Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk.

BACKGROUND: Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer risk in previous studies. However, it is unclear how many years must pass following cessation of these habits before the risk is reduced, and whether the risk ultimately declines to the level of never smokers or never drinkers. METHODS: We pooled individual-level data from case-control studies in the International Head and Neck Cancer Epidemiology Consortium. Data were available from 13 studies on drinking cessation (9167 cases and 12 593 controls), and from 17 studies on smoking cessation (12 040 cases and 16 884 controls). We estimated the effect of quitting smoking and drinking on the risk of head and neck cancer and its subsites, by calculating odds ratios (ORs) using logistic regression models. RESULTS: Quitting tobacco smoking for 1-4 years resulted in a head and neck cancer risk reduction [OR 0.70, confidence interval (CI) 0.61-0.81 compared with current smoking], with the risk reduction due to smoking cessation after >/=20 years (OR 0.23, CI 0.18-0.31), reaching the level of never smokers. For alcohol use, a beneficial effect on the risk of head and neck cancer was only observed after >/=20 years of quitting (OR 0.60, CI 0.40-0.89 compared with current drinking), reaching the level of never drinkers. CONCLUSIONS: Our results support that cessation of tobacco smoking and cessation of alcohol drinking protect against the development of head and neck cancer.

The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause.

Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤ 55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤ 55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients.

A fetal sheep liver extract containing immunostimulatory substances including LPS acts as leukocyte activator in cells of LPS responder and non responder mice.

Purified fractions from a fetal sheep liver extract (FSLE) were investigated, in a murine model, for induction of leukocyte stimulating activities. The fractions FSLE-1 and FSLE-2 induced splenocyte proliferation in vitro in C57Bl/10ScSn (LPS responder) mice comparable to LPS, and in C57Bl/10ScCr (LPS non responder) mice. They also stimulated the release of nitrogen radicals in bone marrow-derived macrophages (BMDM) from several mouse inbred strains including both C57Bl/10ScSn and C57Bl/10ScCr mice. Stimulation of NO production could be blocked by L-NMMA, an inhibitor of iNOS, and enhanced by the simultaneous addition of IFN-gamma. Moreover, stimulation of macrophages by FSLE-1 and FSLE-2 induced a cytostatic effect of the activated macrophages for Abelson 8-1 tumor cells. The stimulatory activity of the purified fractions is partially due to trace amounts of LPS derived from the fetal liver extract which was enriched during purification. Our results may help to explain the beneficial effect of the extract in patients which has been observed clinically.

Position of indapamide , a diuretic with vasorelaxant activities, in antihypertensive therapy.

Introduction: Diuretics play a pivotal role in the management of hypertension. A large experience has been accumulated with indapamide , a long-acting thiazide-like diuretic that lowers blood pressure (BP) primarily through its natriuretic diuretic effect. Some of its long-term antihypertensive efficacy may be due to calcium antagonist-like vasorelaxant activities. Indapamide has protecting effects in a variety of conditions associated with high cardiovascular risk, such as diabetes, left ventricular hypertrophy, nephropathy and stroke. It is highly effective in lowering BP, whether given alone or in combination. Indapamide is well tolerated and has the advantage of having no adverse impact on glucose and lipid metabolism. Today, thiazide-like diuretics are regarded more and more as preferred drugs, when diuretic therapy is required to lower BP. Areas covered: The aim of this paper is to review the experience accumulated with indapamide. It is limited to clinical studies that are relevant for the everyday management of hypertensive patients, whether or not they exhibit cardiovascular or renal disease. Expert opinion: Indapamide, because of its well-documented beneficial effects on cardiovascular and renal outcomes, represents a safe and valuable option for treating patients with high BP. There is, however, still room for new trials evaluating the combination of this diuretic with other types of antihypertensive drugs, in particular a calcium antagonist such as amlodipine. There is also the need to compare the indapamide-perindopril and indapamide-amlodipine combinations, in terms of antihypertensive efficacy, tolerability and effects on target organ damage and, ideally, on cardiovascular mortality.

Introduction of Trojan sex chromosomes to boost population growth.

