudi Arabia and possible preventives measures (32-34). In the coming years, we will survey prospectively in these cohorts the outcome of emerging infectious diseases including Rift Valley fever, Crimean-Congo fever, Alkhurma fever and dengue fever (35-38). Pilgrims will be included at pre-travel consultation and administer a questionnaire before and after travel. Nasal swab and blood samples will be collected for the purpose of detecting antibodies and viral DNA before and after travel.
1.2.2. Military personnels deployed overseas
Each year, more than French 20 000 soldiers are sent overseas, including in areas endemic for malaria that remains a challenge for the Forces (9). The use of efficient chemoprophylaxis, relevant diagnosis tools and new treatment strategies for primary attacks and relapses are of concern (39-41). A prospective study will be conducted on the assessment of diagnosis tools (smears, antigen rapid tests, PCR) among all patients hospitalized for imported malaria at the Laveran Hospital. The relevance of the use of Maldi-Tof screening will be also studied. A retrospective study will be conducted on the significance of gametocytes in imported malaria on a cohort of about 300 cases. We will also study the clinical and laboratory features of patients with imported P. vivax and P. ovale malaria hospitalized in the 9 French military hospitals (about 400 cases expected). A1so, we will monitor the management of primaquine therapy (tolerance and efficacy data, dosage) in 70 patients with relapsing malaria.
After our initial contribution on the various aspects of acute Chikungunya infection, we will focus on late manifestations of the disease (42). A cohort of 752 military personnel that were staying onReunionisland during the 2005-2006 outbreak (1/6 had been infected) is regularly followed by questioning on symptoms and quality of life. Data from the 2-years follow-up will be analysed. The 5-year follow-up is being designed to study clinical features of the chronic rheumatism and biological changes, including cryoglobulinemia and other immunological changes and genetic substratum.
Homeless are estimated to be 1500 individual in Marseilles. We reported that 22% of them have body lice which are vectors for Trench Fever ( Bartonella quintana) epidemic typhus ( Rickettsia prowazekii) and relapsing fever ( Borrelia recurrentis) (4;43). Controlling body louse should control the infectious diseases they transmit. Delousing, although ideal is still unsuccessful (44). Mass treatment with ivermectin is efficient but the effect is transient suggesting that it cannot be a unique method (45;46).
No resistance of the body louse has yet been reported to permethrin. Two projects will be carried on
- « Eradication of the body louse by permethrin impregnated clothes. Double Blind randomized comparative trial versus placebo in deprived population of Marseille. Funded by #300 K€ (PHRC national 2010).
- Evaluation of genomic resistance to permetrin in the body louse before and during clinical trail by detection of mutation associated to loci M8151, T9171 et L920F of the alpha sub unit Sodium dependant transmembrane channel by pyro sequencing
3. 1. Ticks-, Lice- and Flea-borne emerging bacteria
Screening arthropods by molecular biology using broad range primers and culture the detected agent, particularly if it is a new microorganism, is one approach that has been used at this time for detecting new infectious agent. This will be part of a global project of URMITE with additional steps: making antigens and testing the presence of antibodies in the population to characterize and describe the new disease and finally isolate the agent in human and establish animal model for physiopathology. As an example this is the way we described some new rickettsiosis such as TIBOLA, LAR (47). As for the 2008-2011 university period (48-55), we will continue to collect ticks and fleas in the field worldwide (with a specific interest for some areas such asSenegal) and detect by PCR bacteria, including bacteria of unknown pathogenicity. Some of those who have been detected in the past are under investigation for their pathogenic role in human. In addition new approach to study identification of ticks and tick and flea- bacteria association, we will develop molecular tools (gene sequencing) and new approach.
On the other hand, Crimean Congo hemorrhagic fever is actually spreading in the borders of Europe and cases have been recorded in countries of the Mediterranean borders (Turkey and Greece) (56). We will investigate 2 potentials vectors of CCHF in southern France: Hyalomma lusitanicum in Camargue and H. marginatum marginatum in all south east and Corsica (57). A typology of favourable environments will be described, and ticks will be tested by Molecular tools to detect CCFH virus.
3. 2. Sand-flies and Emerging microorganisms
Toscana virus (TOSV) transmitted has recently reemerged in southern France where it is transmitted by the sandfly by P.perniciosus (20). Other sandfly fevers agent might emerge in the near future there (58). Since 2009 we have identified permanent foci of transmission in south east France and some results are questioning : early cases in May when sandflies density are low et most of females are nulliparous, infection of P.perniciosus by lizards trypanosomatidae suggesting with previous data on S.minuta infection by TOSV that TOSV is possibly circulating in Lizards and geckos. We propose to conduct a longitudinal entomological and serological studies in two endemic areas near Marseille and Toulon to asses the dynamic of P.perniciosus populations, the level of the different phleboviruses circulation and to identify the blood feedings behaviours of the different species of vectors. Catches will be conducted from April to November during the incoming years. Blood meals identification will be done by molecular tools or serological methods according to potential blood meal sources of the area (domestic or wild fauna) (59). Serologic studies will be conducted in domestic and wild fauna to search TOSV infection traces. The immune response of dogs against P.perniciosus saliva is currently under investigation. If relevant, this tool will be used to assess the level of exposition of animals to P.perniciosus in the two foci.
