Infection and Epidemiology Department Activity Report

The Department of Infection and Epidemiology was created in 2006 from a number of laboratories originating from the Department of Molecular Medicine and the Department of Ecosystems and Epidemiology of Infectious Diseases. It is presently composed of 13 research units, one junior group (G5), 2 laboratories including the "Trypanosoma infectious processes" laboratory recently welcomed in the department, and one facility (PF-8, Genotyping of Pathogens and Public Health).

The Department includes microbiologists, epidemiologists and immunologists who are interested in the epidemiology and pathophysiology of infections as well as the biology of certain pathogens and their vectors. Our main interest is in the host-microbe interactions. Another strengh is the use of clinical and/or environmental samples/isolates rather than reference strains to study the complex biology and ecology of pathogenic microbes and their vectors. We take a holistic view of the host, using experimental models relevant to the clinical conditions and keeping in mind the patients. This is evident from the intrinsic missions of the Urgent Response to Biological Threats laboratory (CIBU), the nine National Reference Centers (CNR), and the four WHO reference centers (CCOMS) as well as from the presence of clinicians and microbiologists involved in the daily management of patients.

The ultimate objective of the Department is to further our understanding of infection biology through knowledge of epidemiology, host response and the pathogens themselves. It is, therefore, an intrinsically multidisciplinary study of a range of pathogens (viruses, bacteria, parasites and fungi), vectors (Aedes aegypti, Culex pipiens etc.) and their associated infections using diverse approaches (epidemiology, immunology, microbiology, genomics, cellular biology, histopathology, clinical research, vector ecology and biology etc.). Much of the work is done in collaboration with research units within (including with the Histotechnology and Pathology research unit) and outside the Campus, with facilities that includes PF-8 and the Dynamic Imaging Facility (Cellular Biology and Infection department). Of note, a "HiSEQ-2000 Illumina" machine was acquired in 2010 at the Pasteur Genomics Center. This second generation sequencer will be operated by PF-8 for genomic characterization of emerging pathogens.

Highlights

Understanding the role of humans in the dispersal of predominantly animal pathogens is essential for their control. In a country where HCV prevalence is extremely high, the Epidemiology of Emerging Diseases Unit documented that less than 5% of all new infections were related to transmission within the family setting.  Prevention of HCV transmission in health-care facilities should remain the priority.

The Lyssavirus Dynamics and Host Adaptation Unit used newly developed Bayesian phylogeographic methods to unravel the dynamics and determinants of the spread of dog rabies virus (RABV) in North Africa. They demonstrated that the contemporary viral distribution extends beyond that expected for RABV transmission in African dog populations. These results are strongly supportive of human-mediated dispersal, and demonstrate how an integrated phylogeographic approach will turn viral genetic data into a powerful asset for characterizing, predicting, and potentially controlling the spatial spread of pathogens. The Insects and Infectious Diseases Unit and collaborators in the EDEN project detected West Nile virus in overwintering mosquitoes in Czech Republic and Romania confirming vertical transmission. The Pharmacoepidemiology and Infectious Diseases Unit initiated a new scientific program entitled Children Antibiotic Resistant infection in Low Income countries (ChARLI). The challenge of this program is to estimate the incidence rate as well as the medical consequences of bacterial resistance in neonatal and children infections in developing countries. It will be based in the International Network of the Pasteur Institutes, at least during the first years. The Molecular Prevention and Therapy of Human Diseases Unit evaluates the consequences of extensive vaccination of human populations on the microbe targeted by the vaccine, the bacterial ecosystem and the human population. By comparing the bacteria circulating in different regions of the world, the Bordetella team was able to demonstrate that the herd immunity induced by pertussis subunit vaccines, in contrast to whole-cell vaccine induced immunity, can (i) control the virulence of Bordetella pertussis isolates if the vaccine coverage increases in the human population (ii) induce changes of the other agent of whooping cough, B. parapertussis.

The Invasive Bacteria Unit combines research on pathophysiological aspects of Neisseria meningitidis and surveillance activities of the national reference centre for meningococci that is hosted by the Unit. Their work on the induction of apoptosis and inflammation by N. meningitis in infected cells allowed them to detect the emergence of a new hyperinvasive serogroup clone that was involved is several outbreaks in France. These findings contributed to the decision of the health authorities to introduce routine vaccination against the disease in France in 2010. In collaboration with Claire Poyart (Institut Cochin, Inserm), The G5 on Microorganisms and Host Barriers uncovered how a novel surface protein of Group B streptococcus mediates hypervirulence and miningeal tropism in neonates. Using unpurified isolates from patients with cryptococcosis, molecular tools and animal models of infection, the Molecular Mycology Unit discovered that the concept of one strain/one infection does not hold true for Cryptococcus neoformans, the yeast responsible for cryptococcosis, and this may apply to other environmentally-acquired fungal pathogens. The possibility that mixed and/or evolving infections occurred during cryptococcosis in human should be taken into account when developing therapeutic strategies against these pathogens. The Trypanosoma Infectious Processes laboratory identified proline racemase (TcPRAC) as a promising biochemical target for the design of new chemotherapies against Chagas’ disease, the American trypanosomiasis. Using molecular dynamic strategies and virtual screening of chemical libraries, two soluble inhibitors of TcPRAC were identified. Increasing doses of these compounds hampered Trypanosoma cruzi intracellular differentiation and fate in mammalian host cells, confirming the potential of these molecules as good candidates for drug development.