Conservation programs that deal with small or declining populations often aim at a rapid increase of population size to above-critical levels in order to avoid the negative effects of demographic stochasticity and genetic problems like inbreeding depression, fixation of deleterious alleles, or a general loss of genetic variability and hence of evolutionary potential. In some situations, population growth is determined by the number of females available for reproduction, and manipulation of family sex ratios towards more daughters has beneficial effects. If sex determination is predominantly genetic but environmentally reversible, as is the case in many amphibia, reptiles, and fish, Trojan sex chromosomes could be introduced into populations in order to change sex ratios towards more females. We analyse the possible consequences for the introduction of XX-males (XX individuals that have been changed to phenotypic males in a XY/XX sex determination system) and ZW males, WW males, or WW females (in a ZZ/ZW sex determination system). We find that the introduction of WW individuals can be most effective for an increase of population growth, especially if the induced sex change has little or no effect on viability.

Role and regulation of islet-Brain 1 in pancreatic β-cells

Résumé : L'insuline est produite et sécrétée par la cellule ß-pancréatique. Son rôle est de régler le taux de sucre dans le sang. Si ces cellules meurent ou échouent à produire suffisamment de l'insuline, les sujets développent le diabète de type 2 (DT2), une des maladies les plus communes dans les pays développés. L'excès chronique des lipoprotéines LDL oxydés (oxLDL) et/ou des cytokines pro-inflammatoires comme l'interleukine-1ß (IL-1ß) participent au dérèglement et à la mort des cellules ß. Nous avons montré qu'une chute des niveaux d'expression de la protéine nommée «mitogen activated protein kinase 8 interacting protein 1» ou «islet brain 1 (IB 1)» est en partie responsable des effets provoqués par les oxLDL ou IL-1ß. IB1 régule l'expression de l'insuline et la survie cellulaire en inhibant la voie de signalisation « c-jun N-terminal Kinase (JNK)». La réduction des niveaux d'expression d'IB1 provoque l'activation de la voie JNK en réponse aux facteurs environnementaux, et ainsi initie la réduction de l'expression de l'insuline et l'induction du programme de mort cellulaire. Les mimétiques de l'hormone "Glucagon-like peptide 1", tel que l'exendin-4 (ex-4), sont une nouvelle classe d'agents hypoglycémiants utilisés dans le traitement du DT2. Les effets bénéfiques de l'ex-4 sont en partie accomplis en préservant l'expression de l'insuline et la survie des cellules ß contre les stress associés au DT2. La restauration des niveaux d'expression d'IB1 est un des mécanismes par lequel l'ex-4 prodigue son effet sur la cellule. En effet, cette molécule stimule l'activité du promoteur du gène et ainsi compense la réduction du contenu en IB1 causée par le stress. Outre ce rôle anti-apoptotique, dans ce travail de thèse nous avons mis en évidence une autre fonction d'IB1 dans la cellule ß. La réduction de l'activité ou des niveaux d'expression d'IB1 induisent une réduction importante de la sécrétion de l'insuline en réponse au glucose. Le mécanisme par lequel IB1 régule la sécrétion de l'insuline implique à la fois le métabolisme du glucose et éventuellement le transport vésiculaire en contrôlant l'expression de la protéine annexin A2. En résumé, IB 1 est une molécule clé à travers laquelle l'environnement du diabétique pourrait exercer un effet délétère sur la cellule ß. L'amélioration de l'activité d'IB1 et/ou de son expression devrait être considérée dans les approches thérapeutiques futures visant à limiter la perte des cellules ß dans le diabète. Abstract : ß-cells of the pancreatic islets of Langerhans produce and secrete insulin when blood glucose rises. In turn, insulin ensures that plasma glucose concentrations return within a relatively narrow physiological range. If ß-cells die or fail to produce enough insulin, individuals develop one of the most common diseases in Western countries, namely type 2 diabetes (T2D). Chronic excess of oxidized low density lipoproteins (oxLDL) and/or pro-inflammatory cytokines such as interleukin 1-ß (IL-1ß) contribute to decline of ß-cells and thereby are thought to accelerate progression of the disease overtime. We showed that profound reduction in the levels of the mitogen activated protein kinase 8 interacting protein 1 also called islet brain 1 (IB1) causes ß-cell failure accomplished by oxLDL or IL-1 ß. IB1 regulates insulin expression and cell survivals by inhibiting the c-Jun N-terminal Kinase pathway. Diminution in IB 1 levels leads to an increase in activation of the JNK pathway induced by environmental stressors, and thus initiates loss of insulin expression and programmed cell death. The mimetic agents of the glucoincretin glucagon-like peptide 1 such as exendin-4 (ex-4) are new class of hypoglycaemic medicines for treatment of T2D. The beneficial property is in part achieved by preserving insulin expression and ß-cell survival against stressors related to diabetes. Restored levels in IB 1 account for the cytoprotective effect of the ex-4. In fact, the latter molecule .stimulates the promoter activity of the gene and thus compensates loss of IB1 content triggered by stress. Beside of the anti-apoptotic role, an additional leading function for IB 1 in ß-cells was highlighted in this thesis. Impairment in IB1 activity or silencing of the gene in ß-cells revealed a major reduction in insulin secretion elicited by glucose. The mechanisms whereby IB 1 couples glucose to insulin release involve glucose metabolism and potentially, vesicles trafficking by maintaining the levels of annexin A2. IB 1 is therefore a key molecule through which environmental factors related to diabetes may exert harmful effects on ß-cells. Improvement in IB 1 activity and/or expression should be considered as a target for therapeutic purpose.

