La réponse immunitaire innée est induite par des infections microbiennes ou des lésions tissulaires. L’étude de sa régulation est l'un des aspects les plus étudiés actuellement en immunologie, et porte notamment sur divers aspects du contrôle des agents pathogènes, du développement de vaccins et de la thérapie contre les maladies inflammatoires chroniques. L’ADN peut jouer le rôle de ligand endogène et induire une réaction immunitaire forte chez les animaux. Des souris déficientes pour la DNaseII lysosomiale accumulent de l’ADN dans leurs macrophages, notamment celui provenant des noyaux expulsés des érythroblastes lors de leur maturation en érythrocytes. Elles n’arrivent pas à les dégrader. Elles produisent en réponse de grandes quantités d’interférons de type I. Les souris meurent d'anémie au stade embryonnaire. Ce phénomène m’a amenée à poser une question importante: Comment les cellules reconnaissentelles l'ADN et comment y répondentelles? Pour savoir comment les cellules reconnaissent et répondent à l'ADN, nous avons visé trois objectifs spécifiques: I. Mise au point un modèle in vivo de drosophile pour étudier la réponse immunitaire innée contre l'ADN II. Dissection génétique de la réponse immunitaire induite par l'ADN III. Trouver des récepteurs de l’AND A l’issu de mon travail de thèse, je peux proposer que (i) la réponse immunitaire induite par l’ADN repose sur la voie IMD chez la drosophile, (ii) IK2 (TBK1), CG1667 (TMEM173), et EYA (EYA4) sont des molécules clés dans la cascade de signalisation en aval de la détection de l'ADN chez la drosophile, (iii) EYA est liée à la voie IMD au niveau de RELISH ou IKKβ, (iv) Orthologue drosophile LRRFIP1 de l'ADN des mammifères capteur est responsable de la détection de l'ADN dans le modèle DNaseII mouche déficiente (v) chez la drosophile CG3800 (CNBP) est un candidat pour la détection d'AND dans les insectes et les mammifères. / Innate immune responses are initiated during infections and tissue damage, and largely impact on various human diseases. DNA has been shown to be a strong innate immune stimulator in animals. For example, DNaseII deficient mice accumulate undigested DNA in macrophages from the expelled nuclei of erythroid progenitor cells, produce large amounts of type I Interferons in DNA-accumulated cells, and die from anemia at the embryonic stage. This phenomenon brought us an important question: How does cells recognize DNA and respond to it? To answer the question, we took three approaches: (1) Establishing in vivo model to study the innate immune response against DNA (2) Genetic dissection of the DNA-mediated immune response (3) Finding DNA sensors In my thesis project, we provide (1) DNA-mediated immune responses relies on the IMD pathway in Drosophila, (2) IK2(TBK1), CG1667(TMEM173, STING), and EYA(EYA4) are key molecules in the downstream signaling cascade of DNA sensing in Drosophila, (3) EYA is linked to the IMD pathway at the level of RELISH or IKKβ, (4) Drosophila orthologue of mammalian DNA sensor LRRFIP1 is responsible for DNA sensing in DNaseII deficient fly model, (5) Drosophila CG3800(CNBP) is a candidate for DNA sensing in both insects and mammals.

