Institut Pasteur

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH IN SUPPORT OF BTO IN THE AMOUNT OF 2,316,293 ON CONTRACT HR0011-17-2-0023.

RESEARCH, INNOVATION, SURVEILLANCE & EVALUATION (RISE) PROJECT IN MADAGASCAR

INTER-REGIONAL STUDY OF TRANSMISSION, ADAPTATION AND PATHOGENESIS OF VIRUSES WITH PANDEMIC POTENTIAL IN SOUTHEAST ASIA AND WEST/CENTRAL AFRICA

SURVEILLANCE AND DATA FOR MANAGEMENT (SDM) PROJECT

D18AC00030

TA TO SUPPORT PROJECT DEVELOPMENT WORK FOR A COVID-19 VACCINE MANUFACTURING FACILITY IN SENEGAL.

COMPREHENSIVE CHARACTERIZATION OF THE GENETIC FACTORS AND THE HOST IMMUNE RESPONSE ASSOCIATED TO PROTECTION FROM CLINICAL PLASMODIUM VIVAX MALARIA - WE CURRENTLY HAVE A VERY LIMITED UNDERSTANDING OF THE FACTORS, EITHER GENETIC OR IMMUNE-RELATED, CONFERRING PROTECTION TO CLINICAL PLASMODIUM VIVAX (PV) MALARIA. DECIPHERING THE MECHANISMS UNDERLYING SUCH PROTECTION WOULD ALLOW THE DESIGN OF TAILORED INTERVENTION STRATEGIES FOR THE ELIMINATION OF PV. PRODUCTION OF ANTI-PV DUFFY BINDING PROTEIN (DBP) BINDING-INHIBITORY ANTIBODIES (BIABS) IS ASSOCIATED TO FUNCTIONAL AND PROTECTIVE IMMUNITY AGAINST PV MALARIA. ONLY A MINORITY OF INDIVIDUALS DEVELOPS SUCH ANTIBODIES AND THE MECHANISMS ENABLING THEIR PRODUCTION ARE UNKNOWN. INDIVIDUALS NOT PRODUCING BIABS CAN STILL BE PROTECTED AGAINST PV CLINICAL MALARIA INDICATING THAT ADDITIONAL IMMUNOLOGICAL AND/OR GENETIC FACTORS CAN CONFER PROTECTION. LEVERAGING A LONGITUDINAL COHORT WE HAVE CONSTITUTED IN ENDEMIC AREA OF CAMBODIA, WE HAVE IDENTIFIED INDIVIDUALS DISPLAYING REMARKABLE CLINICAL PROTECTION AGAINST PV AND THE OVERALL GOAL OF THIS PROPOSAL AIMS AT CHARACTERIZING THE FACTORS ENABLING SUCH PROTECTION. THE FIRST SPECIFIC AIM (SA1) WILL BE TO UNDERSTAND THE FACTORS THAT DRIVE THE PRODUCTION OF ANTI-PVDBP BIABS AND THEREFORE FURTHER CLINICAL