A discrete forest in a continuous landscape : investigating interactions between natural resource management and sustainable development

Summary Forests are key ecosystems of the earth and associated with a large range of functions. Many of these functions are beneficial to humans and are referred to as ecosystem services. Sustainable development requires that all relevant ecosystem services are quantified, managed and monitored equally. Natural resource management therefore targets the services associated with ecosystems. The main hypothesis of this thesis is that the spatial and temporal domains of relevant services do not correspond to a discrete forest ecosystem. As a consequence, the services are not quantified, managed and monitored in an equal and sustainable manner. The thesis aims were therefore to test this hypothesis, establish an improved conceptual approach and provide spatial applications for the relevant land cover and structure variables. The study was carried out in western Switzerland and based primarily on data from a countrywide landscape inventory. This inventory is part of the third Swiss national forest inventory and assesses continuous landscape variables based on a regular sampling of true colour aerial imagery. In addition, land cover variables were derived from Landsat 5 TM passive sensor data and land structure variables from active sensor data from a small footprint laserscanning system. The results confirmed the main hypothesis, as relevant services did not scale well with the forest ecosystem. Instead, a new conceptual approach for sustainable management of natural resources was described. This concept quantifies the services as a continuous function of the landscape, rather than a discrete function of the forest ecosystem. The explanatory landscape variables are therefore called continuous fields and the forest becomes a dependent and function-driven management unit. Continuous field mapping methods were established for land cover and structure variables. In conclusion, the discrete forest ecosystem is an adequate planning and management unit. However, monitoring the state of and trends in sustainability of services requires them to be quantified as a continuous function of the landscape. Sustainable natural resource management iteratively combines the ecosystem and gradient approaches. Résumé Les forêts sont des écosystèmes-clés de la terre et on leur attribue un grand nombre de fonctions. Beaucoup de ces fonctions sont bénéfiques pour l'homme et sont nommées services écosystémiques. Le développement durable exige que ces services écosystémiques soient tous quantifiés, gérés et surveillés de façon égale. La gestion des ressources naturelles a donc pour cible les services attribués aux écosystèmes. L'hypothèse principale de cette thèse est que les domaines spatiaux et temporels des services attribués à la forêt ne correspondent pas à un écosystème discret. Par conséquent, les services ne sont pas quantifiés, aménagés et surveillés d'une manière équivalente et durable. Les buts de la thèse étaient de tester cette hypothèse, d'établir une nouvelle approche conceptuelle de la gestion des ressources naturelles et de préparer des applications spatiales pour les variables paysagères et structurelles appropriées. L'étude a été menée en Suisse occidentale principalement sur la base d'un inventaire de paysage à l'échelon national. Cet inventaire fait partie du troisième inventaire forestier national suisse et mesure de façon continue des variables paysagères sur la base d'un échantillonnage régulier sur des photos aériennes couleur. En outre, des variables de couverture ? terrestre ont été dérivées des données d'un senseur passif Landsat 5 TM, ainsi que des variables structurelles, dérivées du laserscanning, un senseur actif. Les résultats confirment l'hypothèse principale, car l'échelle des services ne correspond pas à celle de l'écosystème forestier. Au lieu de cela, une nouvelle approche a été élaborée pour la gestion durable des ressources naturelles. Ce concept représente les services comme une fonction continue du paysage, plutôt qu'une fonction discrète de l'écosystème forestier. En conséquence, les variables explicatives de paysage sont dénommées continuous fields et la forêt devient une entité dépendante, définie par la fonction principale du paysage. Des méthodes correspondantes pour la couverture terrestre et la structure ont été élaborées. En conclusion, l'écosystème forestier discret est une unité adéquate pour la planification et la gestion. En revanche, la surveillance de la durabilité de l'état et de son évolution exige que les services soient quantifiés comme fonction continue du paysage. La gestion durable des ressources naturelles joint donc l'approche écosystémique avec celle du gradient de manière itérative.