O diabetes tipo 1 (DM1) é uma doença autoimune caracterizada pela destruição das células ? presentes nas ilhotas pancreáticas por linfócitos T autorreativos, especialmente Th1 e Th17, levando o indivíduo a um estado de hiperglicemia. Embora existam diversos estudos que abordam a resposta imune adaptativa no contexto do DM1, poucos trabalhos tentaram elucidar o papel da resposta imune inata no desenvolvimento da doença. Neste contexto, observamos que camundongos WT pré-diabéticos possuem um aumento significativo na expressão gênica e proteica do receptor AIM2 e de moléculas relacionadas à sua via de ativação e sinalização (Caspase-1, IL-1? e IL-18) nos linfonodos pancreáticos (LNPs) e no íleo. Posteriormente, foi verificado que camundongos deficientes do receptor AIM2 tornaram-se mais suscetíveis ao DM1, comprovado por elevados níveis de glicose sanguínea e menor produção de insulina em relação aos animais selvagens (WT) após a administração com estreptozotocina (STZ). Tal suscetibilidade está relacionada a um processo de disbiose e aumento da translocação de bactérias da microbiota intestinal para os LNPs de camundongos AIM2-/-. De maneira interessante, o inflamassoma AIM2 foi ativado apenas na presença de DNA fecal de animais diabéticos, que possui uma microbiota em disbiose, uma vez que resultou na produção significativa da citocina IL-1?. Também foi constatado que a ativação do receptor AIM2 na mucosa intestinal regulou a expressão gênica e proteica de proteínas de junção celular, peptídeos antimicrobianos e mucinas, como forma de minimizar a translocação de bactérias da microbiota para os LNPs. Adicionalmente, foi visto que a ativação do receptor AIM2 contribui para a indução de células Th17 intestinais, para a migração de neutrófilos no intestino, assim como para a expressão das citocinas IL-23, IL-17 e IL-22 no íleo. Por fim, mostramos que o receptor AIM2 modulou negativamente a ativação de células dendríticas expressando TLR4 e TLR9, que correlacionou com o aumento de células Tc1 patogênicas nos LNPs. De forma geral, nossos resultados demonstram que a ativação do receptor AIM2 na mucosa intestinal desempenha um importante papel em controlar a homeostase da microbiota intestinal, manter a integridade da barreira intestinal, e consequentemente. / Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of ? cells present in the pancreatic islets by autoreactive T lymphocytes, especially Th1 and Th17, leading to a state of hyperglycemia. There are many studies that address the role of adaptive immune response, so only some studies have attempted to elucidate the role of the innate immune response in the context of T1D. In this regard, we observed that pre-diabetic WT mice have a significant increase in the gene and protein expression of the AIM2 receptor and in molecules related to its activation and signaling pathways (Caspase-1, IL- 1? and IL-18) in the pancreatic lymph nodes (PLNs) and in the ileum. Subsequently, it was verified that AIM2 receptor deficient mice became more susceptible to T1D, as proved by blood glucose levels and lower insulin production compared to wild-type mice (WT) after administration of streptozotocin (STZ). This susceptibility was related to a process of dysbiosis and increased translocation of bacteria from gut microbiota to PLNs in AIM2-/- mice. Interestingly, the AIM2 inflammasome was activated in the presence of fecal DNA from diabetic mice, which has a gut microbiota in dysbiosis, since resulted in significant production of IL-1?. It was found that activation of the AIM2 receptor in the intestinal mucosa regulated the gene and protein expression of tightjunction proteins, antimicrobial peptides and mucins in order to minimizing a bacterial translocation of the microbiota to the PLNs. In addition, it was seen that activation of the AIM2 receptor contributes to induction of intestinal Th17 cells, to neutrophil migration in the intestine, as well as for expression of IL-23, IL-17 and IL-22 cytokines in the ileum. Finally, we show that the AIM2 receptor negatively modulated the activation of dendritic cells expressing TLR4 and TLR9, which correlated with the increase of pathogenic Tc1 cells in the PLNs. In general, the results demonstrate that activation of the AIM2 receptor in the intestinal mucosa plays an important role in controlling the composition of gut microbiota homeostasis, maintaining the intestinal barrier function, and consequently reducing the bacterial translocation to the PLNs, conferring a protective effect to the immunopathogeny against to DM1.