PROTECTION AGAINST PV. BY PHENOTYPING AND FUNCTIONALLY CHARACTERIZING DBP-SPECIFIC CD4+ T CELLS AND B CELLS IN NATURALLY INFECTED PARTICIPANTS WITH CHARACTERIZED AMOUNTS OF BIABS, WE WILL HAVE A BETTER UNDERSTANDING OF THE ADAPTIVE IMMUNE RESPONSE OF INDIVIDUALS LEADING TO THE PRODUCTION OF NATURALLY-ACQUIRED ANTI-PVDBP BIABS. ON THE OTHER HAND, BY CHARACTERIZING THE PVDBP ALLELIC POLYMORPHISM AND ISOFORMS PRODUCED BY ISOLATES COLLECTED FROM INDIVIDUALS WITH VARIOUS LEVELS OF BIABS, WE WILL DETERMINE IF PARASITE GENETIC FACTORS ARE ALSO CONTRIBUTING TO THE ACQUISITION OF BIABS. THE SECOND AND THIRD SA WILL BE TO DECIPHER THE GENETIC (SA2) OR IMMUNE (SA3) FACTORS LEADING TO PROTECTION AGAINST PV MALARIA FOR INDIVIDUALS NOT PRODUCING ANTI-PVDBP BIABS. IN SA2, WE WILL COMPARE THE GENE EXPRESSION PROFILES AND GENOTYPES OF PARASITES ISOLATED FROM CHRONICALLY-INFECTED ASYMPTOMATIC INDIVIDUALS AND FROM SYMPTOMATIC TREATMENT-SEEKING PATIENTS TO IDENTIFY PARASITE FACTORS DIFFERENTIATING THESE TWO DRASTICALLY DIFFERENT CLINICAL OUTCOMES. WE WILL ALSO DETERMINE THE HUMAN ERYTHROCYTE PROTEINS’ POLYMORPHISM OF INDIVIDUALS DISPLAYING CONTRASTED CLINICAL OUTCOME OF INFECTION TO IDENTIFY HOST GENETIC FACTORS CONFERRING PROTECTION. ANY HOST POLYMORPHISM IDENTIFIED WILL BE FUNCTIONALLY TESTED IN VITRO FOR PV INVASION/DEVELOPMENT ALTERATIONS. IN SA3, WE WILL IDENTIFY HOST IMMUNE FACTORS ASSOCIATED TO PROTECTION FROM CLINICAL PV MALARIA. USING THE SAME PATIENT COHORT AS SA2, WE WILL STUDY EX VIVO AND IN VITRO THE IMMUNE RESPONSES IN PV-INFECTED PATIENTS. USING SINGLE CELL CULTURES OF ANTIGEN-SPECIFIC B CELLS, WE AIM TO IDENTIFY NOVEL HUMORAL TARGETS ON THE PV MEROZOITE OR IRBC THAT COULD BE INVOLVED IN CONFERRING PROTECTION FROM CLINICAL PV MALARIA TROUGH BLOCKADE OF INVASION OR ALTERNATIVE ANTIBODY EFFECTOR FUNCTIONS.

