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Decembre 2018

Lundi 03/12/2018

Salle Condorcet

Séminaire externe

“ Modeling HIV and Zika pathogenesis in humanized mice ”


 Pr. Ramesh AKKINA ( Dept Microbiology, Immunology and pathology, Colorado State University – USA)

contact : renaud.mahieux@ens-lyon.fr

Humanized mouse (hu-mouse) models harboring a transplanted human immune system permit study of human pathogens in a setting mimicking the human host. Using this unique platform, our ongoing studies are focused on various aspects of viral pathogenesis, latency, therapies and human immune responses to HIV, Dengue and Zika.
HIV-1: In the context of achieving a complete cure for HIV/AIDS, in vitro viral out growth assays (qVOA) are currently the gold standard for measuring latent HIV-1 but these assays often fail to detect very low levels of replication-competent virus as shown with the “Boston patients”. Here we investigated an alternative in vivo approach for sensitive viral detection using hu-mice (hmVOA). Peripheral blood CD4+ T cell samples from HIV subjects on stable ART with undetectable viral loads by RT-PCR were first assayed by in vitro qVOA. Samples in which no virus was detected were injected into hu-mice. Viral outgrowth was seen in the hmVOA assay suggesting that it is more sensitive in detecting latent HIV-1.
HIV-2: Since no animal model exists to study HIV-2, another causative agent for AIDS, hu-mice were evaluated for their susceptibility to HIV-2 infection and testing a three drug formulation of anti-retrovirals (NRTIs abacavir and lamivudine, integrase inhibitor dolutegravir) (trade name, TriumeqR). Results showed that hu-mice are susceptible to HIV-2 infection showing persistent viremia and CD4 T cell loss, key hallmarks of AIDS pathogenesis. Oral drug treatment led to full viral suppression and protection from CD4 T cell depletion. Cessation of therapy resulted in viral rebound and CD4 T cell loss indicating re-emergence of the latent virus.
Zika: While a variety of mouse and NHP models were shown to be susceptible to Zika viral infection, an in vivo model permitting human cell infection and human immune responses is lacking. Our recent experiments showed that hu-mice are susceptible to Zika virus with chronic viremia lasting more than 250 days. Human antibody response is seen. Virus could be detected in multiple organs with histopathology. Renal hemorrhage was a prominent feature in BLT mice.
SIV evolution into HIV: HIV-2 is thought to have originated from an SIV progenitor native to sooty mangabeys. We modeled the initial human transmission of SIVsm and its evolution to HIV-2 in hu-mice. Productive infection was seen during the initial challenge followed by chronic viremia and gradual CD4 T cell decline. Upon sequential serial passages, viral loads increased by the 5th generation leading to a more rapid CD4 T cell decline. Genetic analysis of human adapted virus revealed several amino acid changes in the nef, env and vpr regions.


Amphi Mérieux


5eme journée nationale
De recherche en rhumatologie pédiatrique

Contact : anne-laure.mathieu@inserm.fr






"The foreign within: Drosophila-Spiroplasma interaction as a model of insect endosymbiosis"

Pr. Bruno LEMAITRE (Global Health Institute, EPFL)