La peau constitue l’une des premières lignes de défense contre les menaces extérieures. Elle présente un système nerveux sensoriel particulièrement développé capable d’interagir fonctionnellement avec son système immunitaire. Cependant ces interactions neuro-immunes sont encore très mal comprises et des analyses plus fines sont nécessaires pour décrypter le réel potentiel de ces neurones à réguler les réponses immunitaires. Nos travaux, présentés ici, se concentrent sur le rôle d'une sous-population de neurones sensoriels innervant la peau identifiée par le marqueur GINIP. La déplétion conditionnelle de ces neurones in vivo (souris GINIP-DTR), à révélé leur rôle central dans le contrôle de l'inflammation et de la réparation des tissus cutanés suite à une exposition aux UV. Les souris dépourvues de neurones GINIP+ présentent une augmentation du nombre de macrophages inflammatoires et des lésions profondes du derme comparées aux souris sauvages. Afin de disséquer les mécanismes moléculaires impliqués, nous nous sommes intéressés à la protéine XXX, un médiateur produit par une sous population de neurones GINIP+, les C-LTMR. In vitro, XXX réduit l’expression de cytokines pro-inflammatoires et favorise la production de médiateurs anti-inflammatoires par les macrophages. In vivo, l’absence de cette molécule (souris XXX-KO) accélère la différentiation des monocytes infiltrant en macrophages résidents, les rendant incapables de résoudre la fibrose du derme induite par les UV. Ces résultats suggèrent que les C-LTMR régulent fonctionnellement des cellules myéloïdes via XXX. / The skin is one of the body’s first lines of defense against external threats. This complex tissue contains a highly developed sensory nervous system and an immune system can cooperate to maintain homeostasis. However, these neuro-immune interactions are still poorly understood and further analyses are necessary to understand their role in skin immune response and tissue repair.The goal of the work presented here is to explore the role of a subset of skin sensory neurons identified by the marker GINIP. In vivo, the conditional depletion of these neurons (GINIP-DTR mice) revealed their central role in the control of inflammation and in the repair of skin exposed to UV (ultrat-violet) irradiation. Compared to wild type controls, mice lacking GINIP+ neurons displayed an increase in inflammatory macrophage number in the dermis associated with deep damage. To decipher the molecular mechanisms involved, we focused on the protein XXX, a mediator produced by a subset of GINIP+ neurons, the C-LTMR. In vitro, XXX reduced the expression of pro-inflammatory cytokines and promoted anti-inflammatory factors by macrophages. In vivo, the lack of this molecule (XXX KO mice) accelerated the differentiation of infiltrating monocytes in dermis resident macrophages, making them unable to resolve the fibrosis induced by UV treatment. These results suggest that C-LTMR regulates the myeloid cell response to UV irradiation via XXX.

<p>Antimicrobial peptides (AMPs) play a key role in the innate immune response. They can be ubiquitously found in a wide range of eukaryotes including mammals, amphibians, insects, plants, and protozoa. In lower organisms, AMPs function merely as antibiotics by permeabilizing cell membranes and lysing invading microbes. Prediction of antimicrobial peptides is important because experimental methods used in characterizing AMPs are costly, time consuming and resource intensive and identification of AMPs in insects can serve as a template for the design of novel antibiotic. In order to fulfil this, firstly, data on antimicrobial peptides is extracted from UniProt, manually curated and stored into a centralized database called dragon antimicrobial peptide database (DAMPD). Secondly, based on the curated data, models to predict antimicrobial peptides are created using support vector machine with optimized hyperparameters. In particular, global optimization methods such as grid search, pattern search and derivative-free methods are utilised to optimize the SVM hyperparameters. These models are useful in characterizing unknown antimicrobial peptides. Finally, a webserver is created that will be used to predict antimicrobial peptides in haemotophagous insects such as Glossina morsitan and Anopheles gambiae.</p>

<p>Antimicrobial peptides (AMPs) play a key role in the innate immune response. They can be ubiquitously found in a wide range of eukaryotes including mammals, amphibians, insects, plants, and protozoa. In lower organisms, AMPs function merely as antibiotics by permeabilizing cell membranes and lysing invading microbes. Prediction of antimicrobial peptides is important because experimental methods used in characterizing AMPs are costly, time consuming and resource intensive and identification of AMPs in insects can serve as a template for the design of novel antibiotic. In order to fulfil this, firstly, data on antimicrobial peptides is extracted from UniProt, manually curated and stored into a centralized database called dragon antimicrobial peptide database (DAMPD). Secondly, based on the curated data, models to predict antimicrobial peptides are created using support vector machine with optimized hyperparameters. In particular, global optimization methods such as grid search, pattern search and derivative-free methods are utilised to optimize the SVM hyperparameters. These models are useful in characterizing unknown antimicrobial peptides. Finally, a webserver is created that will be used to predict antimicrobial peptides in haemotophagous insects such as Glossina morsitan and Anopheles gambiae.</p>