KEY DETERMINANTS OF THE NATURAL HISTORY OF LEISHMANIA MAJOR INFECTION

EXTENT, DYNAMICS AND MECHANISMS OF PLASMODIUM VIVAX IMMUNE EVASION CAUSED BY PVDBP GENE AMPLIFICATION - ELIMINATION OF PLASMODIUM VIVAX (PV) MALARIA PARASITES WOULD GREATLY BENEFIT FROM A BLOOD-STAGE VACCINE. PVDBP IS A PARASITE LIGAND INVOLVED IN ERYTHROCYTE INVASION THROUGH THE INTERACTION WITH ITS HUMAN RECEPTOR, THE DUFFY PROTEIN. THIS INTERACTION IS CRITICAL FOR THE PARASITE’S ENTRY MAKING PVDBP THE MOST ADVANCED CANDIDATE FOR A BLOOD-STAGE VACCINE WITH PHASE II CLINICAL TRIALS UNDERGOING. RECENT WORK HAS IDENTIFIED AND CHARACTERIZED HUMAN MONOCLONAL ANTIBODIES (HUMABS) THAT ALLOW STRAIN-TRANSCENDING NEUTRALIZATION OF PARASITES REGARDLESS OF THEIR PVDBP SEQUENCE DIVERSITY. HOWEVER, WE HAVE DEMONSTRATED THAT PV COLLECTED IN CAMBODIA WITH MULTIPLE COPIES OF THE PVDBP GENE WERE ABLE TO OVERCOME IN VITRO NEUTRALIZATION BY THESE HUMABS. THESE OBSERVATIONS PROVIDED THE FIRST EVIDENCE FOR AN EVOLUTIONARY ADVANTAGE FOR PVDBP AMPLIFICATION, WIDESPREAD IN PV POPULATIONS, AND CREATED A NEW PARADIGM IN WHICH TO CONSIDER PATHOGEN IMMUNE EVASION MECHANISMS. THESE RESULTS RAISE THE CONCERN THAT IMPLEMENTATION OF A PVDBP VACCINE MAY SELECT FOR MULTI-PVDBP COPY PARASITES. THE OVERALL GOAL OF THIS PROPOSAL IS PRECISELY TO DETERMINE IF PVDBP AMPLIFICATION WILL LIKELY COMPROMISE A PVDBP VACCINE STRATEGY. THE FIRST SPECIFIC AIM (SA) IS TO DETERMINE TO WHAT EXTENT MULTI-PVDBP COPY PARASITES GENETICALLY DISTANT FROM CAMBODIAN ISOLATES RESPOND TO ANTI-PVDBP HUMABS AND TO EVALUATE IF PVDBP AMPLIFICATION IS ASSOCIATED TO DUFFY POLYMORPHISMS IN HUMAN POPULATIONS. BY EVALUATING THE IN VITRO NEUTRALIZATION BY ANTI-PVDBP HUMABS OF SINGLE AND MULTI-PVDBP