3. 3. Mosquitoes and Emerging microorganisms
In the recent years, we used remote sensing tools to predict An. arabiensis (malaria vector) aggressiveness inDakar, confronting entomologic field data and remote sensing risk map. Entomologic data have been collected in 45 districts ofDakar and high resolution SPOT (Satellite Pour l’Observation de la Terre) satellite images have been acquired both in dry and wet seasons. An operational model is currently on study to forecast malaria risk in urban sahelian environment according remote sensing data. This model will be test in N’djamena,Chad. This model could probably not be used to predict malaria risk in equatorialAfrica. We have conducted during one year an entomological assessment of malaria transmission in four districts ofLibreville,Gabon. This work will be continued and other remote sensing tools like radar will be used to product risks maps.
3. 4. Bed Bugs and emerging diseases
The bed bug (Cimex lectularius) is emerging all over the world due to travel, and insecticides resistance. It is a disease poorly describe that merits better clinical description. A tremendous number of bacteria and parasites have been associated to bedbug but until now none have been implicated in human diseases.
Two projects have been initiated both funded by PHRC 2009 (# 300K€)
- Study of the vector capacity of Cimex lectularius. This is a study implicating different research units : UMITE for detection by PCR of Bartonella, Rickettsiae, UMR IRD 190 for virus, molecular identification of the arthropod will be carried out at LIN UR016 Montpellier and insecticide susceptibility at CHU Nice
- Clinical features of Cimex lectularius bites in human being. Clinical descriptive study at J1, J7, J15, J30.
To improve our knowledge on the epidemiology of emerging infection we developed experimental entomology to understand the natural cycle of infectious agent transmitted by arthropods. We already set up a rabbit model to explain the cycle of several tick-borne rickettsiae in ticks (60-62).
4. 1. Ticks
Rickettsia conorii conorii is the etiological agent of Mediteranean Spotted Fever (MSF), transmitted by the brown dog tick, Rhipicephalus sanguineus. Rh. sanguineus- R. conorii conorii relationships as well as the ecology of MSF are still poorly understood one century after the description of the disease (63). Also ticks naturally infected have been shown to maintain the rickettsia, the prevalence of infected Rh. sanguineus in nature is low. Nothing is known on the influence of extrinsic factors on the tick-rickettsia relationships. Temperature may influence not only the vectors behaviours as we recently demonstrated (64), but also the vectors-microorganisms relationships. The influence of temperature in the survival of several stages of Rh. sanguineus naturally infected with R.conorii with uninfected. The mortality of engorged nymphs and adults infected with R. conorii exposed during one month at low temperature (4°C) and then transferred to25°C, will be studied compared to uninfected ticks. Other temperature range will be studied (37°C).
4. 2. Lice
Differentiation between head and body louse is still a debate (65-67). Until now no tests including sequence analysis have been able to separate them. That close relationship suggests that one is the parent of the other. We made the hypothesis that the body louse belong to the head lice (68). To test this hypothesis it is needed to develop more sensitive test such as MST or microsatellites. Proteome analysis should also give an answer to this question
4. 3. Fleas
We aim to set up infected and not infected flea laboratory colonies to study interaction between Ctenocephalides felis (the cat flea) with R. felis, the agent of Cat flea spotted fever (3), as well as other bacteria. The first step will be the development of an artificial system for blood feeding of fleas. Fleas will be thereafter infected by R. felis as well as other organisms. The transmission of the bactaria in fleas as well as the consequences on the flea survival will be studied.
4. 4. Arthropods and Saliva
Antibody responses against arthropod saliva have been used to assess the level of population’s exposition to vector bite and the efficacy of vector control programs (71;72). Peptides are now available to assess the exposition for the main malaria vector in Africaand in South America. Specific peptides are in development to measure the exposition to arbovirus vectors (73;74). We will confront the results of entomologic and serologic studies conducted in the same time in different districts of Dakarto measure the exposure to An. gambiae s.l.. A project will begin in south east France to assess the exposure of soldiers to Ae. Albopictus bites. Entomologic studies using human landing catches, Bg sentinels traps will be conducted in military camps of Var and Corsica (16). These works will be used to validate in the field the predictive value of the specific peptides actually in development to measure Ae. Albopictus exposure.
We will also conduct studies on antibody response of rabbits against ticks vectors in France: Rh. sanguineus, D. reticulatus and I. ricinus. Rabbits will be exposed to ticks bites and sera will collected at different times after exposure.
In the same way, we will study the immune response of dogs to P.perniciosus bites. A proteomic approach has been chosen to describe the salivary gland proteome of P.perniciosus using a lab strain (75). We will test sera of (i) dogs naturally exposed to P.perniciosus and P.ariasi in South France, (ii) dogs exposed in the lab to P.perniciosus, (iii) dogs originating from north of France in area without P.perniciosus, and (iv) dogs never exposed to sandflies. In these models, western blots 1D and 2D will be used to assess the existence of specific antigenic proteins. Mass spectrometry would be used to identify the antigenic proteins. If relevant, recombinant proteins will be produced and tested on sera of dogs and humans exposed to arthropod bites (76). The same methodology will be used to assess the exposure to human body lice.
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