Mon travail de Thèse a porté sur la description de l’immunité antibactérienne de la planaire, et plus particulièrement la mémoire immunitaire innée.La mémoire immunitaire innée constitue une ligne de défense de l’hôte à la réinfection qui ne fait intervenir que des composants de l’immunité innée. Présente chez les vertébrés et les invertébrés, ces derniers constituent un modèle de choix car dépourvus d’immunité acquise. La planaire dispose d’une mémoire immunitaire innée envers S. aureus, qui, suite à une réinfection, se traduit par une élimination exacerbée. La déplétion des planaires en cellules souches et la greffe tissulaire ont permis de mettre en avant les cellules souches comme acteurs principaux de cette réponse immunitaire. Un criblage RNAi associé à un profilage transcriptomique ont fait ressortir des gènes en les hiérarchisant au sein d’une voie de signalisation impliquant un récepteur au peptidoglycane (pgrp-2), une histone méthyltransférase (setd8.1), et un mécanisme effecteur dans l’élimination bactérienne (p38 et morn2). Setd8.1, histone méthyltransférase, se placerait au cœur du processus en déposant des marques épi-génétiques sur des loci de l’ADN, garantissant l’expression accrue des gènes effecteurs suite à la réinfection. Ce mécanisme, décrit chez l’Homme, n’avait jusqu’alors jamais impliqué des cellules souches, ni ce type d’histone méthyltransférase comme acteurs dans la mémoire immunitaire innée.Collectivement, l’investigation du système immunitaire de la planaire a permis la découverte de mécanismes de défense antibactérienne inédits, dont le transfert à l’Homme pourrait compléter l’approche actuelle du traitement des maladies infectieuses. / My Thesis work has focused on the description of the planarian antibacterial immunity, and more precisely the innate immune memory.The innate immune memory forms a host defense line to the reinfection which only involves components from innate immunity. Present in vertebrates and invertebrates, invertebrates are a model of choice because devoid of acquired immunity. The planarian has an innate immune memory against S. aureus, which, after a reinfection, displays an exacerbated elimination. The depletion of stem cells from planarians and tissue graft highlighted stem cells as the main actors of this immune response. An RNAi screening combined with a transcriptomic profiling brought out genes and classified them within a signaling pathway involving a peptido-glycan receptor (pgrp-2), a histone methyltransferase (setd8.1), and an effector mechanism of the bacterial elimination (p38 and morn2). Setd8.1, histone methyltransferase, would be the core of the process putting epigenetic marks on DNA loci, ensuring the increased expression of effector genes after reinfection. This mechanism, described in humans, has neither involved stem cells, nor this type of histone methyltransferase as actors in the innate immune memory.Collectively, the investigation of the planarian immune system allowed the discovery of new antibacterial defense mechanisms, and transferring it to humans could complete the actual approach of the infectious disease treatment.

Surfactant proteins, SP-A and SP-D, are collagen-containing calcium-dependent (C-type) lectins, called, collectins. Their primary structure has four regions: a cysteine-linked N- terminal region involved in multimerization, a collagen region composed of Gly-X-Y repeats, coiled-coil neck region, and the C-terminal carbohydrate recognition domains (CRD) or C-type lectin domain. SP-A looks like a bouquet, while SP-D is a cruciform- like structure, with four arms of equal length. SP-A and SP-D have been shown to act as innate immune molecules at pulmonary as well as extra-pulmonary sites by binding to pathogens, allergens and apoptotic/necrotic cells via their CRD region. SP-A and SP-D can induce pathogen neutralization and enhanced phagocytosis. In addition, SP-A and SP-D can interact via CRDs with allergens and dampen allergic reaction in vitro and in vivo. This thesis examines in vitro interaction of a recombinant fragment of human SP-D containing neck and CRD regions (rhSP-D) with IAV and Aspergillus fumigatus, in addition to characterizing a dichotomy of the effects of SP-A and SP-D on dendritic cells in an attempt to explain how SP-A and SP-D modulate DC functions differentially. Experiments involving interaction of rhSP-D with IAV pandemic strain show that it can be a restrictive factor against the virus, in addition to modulating immune response by a macrophage cell line. The rhSP-D can have anti-A. fumigatus effect directly and indirectly in the context of pathogen as well as allergen. A comparison has been made between two recombinant fragments of SP-D that have been expressed with and without 8 Gly-X-Y repeats for their fungistatic properties. The effects of SP-A and SP-D on cultured DC maturation, and effector cytokine and proliferative response of co-cultured cells have also been examined in vitro.