COPY PARASITES FROM ETHIOPIA, WE WILL BE ABLE TO EVALUATE THE EXTENT OF THE IMMUNE EVASION PHENOTYPE CONFERRED BY PVDBP AMPLIFICATION DESCRIBED WITH CAMBODIAN PV. BY (I) ASSOCIATING IN VITRO INVASION RATES WITH THE FULL-LENGTH DUFFY SEQUENCES OF INVADED ERYTHROCYTES, AND (II) PROSPECTIVELY TESTING FOR ASSOCIATION BETWEEN PVDBP COPY NUMBER AND HUMAN DUFFY SEQUENCES IN PARTICIPANTS ENROLLED IN LONGITUDINAL COHORTS IN CAMBODIA AND IN ETHIOPIA, WE WILL BE ABLE TO DETERMINE THE RELATION BETWEEN PVDBP AMPLIFICATION AND DUFFY HUMAN POLYMORPHISM. OUR SECOND SA WILL BE TO EVALUATE THE WITHIN-HOSTS AND WITHIN-POPULATION DYNAMICS OF PVDBP AMPLIFICATION OVER TIME. THROUGH THE ANALYSIS OF THE SEROLOGICAL DYNAMICS OF OUR LONGITUDINAL COHORTS’ PARTICIPANTS, THE MEASURE OF PV INFECTIONS AND THE PVDBP COPY NUMBER OF INFECTING PARASITES, WE WILL BE ABLE TO TEST IF THE GENE AMPLIFICATION IS SELECTED IN VIVO BY THE IMMUNE STATUS OF HUMAN HOSTS AND HOW IT CORRELATES WITH CHANGES IN PV PREVALENCE IN THE POPULATION. IN VITRO EXPERIMENTAL EVOLUTION OF PK LINES WILL PROVIDE COMPLEMENTARY EVIDENCE FOR SELECTION OF PVDBP AMPLIFICATION BY ANTI-PVDBP HUMABS. OUR THIRD SA WILL BE TO DECIPHER THE MOLECULAR MECHANISMS ENABLING MULTI-COPY PARASITES TO EVADE ANTI-PVDBP HUMABS’ NEUTRALIZATION. WE WILL SPECIFICALLY TEST IF IMMUNE EVASION RESULTS FROM INCREASED PROTEIN QUANTITY PRODUCED BY MULTI-COPY PARASITES AND/OR FROM EPITOPE VARIATIONS THROUGH MULTIPLE, DIFFERENT ALLELES AND VARIANTS PRESENT SIMULTANEOUSLY IN A GIVEN PARASITE. THROUGH A COMBINATION OF PHENOTYPING AND GENOMIC APPROACHES, OUR RESULTS WILL PROVIDE INVALUABLE DATA TO INFORM ON STRATEGIES TO OVERCOME THIS IMMUNE EVASION IN THE CONTEXT OF VACCINE DEVELOPMENT. .