Absence of mTOR Inhibitor Effect on Hepatic Cyst Growth: A Case Report of a Kidney Transplant Recipient with Autosomal Dominant Polycystic Kidney Disease.

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies.

Neurologie [News in neuroloey 2014].

In 2014, breastfeeding during maternal antiepileptic therapy seems to be safe for the children and can be recommended. Intravenous thrombolysis by Alteplase improves the outcome after a stroke if administered within 4.5 hours and it is also recommended in elderly population over 80 years. ProSavin genic therapy for Parkinson disease is under investigation. The Transcranial Magnetic Stimulation (TMS) has an analgesic effect in neuropathic pain as well as an antidepressant effect. Antagonists of calcitonin gene-related peptide can have a beneficial role in migraine prevention. Diagnostic biomarker panels for Alzheimer disease are under investigation. Oral teriflunomide and dimethyl fumarate (BG-12) for relapsing multiple sclerosis treatment are now available in Switzerland.

Role of the host cell's unfolded protein response in arenavirus infection.

Arenaviruses are enveloped RNA viruses with a nonlytic life cycle that cause acute and persistent infections. Here, we investigated the role of the host cell's unfolded protein response (UPR) in infection of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). In mammalian cells, the endoplasmic reticulum (ER) chaperone protein GRP78/BiP functions as the principal sensor for the induction of the UPR and interacts with three mediators: kinase/endonuclease inositol-requiring protein 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Acute infection with LCMV resulted in a selective induction of the ATF6-regulated branch of the UPR, whereas pathways controlled by PERK and IRE1 were neither activated nor blocked. Expression of individual LCMV proteins revealed that the viral glycoprotein precursor (GPC), but not that of other viral proteins, was responsible for the induction of ATF6. Rapid downregulation of the viral GPC during transition from acute to persistent LCMV infection restored basal levels of UPR signaling. To address a possible role of ATF6 signaling in LCMV infection, we used cells deficient in site 2 protease (S2P), a metalloprotease required for the activation of ATF6. Cells deficient in S2P showed significantly lower levels of production of infectious virus during acute but not persistent infection, indicating a requirement for ATF6-mediated signaling for optimal virus multiplication. In summary, acute LCMV infection seems to selectively induce the ATF6-regulated branch of the UPR that is likely beneficial for virus replication and cell viability, but it avoids induction of PERK and IRE1, whose activation may be detrimental for virus and the host cell.

Acute respiratory and cardiovascular admissions after a public smoking ban in geneva, Switzerland.

BACKGROUND: Many countries have introduced legislations for public smoking bans to reduce the harmful effects of exposure to tobacco smoke. Smoking bans cause significant reductions in admissions for acute coronary syndromes but their impact on respiratory diseases is unclear. In Geneva, Switzerland, two popular votes led to a stepwise implementation of a state smoking ban in public places, with a temporary suspension. This study evaluated the effect of this smoking ban on hospitalisations for acute respiratory and cardiovascular diseases. METHODS: This before and after intervention study was conducted at the University Hospitals of Geneva, Switzerland, across 4 periods with different smoking legislations. It included 5,345 patients with a first hospitalisation for acute coronary syndrome, ischemic stroke, acute exacerbation of chronic obstructive pulmonary disease, pneumonia and acute asthma. The main outcomes were the incidence rate ratios (IRR) of admissions for each diagnosis after the final ban compared to the pre-ban period and adjusted for age, gender, season, influenza epidemic and secular trend. RESULTS: Hospitalisations for acute exacerbation of chronic obstructive pulmonary disease significantly decreased over the 4 periods and were lowest after the final ban (IRR = 0.54 [95%CI: 0.42-0.68]). We observed a trend in reduced admissions for acute coronary syndromes (IRR = 0.90 [95%CI: 0.80-1.00]). Admissions for ischemic stroke, asthma and pneumonia did not significantly change. CONCLUSIONS: A legislative smoking ban was followed by a strong decrease in hospitalisations for acute exacerbation of chronic obstructive pulmonary disease and a trend for reduced admissions for acute coronary syndrome. Smoking bans are likely to be very beneficial for patients with chronic obstructive pulmonary disease.