Streptococcus pneumoniae est un pathogène humain majeur causant des pneumonies, méningites et septicémies. Pour assurer sa survie et sa dissémination le pneumocoque déploie un ensemble de facteurs de virulence favorisant l'invasion des tissus et l'évasion du système immunitaire. Une classe particulière de protéines dites « moonlighting », ne sont associées à aucun système d'export connu et pourtant se trouvent localisées en surface du pneumocoque. Les protéines « moonlighting » sont des protéines cytoplasmiques conservées, localisées dans divers compartiments cellulaires et présentant des fonctions additionnelles. La glycéraldéhyde-3-phosphate déshydrogénase (GAPDH) est retrouvée en surface de nombreuses cellules et exerce divers rôles dans les processus de virulence d'organismes pathogènes. La GAPDH de surface du pneumocoque agit comme un facteur de virulence en recrutant le plasminogène / la plasmine de l'hôte, ce qui facilite l'invasion bactérienne à travers la matrice extracellulaire et les barrières endothéliales et épithéliales. Cependant, les mécanismes permettant l'export et la fixation de la GAPDH à la surface de la bactérie n'avaient pas encore été découverts. Ce travail démontre que la GAPDH est relarguée par lyse cellulaire et s'associe au peptidoglycane. C1q, un composant clé de la voie classique du complément, est un acteur majeur dans la réponse aux infections microbiennes et peut également détecter des éléments nocifs du soi-altéré comme les cellules apoptotiques. L'usage d'approches expérimentales complémentaires a permis d'identifier la GAPDH comme un partenaire de C1q quand elle est exposée en surface de S. pneumoniae et de cellules apoptotiques humaines. Néanmoins et de manière plutôt inattendue, seule la GAPDH du pneumocoque active la cascade du complément à la différence de la protéine homologue humaine. Ces résultats encouragent la poursuite d'études afin de comprendre comment la reconnaissance par C1q de deux protéines très proches peut conduire à de telles différences sur ses propriétés d'activation du complément. / Streptococcus pneumoniae is a major human pathogen, which causes pneumonia, meningitis and septicemia. To insure its survival and dissemination, the pneumococcus deploys an array of virulence factors promoting invasion of tissues and evasion from the immune system. A particular class of proteins not associated with any known export system, the moonlighting proteins, is found at the pneumococcal surface. Moonlighting proteins are conserved cytoplasmic metabolic enzymes or molecular chaperones localized in various cellular compartments and exhibiting additional functions. The glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is found at the surface of numerous eukaryotic and prokaryotic cells, and display diverse roles in the virulence processes of pathogenic organisms. The pneumococcal surface GAPDH acts as a virulence factor by binding to host plasminogen/plasmin, which facilitates the bacterial invasion through the extracellular matrix and the endothelial and epithelial cell barriers. However, the mechanisms leading to the GAPDH export and binding to the bacterial surface had not been deciphered yet. This work demonstrates that the GAPDH is released upon cell lysis and associates with the peptidoglycan. C1q, a key component of the classical complement pathway, is a major player in the response to microbial infection and has been shown to detect noxious altered-self substances such as apoptotic cells. The use of complementary experimental approaches allowed the identification of the GAPDH as a C1q partner when exposed at the surface of S. pneumoniae and human apoptotic cells. However, and rather unexpectedly, the pneumococcal GAPDH activates the complement cascade unlike the human one. Those results encourage further studies in order to understand how C1q recognition of two closely related proteins can lead to such striking differences on its complement activation properties.