ADVANCING INFECTIOUS DISEASE AND RESPONSE IN SENEGAL

GENOMICS OF MOSQUITO RESISTANCE TO PLASMODIUM

PREPAREDNESS AND RESPONSE TO AVIAN AND PANDEMIC INFLUENZA IN MADAGASCAR

SUSTAINING SURVEILLANCE NETWORKS AND RESPONSE TO SEASONAL AND PANDEMIC INFLUENZA

SURVEILLANCE AND RESPONSE TO AVIAN AND PANDEMIC INFLUENZA IN MADAGASCAR - THIS PROPOSAL IS BEING SUBMITTED BY THE NATIONAL INFLUENZA CENTER (NIC) MADAGASCAR, A DEPARTMENT OF THE INSTITUT PASTEUR OF MADAGASCAR (IPM) ON BEHALF OF THE MINISTRY OF PUBLIC HEALTH (MOPH) OF THE REPUBLIC OF MADAGASCAR. DESIGNED BY THE WHO AS THE NATIONAL REFERENCE FOR INFLUENZA IN 1978, THE NIC MADAGASCAR IS MEMBERS OF GISRS (GLOBAL INFLUENZA SURVEILLANCE AND RESPONSE SYSTEM) AND PARTICIPATES ACTIVELY TO THE INFLUENZA SURVEILLANCE SINCE MORE THAN 40 YEARS. THE PROJECT IS DESIGNED TO SUSTAIN NATIONAL INFLUENZA ACTIVITIES CONDUCTED BY THE NIC UNDER PREVIOUS CDC COOPERATIVE AGREEMENT, AND STRENGTH NATIONAL CAPACITIES IN PREPAREDNESS, EARLY DETECTION AND RESPONSE TO AVIAN AND PANDEMIC INFLUENZA AS WELL AS EMERGING/RE-EMERGING INFECTIOUS DISEASE WITH POTENTIAL THREATS.THREE GOALS WILL BE ADDRESSED UNDER THIS PROJECT:GOAL 1: TO MAINTAIN AND CONSOLIDATE ROUTINE ILI, SARI AND MORTALITY SURVEILLANCE IN MADAGASCAR TO GENERATE ROBUST DATA SO AS TO SIGNIFICANTLY IMPACT POLICY DEVELOPMENT FOR THE COUNTRY AND POTENTIALLY FOR THE REGION, WHILE WORKING TOWARD DOWN-SCALING AND LONG-TERM SUSTAINABILITY OF THE ILI AND SARI SURVEILLANCE NETWORK IN MADAGASCAR. SINCE OUR BIOLOGICAL SARI SURVEILLANCE DEPENDS ONLY ON TWO SITES, THIS WILL ENTAIL TO REINFORCE THE SARI SURVEILLANCE SYSTEM FROM ITS CURRENT LEVEL IN ORDER TO OBTAIN ROBUST DATA ON HOSPITALIZED SARI PATIENTS WITH PARTICULAR EMPHASIS ON IMPORTANT HIGH-RISK GROUPS. THESE DATA WILL BE USED TO FORMULATE APPROPRIATE POLICIES FOR INFLUENZA SURVEILLANCE AND VACCINATION INTERVENTIONS (ESPECIALLY IN HIGH-RISK GROUPS IN MADAGASCAR) AND ENCOURAGE THE MINISTRY OF PUBLIC HEALTH TO FUND THESE ACTIVITIES IN THE FUTURE.GOAL 2: TO CONSOLIDATE THE LABORATORY CAPACITY SO AS TO SERVE AS NATIONAL AND REGIONAL REFERENCE LABORATORY FOR ZOONOTIC INFLUENZA, TO PROVIDE TRAINING AND SUPPORT TO THE COUNTRY AND REGION, AND TO ESTABLISH ADDITIONAL TECHNOLOGY. THANKS TO THE AGREEMENT BETWEEN IPM AND THE DIRECTION OF VETERINARY SERVICE ( DSV) OF THE MINISTRY OF LIVESTOCK, CLOSE COLLABORATIONS WITH THE ANIMAL HEALTH SURVEILLANCE SYSTEMS WILL BE SET UP WITH THE AIM TO MONITOR POTENTIAL ZOONOTIC EMERGENCE OF AVIAN INFLUENZA.GOAL 3: TO USE THE FINDINGS AND EXPERIENCES FROM INFLUENZA SURVEILLANCE TO SUSTAIN AND REINFORCE THE DIAGNOSTIC OF COVID-19 IN THE COUNTRY IN ORDER TO INCREASE NATIONAL CAPACITY MANAGEMENT OF SEVERE CASES AND IMPROVE THE COVID-19 SURVEILLANCE. TWO MAIN COMPONENTS ARE ADDRESSED TO REACH THESE GOALS:COMPONENT 1: SURVEILLANCE AND EMERGING DISEASE PREPAREDNESS OF INFLUENZACOMPONENT 2: SURVEILLANCE AND RESPONSE TO NON-INFLUENZA RESPIRATORY VIRUSES