Host: François Leulier francois.leulier@ens-lyon.fr

Virtually every species of insect harbors facultative bacterial endosymbionts that are transmitted from females to their offspring, often in the egg cytoplasm. These symbionts play crucial roles in the biology of their hosts. Many manipulate host reproduction in order to spread within host populations. Others increase the fitness of their hosts under certain conditions, for example by increasing tolerance to heat or by protecting their hosts against natural enemies. However, in spite of the growing interest in endosymbionts, very little is known about the molecular mechanisms underlying most endosymbiont-insect interactions. To fill this gap, we are dissecting the interaction between Drosophila and its native endosymbiont Spiroplasma poulsonii. Spiroplasma are members of the Mollicutes, a wall-less eubacterial group related to the Gram-positive lineage, which are very widespread and is likely to be present in over 5% of all insect species.
Our study has shown that S. poulsonii resides in large numbers in the hemolymph (the insect blood) of larvae and adults. Surprisingly S. poulsonii cells are neither detected nor affected by the Drosophila immune system, but their proliferation is constrained by the availability of hemolymph lipids. We hypothesize that this dependence on lipids couples the proliferation of S. poulsonii to the nutritional state of its host. We have also provided strong evidences that the ability of Spiroplasma to protect Drosophila against infestation by parasitoid wasps (a parasite of Drosophila) relies on a competition for host lipids. Recently, we have also shown that Spiroplasma uses the yolk uptake machinery to colonize the germ line, thus ensuring an efficient vertical transmission.
Spiroplasma is also a male killer, and it has been hypothesized that this reproductive manipulation is one of the driving forces that maintains this facultative endosymbiont in fly populations. In collaboration with the Fukatsu laboratory (Japan), we have shown that Spiroplasma targets the dosage compensation system of Drosophila, a machinery that is assembled only in males to regulate X chromosome expression. We are currently investigating in further details the mechanism of male killing. In parallel, our laboratory has sequenced the genome of several strains of S. poulsonii and developed new approaches to cultivate (for the first time) this bacterium in vitro and to transform it. These works pave the route to the genetic manipulation of this symbiont.
We believe that the fundamental knowledge generated on the Drosophila-Spiroplasma interaction will serve as a paradigm for other endosymbiont-insect interactions (ex. Wolbachia) which are less amenable to genetic studies.



Amphi Pasteur

Forum infectiologie

“ Immune clocks : is there an ideal time to vaccinate and to fight infections ”


Pr. Nicolas CERMAKIAN ( McGill University – Douglas Institute Research Centre Montréal - Canada)

contact : yann.leverrier@inserm.fr

Recent research has shown that various aspects of the immune system are regulated by circadian clocks, and thus, present 24 h rhythms. A short overview of the circadian control of immune functions will be presented, followed by our recent
data about the circadian regulation of T cell response to antigen presentation, the infection by the parasite Leishmania, and immune responses in human subjects under night shift schedules.




Mardi 11/12/2018

Matmut stadium

Immunotherapies for Infectious Diseases Congress 2018 (I4ID2018)

The 2nd Immunotherapies for Infectious Diseases Congress 2018 (I4ID2018), organized by MabDesign and BIOASTER, will bring together pharmaceutical industries, research labs, clinicians, service providers, technology developers and policy makers to exchange about the development of immunotherapy solutions for prevention and treatment of infectious diseases.
The Scientific Committee has set-up an exciting program for the I4ID 2018 Congress, focusing on “Host-Directed Therapies to fight Infectious Diseases” that includes keynote lectures, pitch talks of new creative projects, and industrial talks from big pharmaceutical companies. The I4ID 2018 Congress program also contains several opportunities for networking and dedicated time for business partnering.
The topics covered during this meeting are:
· Targeting the Immune System to fight Bacterial Infections
· Targeting the Immune System to fight Sepsis
· Innovation on HDT approaches to treat Infectious Diseases
· Targeting the Immune system to fight Viral Infections
Bringing into clinic Host-directed therapies: safety and efficiency
· Developing Next-Generation of host-directed therapies




Amphi Pasteur

Séminaire externe

“ Les Héparanes Sulfate : des régulateurs « glycobiologiques ”