The Urgent Response to Biological Threats laboratory (CIBU) chose the technology of high-density oligonucleotide microarrays that enables rapid identification of genetic variants and determination of their nucleotide sequence at single base-pair resolution to study Influenza viruses from different host origins, isolated over a period of about 50 years. This technology was able to identify the type and subtype of influenza viruses but also had a strong discriminatory power at the level of viral variants. The Enteric Bacterial Pathogens unit and the National Reference Center for Vibrio characterized a new variant of Vibrio cholerae O1 with decreased susceptibility to ciprofloxacin that has been circulating in West Africa since 2009. This strain might be similar to those causing the cholera outbreak in Haiti. Whole-genome sequencing of this strain, the Haitian one and other representative strains is currently performed to better understand the origin of the Haitian cholera strain.

In collaboration with Matthew Albert (Institut Pasteur, Inserm), G5 on Microorganisms and Host Barriers showed that type I IFN controls chikungunya virus via its action on non-hematopoetic cells. The Antiviral immunity, Biotherapy and Vaccine (IABV) research unit discovered that once infected, dendritic cells (DC) become resistant to NK-mediated cytotoxicity. This resistance is due to the dramatic upregulation of two key inhibitors of apoptosis, cIAP-2 and c-FLIP, resulting in their lack of sensitivity to the death ligand TRAIL released by NK cells. The alarmin HMGB1, expressed at NK-DC synapse, was found responsible for the induction of the two apoptosis inhibitors, and counteracting HMGB1 restored the susceptibility of HIV-infected DC to NK cell killing. These observations provide evidence for the first time of the crucial role of HMGB1 in the establishment of viral reservoirs in AIDS. Two patents have protected these findings. The Cellular Immunology and Immunogenetics Unit previously showed that the IL-7 Receptor (IL-7R) is not functional in HIV-infected individuals. The characterization of the IL-7 signalosome from healthy individuals uncovered that, after IL-7 activation, IL-7R complexes compartmentalize into rafts and interact with the cytoskeleton. Inhibition of these molecular events demonstrated their specific role in signal transduction. In HIV-infected patients, before any specific activation, IL-7R complex is already compartmentalized into abnormal macrostructures. Abnormal activation of the immune system of HIV patients is thus linked to molecular defects that may explain the lack of IL-7 response and therefore the persistent CD4 lymphopenia observed in HIV-infected patients.

The alteration of the immune system in patients with systemic inflammation was monitored for the first time in monocyte subsets. The Cytokines and Inflammation Unit showed that the decreased expression of HLA-DR expression was not regulated similarly in CD14^HIGHCD16^- and CD14^LOWCD16⁺ subsets. Furthermore, while both glucocorticoids and IL-10 downregulated the expression of HLA-DR on CD14^HIGHCD16^-, only glucocorticoids could do so on CD14^LOWCD16⁺.

Cystic fibrosis (CF) is due to mutations in the CF transmembrane conductance regulator gene CFTR. The Innate Host Defense and Inflammation Unit examined the role of cytosolic phospholipase A2α (cPLA2α) in the modulation of mucus production and inflammation in CFTR-deficient mice and human epithelial cells in culture. In lungs from Cftr(-/-) mice, mucus overproduction was mimicked by instillation of the cPLA2α product arachidonic acid, and abolished by either a cPLA2α null mutation or pharmacological inhibition. An increased cPLA2α activity was observed in bronchial explants from CF patients. cPLA2α plays a critical role in bronchial mucus hypersecretion and represents a suitable new target for therapeutic intervention in CF.

Teaching

Several staff members of the Infection and Epidemiology department participate in/are responsible for 8 of the 26 Institut Pasteur teaching courses that include lectures and bench work and last 1-8 weeks every year or every other year. The second master promotion of the Pasteur-Cnam School of Public Health graduated in December 2010. Nine students specialised in infectious diseases, among whom five did their internship with Institut Pasteur Research units. They worked on various topics including malaria in Senegal, hepatitis C in Egypt, acute encephalitis in Cambodia, Chikungunya in Madagascar, and infectious disease research priorities in Laos.