SUSTAINING SURVEILLANCE NETWORKS AND RESPONSE TO SEASONAL AND PANDEMIC INFLUENZA

STRENGTHENING THE SURVEILLANCE SYSTEM OF INFLUENZA AND NON INFLUENZA RESPIRATORY PATHOGENS IN TUNISIA: PHASE 3, BUILDING CAPACITIES AND SUSTAINABILITY - THE PRESENT PROJECT AIMS TO STRENGTHEN THE ACHIEVEMENTS AND ENSURE A QUALITY IMPROVEMENT IN ALL ASPECTS AS WELL AS A PROGRESS TOWARDS SUSTAINABILITY AND INTEGRATION OF THE INFLUENZA AND OTHER RESPIRATORY VIRUSES SYSTEM FOR AN OPTIMAL PERFORMANCE AND CAPACITY TO CONTROL EPIDEMICS AT DETECT PANDEMIC THREATS. IN AGREEMENT WITH US-CDC VISION, WE EXPECT TO:1. OBTAIN A PARSIMONIOUS QUALITY-BASED ELECTRONIC SURVEILLANCE SYSTEM OF INFLUENZA AND OTHER RESPIRATORY VIRUSES INTEGRATING PERTINENT STAKEHOLDERS AT THE MINISTRIES OF HEALTH AND AGRICULTURE, DECENTRALIZED, LINKING STAKEHOLDERS AND SECTORS FOR TIMELY SHARING OF EPIDEMIOLOGIC AND INFORMATION CIRCULATING VIRUSES AND CAPABLE OF PRODUCING PERTINENT INFORMATION FOR AN EVIDENCE-BASED CONTROL STRATEGY AND RESPONSE TO PANDEMIC THREATS. 2. ADDRESS A BIG GAP IDENTIFIED IN PREVIOUS SURVEILLANCE SYSTEM THAT CONSIST OF THE WEAK IDENTIFICATION OF CIRCULATING RESPIRATORY PATHOGENS WHICH WILL MOST LIKELY INCLUDE PANDEMIC RELATED PATHOGENS AND UPGRADE THE SURVEILLANCE TO THE LEVEL OF THE ACCURATE IDENTIFICATION OF ETIOLOGICAL AGENTS AND THEIR DISTRIBUTION OVER TIME IN REPRESENTATIVE AREAS OF TUNISIA.3. TO STRENGTHEN THE CAPACITIES, COMPETENCIES AND SKILLS TO DETECT AT AN EARLY STAGE THE EPIDEMIC/PANDEMIC THREATS AND TO ENABLE CONTROL TEAMS TO RESPOND TIMELY AND ADEQUATELY.4. TO SHARE THE EPIDEMIOLOGIC/BIOLOGICAL INFORMATION IN REAL TIME WITH PARTNERS, UN AGENCIES AND THE US-CDC.THIS PROPOSAL AIMS TO PROMOTE QUALITY AND PROGRESS TOWARDS SUSTAINABILITY AND ONE HEALTH APPROACH USING MULTI-SECTORAL TRANSDISCIPLINARY APPROACHES. IT INTEGRATES IN THE SAME ELECTRONIC PLATFORM EPIDEMIOLOGICAL, CLINICAL AND BIOLOGICAL SURVEILLANCE DATA FOR TIMELY SHARING AND EVIDENCE-BASED DECISIONS BY DIFFERENT STAKEHOLDERS. A STEERING COMMITTEE, SUPPORTED BY TECHNICAL AD-HOC COMMITTEES AND RECOGNIZED EXPERTS, REPRESENTING A CONSORTIUM OF PUBLIC HEALTH INSTITUTIONS, INCLUDING A NETWORK OF CERTIFIED LABORATORIES IN CHARGE OF INFLUENZA AN D NON-INFLUENZA RESPIRATORY PATHOGENS SURVEILLANCE, AND SUPPORTED BY THE MINISTRIES OF HEALTH AND AGRICULTURE, ENSURES GOVERNANCE, IMPLEMENTATION AND EVALUATION OF THE PROJECT. ULTIMATELY, THIS SYSTEM WILL BE SUSTAINABLE AND MOST APPROPRIATE FOR INFLUENZA AND NON-INFLUENZA RESPIRATORY PATHOGENS SURVEILLANCE AND CONTROL AS WELL AS PANDEMIC PREPAREDNESS AND RESPONSE.