 Romain VIVES (IBS, Grenoble)

contact : Olivier Reynard

Dans la plupart des organismes pluricellulaires, la coordination des échanges d’information et des interactions entres cellules individuelles est orchestrée par une multitude de protéines extracellulaires solubles. Ces protéines messagères exercent leurs fonctions en interagissant avec des récepteurs spécifiques présents à la surface de cellules cibles, initiant ainsi des réponses biologiques définies. De nombreux mécanismes de régulation contrôlent leur activité, parmi lesquels interviennent une famille de polysaccharides complexes présents en abondance à la surface cellulaire et dans les matrices extracellulaires : les Héparanes sulfate (HS). En fixant ces effecteurs solubles, les HS vont contrôler et orienter leur diffusion, et donc l’accès à leurs récepteurs cellulaires, mais également affecter leur stabilité, structure et réactivité. Les HS jouent de ce fait un rôle central dans la plupart des grands processus physiologiques et pathologiques. Les propriétés d’interaction des HS sont liées à la présence au sein du polysaccharide de régions spécialisées (les domaines S), caractérisées par leur séquence saccharidique et leur profil de sulfatation, et contenant l’information structurale nécessaire à la reconnaissance de leurs ligands. L’expression et la structure des HS constituent donc un levier de régulation important pour la cellule, lui permettant d’adapter sa réponse à un vaste répertoire de stimuli externe.
L’objectif de ce séminaire est d’illustrer les multiples rôles fonctionnels des HS en se basant sur les travaux de recherche de notre groupe dans les domaines de l’inflammation et des mécanismes de reconnaissance hôte/pathogènes, ainsi que sur les processus régulant l’expression, la structure et les propriétés biologiques de ces polysaccharides à la surface des cellules.



Salle condorcet

Séminaire externe

« The p21‐mTert knock‐In mouse: Escape of senescence and deregulation of signaling and metabolic pathways. »

Vincent GELI (CRCM, Marseille)          

Contact : F. Palladino


Of the stresses that trigger cellular senescence, unrelenting telomere shortening plays a particularly important role because this serves as a "biological clock" that regulates the lifespan. The "clock" starts ticking when telomerase is shut down before birth in most somatic tissues. A key regulator of cellular arrest in response to telomere shortening is the cyclin-dependent kinase inhibitor p21. p53-dependent upregulation of p21 is thought to be the primary event inducing replicative senescence.  We asked whether aging can be delayed by abrogating telomere shortening in senescent cells by expressing telomerase "only when it is needed" and what would be the consequences of this conditional ectopic expression of telomerase. Indeed, previous studies revealed that overexpression of telomerase promotes cell proliferation and inflammation independently of its activity at telomeres. To this purpose, we have created a knock-in mouse model in which a cassette encoding mCherry-2A-mTert (telomerase) has been inserted after the first exon of p21 (p21-mTert mouse). Our results indicate  that expression of telomerase driven by the p21Cdk1a promoter  decreases the number of senescent cells in the lung parenchyma and prevents  emphysema, either in old mice or in mice experiencing hypoxia. Collectively, our results indicate that p21-mTert mice are protected from lung dysfunction related to cellular senescence. Strikingly, we  also observed unexpected phenotypes associated to this ectopic telomerase expression. Indeed, p21-mTert mice exhibit a gradual increase in body weight, exhibited white fat accumulation, liver dysfunction, steatosis, and hepatocarcinoma. Moreover, p21-mTert mice show clear defects in vascular patterning. The phenotypes exhibited by the p21-mTert mice make this mouse model a very attractive model to understand the canonical and the non canonical role of telomerase.



Amphi Pasteur

Séminaire externe

“ Amino acid sensing and immune Regulation ”



Dr. Marion RUSSIER ( Max Planck Institute of Biochemistry Martinsried - Germany)

contact : sylvain.baize@pasteur.fr

The immune response consumes high amounts of energy and nutrients. Immune cells require external supplies of most amino acids, including non-essential ones. This necessity, called, amino acid auxotrophy, has evolved to become an
immunoregulatory control point to shape immune responses. Mechanistic target of rapamycin (mTOR) complexes 1 and 2 are key signaling hubs in that process. How immune cells integrate information about external amino acids supplies and transfer
signals to growth and activation pathways remains unclear, but has potential for pathway discovery and therapeutics. As an example, arginine sensing and metabolism will be discussed.







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