Distinction – Awards – Nomination

Marc Lecuit obtained an ERC starting grant

Selected publications

1. Berthet N, Leclercq I, Dublineau A, Shigematsu S, Burguière AM, Filippone C, Gessain A, Manuguerra JC. High-density resequencing DNA microarrays in public health emergencies. Nat Biotechnol. 2010; 28(1):25-7. (PMID: 20062034)

2. Blom-Potar MC, Chamond N, Cosson A, Jouvion G, Droin-Bergère S, Huerre M, Minoprio P. Trypanosoma vivax infections: pushing ahead with mouse models for the study of Nagana. II. Immunobiological dysfunctions. PLoS Negl Trop Dis. 2010;4(8). pii: e793(PMID: 20711524)

3. Bouchez V, Brun D, Dore G, Njamkepo E, Guiso N. Bordetella parapertussis isolates not expressing pertactin circulating in France. Clin Microbiol Infect. 2010 (PMID: 20636430 )

4. Deghmane AE, Parent du Chatelet I, Szatanik M, Hong E, Ruckly C, Giorgini D, Lévy-Bruhl D, Alonso JM, Taha MK. Emergence of new virulent Neisseria meningitidis serogroup C sequence type 11 isolates in France. J Infect Dis 2010; 202: 247-250. (PMID 20515410)

5. Desnos-Ollivier M, Patel S, Spaulding AR, Charlier C, Garcia-Hermoso D, Nielsen K, Dromer F. Mixed Infections and In Vivo Evolution in the Human Fungal Pathogen Cryptococcus neoformans. mBio. 2010;1(1) (PMID: 20689742)

6. Diancourt L., Passet V, Nemec A, Dijkshoorn L, Brisse S. The population structure of Acinetobacter baumannii: expanding multiresistant clones from an ancestral susceptible genetic pool. PLoS One 2010; 5:e10034. (PMID: 20383326)

7. Dif F, Wu YZ, Burgel PR, Ollero M, Leduc D, Aarbiou J, Borot F, Garcia-Verdugo I, Martin C, Chignard M, Israel-Biet D, Kita Y, Scholte BJ, Touqui L. Critical role of cytosolic phospholipase A2{alpha} in bronchial mucus hypersecretion in CFTR-deficient mice. Eur Respir J. 2010;36(5):1120-30 (PMID: 20413542)

8. Lardon Z, Watier L, Brunet A., Bernede C, Goudal M, Dacheux L, Rotivel Y, Guillemot D, Bourhy H. Imported episodic rabies increases patient demand for and physician delivery of antirabies prophylaxis. PLoS Negl Trop Dis. 2010, 4(6):e723 (PMID: 20582307)

9. Melki MT, Saïdi H, Dufour A, Olivo-Marin JC, Gougeon ML. Escape of HIV-1-infected dendritic cells from TRAIL-mediated NK cell cytotoxicity during NK-DC cross-talk--a pivotal role of HMGB1.PLoS Pathog. 2010 Apr 15;6(4):e1000862. (PMCID: PMC2855334F)

10. Opatowski L, Mandel J, Varon E, Boëlle PY, Temime L, Guillemot D. Antibiotic dose on resistance selection in the community : a mathematical model of beta-lactams and Streptococcus pneumoniae dynamics. Antimicrob Agents Chemother. 2010 ;54(6) : 2330-7 (PMID: 20231396)

11. PaezJimenez A, Sharaf Eldin N, Rimlinger F, El-Daly M, El-Hariri H, El-Hoseiny M, Mohsen A, Mostafa A, Delarocque-Astagneau E, Abdel-Hamid M, Fontanet A, Mohamed MK, Thiers V.  HCV iatrogenic and intrafamilial transmission in Greater Cairo, Egypt.Gut. 2010;59:1554-60. (PMID: 20947889)

12. Quilici ML, Massenet D, Gake B, Bwalki B, Olson DM. Vibrio cholerae O1 variant with reduced susceptibility to ciprofloxacin, Western Africa. Emerg Infect Dis. 2010;16(11):1804-5. (PMID: 21029554)

13. Rose T, Pillet AH, Lavergne V, Tamarit B, Lenormand P, Rousselle JC, Namane A, Thèze J. Interleukine-7 compartimentilizes its receptor signaling complex to initiate CD4 T lymphocyte response. J. Biol. Chem. 2010; 285 (20): 14898-14908 (PMID: 20167604)

14. Tazi A, Disson O, Bellais S, Bouaboud A, Dmytruk N, Dramsi S, Mistou M-Y, Khun H, Mechler C, Tardieux I, Trieu-Cuot P, Lecuit M*, Poyart C*. The surface protein HvgA mediates Group B streptococcus hypervirulence and meningeal tropism in neonates. J Exp Med. 2010;207(11):2313-22 (PMID: 20956545)

15. Warren HS, Fitting C, Hoff E, Adib-Conquy M, Beasley-Topliffe L, Tesini B, Liang X, Valentine C, Hellman J, Hayden D, Cavaillon JM. Resilience to bacterial infection: difference between species could be due to proteins in serum. J Infect Dis. 2010 ;201(2):223-32 (PMID: 20001600)