STRENGTHENING THE SURVEILLANCE AND CONTROL OF INFLUENZA PROGRAM IMPLEMENTED IN TU

MALAGASY MALARIA TOOL BOX MONITORING AND EVALUATION MALARIA IN MADAGASCAR

TOPICAL TREATMENT OF CUTANEOUS LEISHMANIASIS

STRENGTHENING THE SURVEILLANCE AND CONTROL OF INFLUENZA PROGRAM IMPLEMENTED IN TU

INVESTIGATING SEASONAL DRIVERS OF VIRAL ZOONOSES FROM MADAGASCAR FRUIT BATS

VAR GENE REGULATION MECHANISMS IN MALARIA PARASITE PLASMODIUM FALCIPARUM

LEVERAGING ACCESS TO PARASITE NATURAL DIVERSITY TO IDENTIFY PLASMODIUM VIVAX CULTURE-ADAPTABLE STRAIN. - PLASMODIUM VIVAX (PV) POSES A SIGNIFICANT CHALLENGE DUE TO ITS EXTENSIVE GEOGRAPHICAL DISTRIBUTION, RESULTING IN A CONSIDERABLE BURDEN OF MORBIDITY AND MORTALITY IN REGIONS WHERE IT IS ENDEMIC. DIVERGING FROM PLASMODIUM FALCIPARUM (PF), PV MANIFESTS DISTINCT CHARACTERISTICS, NOTABLY THE PRESENCE OF DORMANT LIVER STAGES AND THE INHERENT IMPEDIMENT TO IN VITRO CULTIVATION. THESE PECULIARITIES PRESENT FORMIDABLE OBSTACLES TO PV MALARIA ELIMINATION. THE DEVELOPMENT OF A ROBUST AND REPRODUCIBLE IN VITRO CULTURE SYSTEM FOR PV WOULD BE A GAME- CHANGER TO DESIGN EFFICACIOUS ANTI-MALARIAL STRATEGIES. THE PHASE I OF OUR PROJECT AIMS TO ESTABLISH ROBUST AND LONG-TERM STABLE IN VITRO CULTURES OF PV CLINICAL ISOLATES. OUR MAIN ADVANTAGE LIES IN HAVING ACCESS TO MULTIPLE CLINICAL ISOLATES THANKS TO OUR MOBILE LABORATORIES INSTALLED IN ENDEMIC REGIONS OF CAMBODIA, AT THE BEDSIDE OF INFECTED PATIENTS. THIS INFRASTRUCTURE ENABLES US TO SYSTEMATICALLY CONDUCT IN VITRO CULTURE TESTS ON SEVERAL HUNDRED FRESH AND HEALTHY PV STRAINS. THIS INITIAL APPROACH WILL FACILITATE THE SELECTION OF PV STRAINS POSSESSING A GENETIC BACKGROUND ADAPTED FOR IN VITRO CULTURE. THE SECOND PART OF THE PROJECT WILL INVESTIGATE OPTIMAL CULTURE CONDITIONS, INCLUDING, BUT NOT LIMITED TO, CULTURE MEDIUM COMPOSITION OR IMPACT OF DIFFERENT CONCENTRATIONS OF O2 AND CO2 ON IN VITRO SURVIVAL OF PV USING A SPECIFICALLY DESIGNED HYPOXIC CHAMBER. WE WILL EXPLORE HEMATOPOIETIC STEM CELLS AS SOURCES OF RETICULOCYTES AND ASSESS THE POTENTIAL OF HUMAN MESENCHYMAL STROMAL CELLS AS SUPPORT CELLS FOR PV SURVIVAL IN VITRO. FINALLY, WE AIM TO ESTABLISH A 3D ORGANOID MODEL CAPABLE OF REPRODUCING THE SPECIFIC CONDITIONS OF THE BONE MARROW, RECOGNIZED AS A PRIMARY SITE OF PV DEVELOPMENT. THE THIRD PART OF THE PROJECT WILL UTILIZE STRAINS WITH THE HIGHEST POTENTIAL FOR IN VITRO CULTURE TO INVESTIGATE THE IN VITRO MODIFICATION OF PV GENOME USING CRISPR CAS9. AS A PROOF OF CONCEPT, WE WILL INSERT A GENE ENCODING GFP. REGARDING THE PHASE II OF THE PROJECT (R33) WE WILL EMPLOY THE GENETIC MODIFICATION METHOD DEVELOPED IN PHASE I TO ESTABLISH DIFFERENT STRAINS OF GENETICALLY MODIFIED PV. THIS AIMS TO STUDY VARIOUS MECHANISMS OF DRUG RESISTANCE AND IDENTIFY POTENTIAL RESISTANCE MARKERS. OUR OBJECTIVE INCLUDES THE STUDY OF THE OVEREXPRESSION OF THE PVCRT OR PVMDR1 GENES AND THE EXPRESSION OF THE V552I AND Y976F VARIANTS IN THE PVKELCH12 AND PVMDR-1 GENES, RESPECTIVELY IN ORDER TO EXPLORE RESISTANCE TO THE MAIN DRUGS CURRENTLY USED IN PV TREATMENT. THIS STUDY HAS THE POTENTIAL NOT ONLY TO PROVIDE TOOLS FOR A BETTER UNDERSTANDING OF PV BIOLOGY BUT ALSO TO IDENTIFY POTENTIAL DRUG RESISTANCE MARKERS CRUCIAL FOR CURRENT MALARIA CONTROL STRATEGIES.