Chromosomal number aberrations and transformation in adult mouse retinal stem cells in vitro.

PURPOSE: The potential of stem cells (SCs) as a source for cell-based therapy on a wide range of degenerative diseases and damaged tissues such as retinal degeneration has been recognized. Generation of a high number of retinal stem cells (RSCs) in vitro would thus be beneficial for transplantation in the retina. However, as cells in prolonged cultivation may be unstable and thus have a risk of transformation, it is important to assess the stability of these cells. METHODS: Chromosomal aberrations were analyzed in mouse RSC lines isolated from adult and from postnatal day (PN)1 mouse retinas. Moreover, selected cell lines were tested for anchorage-dependent proliferation, and SCs were transplanted into immunocompromised mice to assess the possibility of transformation. RESULTS: Marked aneuploidy occurred in all adult cell lines, albeit to different degrees, and neonatal RSCs were the most stable and displayed a normal karyotype until at least passage 9. Of interest, the level of aneuploidy of adult RSCs did not necessarily correlate with cell transformation. Only the adult RSC lines passaged for longer periods and with a higher dilution ratio underwent transformation. Furthermore, we identified several cell cycle proteins that might support the continuous proliferation and transformation of the cells. CONCLUSIONS: Adult RSCs rapidly accumulated severe chromosomal aberrations during cultivation, which led to cell transformation in some cell lines. The culture condition plays an important role in supporting the selection and growth of transformed cells.

Pregnancy and reproduction in autoimmune rheumatic diseases.

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on children.