STRENGTHENING THE SURVEILLANCE SYSTEM OF INFLUENZA IN TUNISIA: PHASE 2, BRIDGING BUILDING CAPACITIES AND SUSTAINABILITY

CELLULAR AND MOLECULAR ARCHITECTURE OF GRANULOMAS IN HUMAN TUBERCULOUS LYMPHADENITIS - ABSTRACT TUBERCULOUS LYMPHADENITIS (TBL) IS THE MOST FREQUENT FORM OF EXTRAPULMONARY OF TB AFFECTING APPROXIMATELY 2000 INDIVIDUALS IN TUNISIA ANNUALLY, SUCH THAT THE DISEASE IS A CLINICAL BURDEN ON THE TUNISIAN HEALTH CARE SYSTEM. SINCE THE OCCURRENCE OF CONCOMITANT PULMONARY TB IN TBL PATIENTS IS INFREQUENT, AND BACILLI ARE RARELY DETECTED BY MICROSCOPY, TBL REPRESENTS A FORM OF TB IN WHICH THE INFECTION IS CONTROLLED AND NOT YET DISSEMINATED, EXCEPT IN IMMUNOCOMPROMISED INDIVIDUALS. TBL IN TUNISIA IS GENERALLY CAUSED BY MYCOBACTERIUM BOVIS OR M. TUBERCULOSIS, YET CANNOT BE DISTINGUISHED CLINICALLY, RADIOGRAPHICALLY, OR PATHOLOGICALLY. THE HISTOLOGIC HALLMARK OF TB IS THE GRANULOMA, AN ORGANIZED COLLECTION OF MACROPHAGES, LYMPHOCYTES, AND OTHER CELL TYPES THAT FUNCTION TO CONTAIN AND KILL INVADING PATHOGENS. HERE, WE WILL TEST THE HYPOTHESIS THAT ELUCIDATION OF THE CELLULAR AND MOLECULAR ARCHITECTURE OF TBL GRANULOMAS WILL LEAD TO THE IDENTIFICATION OF DISEASE BIOMARKERS AND INSIGHT INTO THE MECHANISMS BY WHICH T CELL RESPONSES REGULATES ANTIMICROBIAL RESPONSES IN GRANULOMAS. WE PROPOSE TO STUDY THE CELLULAR AND MOLECULAR ARCHITECTURE OF GRANULOMAS IN TBL BY INTEGRATING SINGLE CELL RNA-SEQUENCING (SCRNA-SEQ) WITH SPATIAL-SEQ OF LYMPH NODE SPECIMENS THAT ARE OBTAINED AS PART OF ROUTINE CLINICAL CARE. THIS PROJECT BRINGS TOGETHER SCIENTISTS FROM THE BENABDESSALEM LAB AT THE INSTITUT PASTEUR DE TUNIS (IPT) WITH SCIENTISTS FROM UCLA, WHO HAVE ALREADY COLLABORATED TO GENERATE PRELIMINARY DATA MEASURING THE SPATIAL DISTRIBUTION OF CELL TYPES AND GENES IN PULMONARY TB AND TBL GRANULOMAS. IN AIM 1, WE WILL DETERMINE THE CELLULAR AND MOLECULAR ARCHITECTURE OF TBL GRANULOMAS, IDENTIFYING BIOMARKERS RELATED TO ANTIMICROBIAL RESPONSES THAT CORRELATE WITH THE CAUSATIVE AGENT, M. BOVIS VS. M. TUBERCULOSIS, AS WELL AS COMPARING THE RESPONSE IN TBL TO PULMONARY TB. IN AIM 2, WE WILL DETERMINE THE CONTRIBUTION OF T CELLS TO CONTROL THE INFECTION IN TBL GRANULOMAS THROUGH ANTIMICROBIAL RESPONSES, INCLUDING RELEVANT CORRELATES TO SPECIFIC MYCOBACTERIAL ANTIGENS IN PERIPHERAL BLOOD. TOGETHER, THESE STUDIES WILL PROVIDE NEW INSIGHT INTO THE MECHANISMS BY WHICH THE INTERSECTION OF T CELL RESPONSES AND GRANULOMA ORGANIZATION IMPACTS HOST CONTROL OF M. BOVIS VS. M. TUBERCULOSIS INFECTION. AS SUCH, OUR STUDIES OF THE SPECIFIC IMMUNE BIOSIGNATURES IN TBL WILL EXPAND OUR UNDERSTANDING OF ITS IMMUNOPATHOGENESIS, LEADING TO IMPROVED CARE FOR PATIENTS WITH TBL. AN IMPORTANT PART OF THIS APPLICATION IS TO ENSURE TRANSFER OF TECHNOLOGY AND RESEARCH TRAINING FROM THE MODLIN LAB AT UCLA TO THE BENABDESSALEM LAB AT IPT.

TOPICAL TREATMENT OF CUTANEOUS LEISHMANIASIS

AVIAN INFLUENZA GENOMIC SEQUESING ACTIVITY

IMPACT OF ZOOPROPHYLAXIS ON ZOONOTIC CUTANEOUS LEISHMANIASIS TRANSMISSION

CSP - WORKSHOP FOR BUILDING RESEARCH AND DEVELOPMENT CAPACITY FOR VECTOR BORNE DISEASES

STRENGHTHENING ADMINSITRATIVE RESERACH CAPACITIES TOWARDS A BETTER SCIENTIFIC COMPETITIVENESS