Social evolution and defences against pathogens in ants

Pathogens represent a threat to all organisms, which generates a coevolutionary arms race. Social insects provide an interesting system to study host-pathogen interactions, because their defences depend on both the individual and collective responses, and involve genetic, physiological, behavioral and organizational mechanisms. In this thesis, I studied the evolutionary ecology of the resistance of ant queens and workers to natural fungal pathogens. Mechanisms that increase within-colony genetic diversity, like polyandry and polygyny, decrease relatedness among colony mates, which reduces the strength of selection for the evolution and maintenance of altruistic behavior. A leading hypothesis posits that intracolonial genetic diversity is adaptive because it reduces the risk of pathogen transmission. In chapter 1, I examine individual resistance in ant workers of Formica selysi, a species that shows natural variation in colony queen number. I discuss how this variation might be beneficial to resist natural fungal pathogens in groups. Overall my results indicate that there is genetic variation for fungal resistance in workers, a requirement for the 'genetic diversity for pathogen resistance' hypothesis. However I was not able to detect direct evidence that group diversity improves the survival of focal ants or reduces pathogen transmission. Thus, although the coexistence of multiple queens increases the within-colony variance in worker resistance, it remains unclear whether it protects ant colonies from pathogens and whether it is comparable to polyandry in other social insects. Traditionally, it was thought that the immune system of invertebrates lacked memory and specificity. In chapter 2, I investigate individual immunity in ant queens and show that they may be able to adjust their pathogen defences in response to their current environment by means of immune priming, which bears similarities with the adaptive immunity of vertebrates. However, my results indicate that the expression of immune priming in ant queens may be influenced by factors like mating status, mating conditions or host species. In addition, I showed that mating increases pathogen resistance in çhe two ant species that I studied (F. selysi and Lasius niger). This raises the question of how ant queens invest heavily in both maintenance and reproduction, which I discuss in the context of the evolution of social organization. In chapter 3,1 investigate if transgenerational priming against a fungal pathogen protects the queen progeny. I failed to detect this effect, and discuss why the detection of transgenerational immune priming in ants is a difficult task. Overall, this thesis illustrates some of the individual and collective mechanisms that likely played a role in allowing ants to become one of the most diverse and ecologically successful groups of organisms. -- Les pathogènes représentent une menace pour tous les organismes, ce qui a engendré l'évolution d'une course aux armements. Les insectes sociaux sont un système intéressant permettant d'étudier les interactions hôtes-pathogènes, car leurs défenses dépendent de réponses aussi bien individuelles que collectives, et impliquent des mécanismes génétiques, physiologiques, comportementaux et organisationnels. Dans cette thèse, j'ai étudié l'écologie évolutive de la résistance des reines et des ouvrières de fourmis exposées à des champignons pathogènes. Les facteurs augmentant la diversité génétique à l'intérieur de la colonie, comme la polyandrie et la polygynie, diminuent la parenté, ce qui réduit la pression de sélection pour l'évolution et la maintenance des comportements altruistes. Une hypothèse dominante stipule que la diversité génétique à l'intérieur de la colonie est adaptative car elle réduit le risque de transmission des pathogènes. Dans le chapitre 1, nous examinons la résistance individuelle à des pathogènes fongiques chez les ouvrières de Formica selysi, une espèce présentant une variation naturelle dans le nombre de reines par colonie. Nous discutons aussi de la possibilité que ces variations individuelles augmentent la capacité du groupe à résister à des champignons pathogènes. Dans l'ensemble, nos résultats indiquent une variation génétique dans la résistance aux champignons chez les ouvrières, un prérequis à l'hypothèse que la diversité génétique du groupe augmente la résistance aux pathogènes. Cependant, nous n'avons pas pu détecter une preuve directe que la diversité du groupe augmente la survie de fourmis focales ou réduise la transmission des pathogènes. Ainsi, bien que la coexistence de plusieurs reines augmente la variance dans la résistance des ouvrières à l'intérieur de la colonie, la question de savoir si cela protège les colonies de fourmis contre les pathogènes et si cela est comparable à la polyandrie chez d'autres insectes sociaux reste ouverte. Traditionnellement, il était admis que le système immunitaire des invertébrés ne possédait pas de mémoire et était non-spécifique. Dans le chapitre 2, nous avons étudié l'immunité individuelle chez des reines de fourmis. Nous avons montré que les reines pourraient être capables d'ajuster leurs défenses contre les pathogènes en réponse à leur environnement, grâce à une pré-activation du système immunitaire (« immune priming ») ressemblant à l'immunité adaptative des vertébrés. Cependant, nos résultats indiquent que cette pré-activation du système immunitaire chez les reines dépend du fait d'être accouplée ou non, des conditions d'accouplement, ou de l'espèce. De plus, nous avons montré que l'accouplement augmente la résistance aux pathogènes chez les deux espèces que nous avons étudié (F. selysi et Lasius niger). Ceci pose la question de la capacité des reines à investir fortement aussi bien dans la maintenance que dans la reproduction, ce que nous discutons dans le contexte de l'évolution de l'organisation sociale. Dans le chapitre 3, nous étudions si la pré-activation trans-générationelle du système immunitaire [« trans-generational immune priming ») protège la progéniture de la reine contre un champignon pathogène. Nous n'avons par réussi à détecter cet effet, et discutons des raisons pour lesquelles la détection de la pré-activation trans-générationelle du système immunitaire chez les fourmis est une tâche difficile. Dans l'ensemble, cette thèse illustre quelques-uns des mécanismes individuels et collectifs qui ont probablement contribué à la diversité et à l'important succès écologique des fourmis.

Hypomorphic mutation in the site-1 protease Mbtps1 endows resistance to persistent viral infection in a cell-specific manner.

The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV), which naturally persists in rodents, represents a model for HIV, HBV, and HCV. Cleavage of the viral glycoprotein precursor by membrane-bound transcription factor peptidase, site 1 (Mbtps1 or site-1 protease), is crucial for the life cycle of arenaviruses and therefore represents a potential target for therapy. Recently, we reported a viable hypomorphic allele of Mbtps1 (woodrat) encoding a protease with diminished enzymatic activity. Using the woodrat allele, we examine the role of Mbtps1 during persistent LCMV infection. Surprisingly, Mbtps1 inhibition limits persistent but not acute viral infection and is associated with an organ/cell type-specific decrease in viral titers. Analysis of bone marrow-derived dendritic cells from woodrat mice supports their specific role in resolving persistent viral infection. These results support in vivo targeting of Mbtps1 in the treatment of arenavirus infections and demonstrate a critical role for dendritic cells in persistent viral infections.