O diabetes tipo 1 (DM1) é uma doença autoimune caracterizada pela destruição das células b presentes nas ilhotas pancreáticas por linfócitos T auto-reativos, especialmente Th1 e Th17, levando o indivíduo a um estado de hiperglicemia. Embora existam diversos estudos que abordam a resposta imune adaptativa no contexto do DM1, poucos trabalhos tentaram elucidar o papel da resposta imune inata no desenvolvimento da doença. Neste contexto, avaliamos o perfil de expressão e o papel do receptor NLRP1 na patogênese do DM1 experimental e em humanos. Nossos dados apontam que no modelo de DM1 induzido por STZ, NLRP1 possui um papel protetor no desenvolvimento da doença de forma independente da ativação do inflamassoma, através da inibição da translocação de bactérias para os linfonodos pancreáticos (LNPs), além de reduzir a diferenciação de células Th17 e Tc17 nos LNPs, o que foi correlacionado à diminuição de IL-17 no pâncreas. Posteriormente, analisamos o papel de NLRP1 em outro modelo experimental, o NOD (nonobese diabetic), onde descrevemos que NLRP1 também é expresso no desenvolvimento da doença. Por fim, avaliamos o papel de NLRP1 em pacientes com DM1, através da genotipagem desses pacientes para um polimorfismo com ganho de função em NLRP1, o rs12150220. Ao contrário do que acontece em camundongos, NLRP1 em humanos parece ter um papel patogênico, uma vez que detectamos mais células T produtoras de IL-17 em células mononucleares do sangue periférico de indivíduos com o polimorfismo, além de níveis elevados da citocina no soro. Em suma, nossos dados apontam para papéis distintos de NLRP1 em camundongos e humanos com DM1, sugerindo cautela ao tentarmos transpor os achados sobre o receptor em camundongos para a clínica. / Type 1 diabetes (T1D) is an autoimmune disease that is caused by the destruction of the pancreatic b cells by autoreactive T cells, especially Th1 and Th17, leading to a state of hyperglycemia. Even though there are several studies on the role of the adaptive immune response in T1D, little is known about the role of an innate immune response in the development of the disease. Thus, we investigated the role of NLRP1 in the pathogenesis of mouse and human T1D. Our data indicate that in STZ-induced T1D, NLRP1 exerts a protective role in the development of the disease in an inflammasome-independent pathway, through the inhibition of bacterial translocation to the pancreatic lymph nodes (PLNs), and inhibition of the differentiation of Th17 and Tc17 cells in the PLNs, which correlated with decreased levels of IL-17 in the pancreas. Then, we analyzed the role of NLRP1 in nonobese diabetic (NOD) mice. We demonstrate that NLRP1 is also expressed in the development of T1D in this murine model. Lastly, we evaluated the role of NLRP1 in T1D patients, by genotyping these individuals for a polymorphism with a gain-of-function in NLRP1, the rs12150220. Unlike murine NLRP1, NLRP1 in humans appears to be pathogenic, considering that we detected more IL-17-producing T cells in peripheral blood mononuclear cells in patients carrying the polymorphism, besides elevated levels of this cytokine in the serum. Overall, our data suggest distinct roles for murine and human NLRP1 in the context of T1D, suggesting carefulness when translating the findings from murine NLRP1 to the clinic.

Made available in DSpace on 2014-07-29T15:30:44Z (GMT). No. of bitstreams: 1 dissertacao eduardo martins de sousa med trop.pdf: 881180 bytes, checksum: dec3e190185b786a8f3ab68beeafdecb (MD5) Previous issue date: 2009-02-11 / Atypical mycobacteria are microorganism s appart from the etiological agents responsible for tuberculosis and leprosy. They are currently considered as emerging pathogens associated with simple surgical procedures, and are resistant to conventional antibiotics. The atypical mycobacterial infections is responsible for three in every 10 thousand people per year, but the incidence has been increasing as the number of individuals infected with HIV also increases. The low virulence of atypical mycobacteria associates its pathogenicity to decreased resistance of the host, and consequently it is necessary to better understand the interaction between host and microorganism. The cellular and humoral immune response of BALB/c mice and C57BL/6 mice infected with M. massiliense isolated from an outbreak of hospitals in the city of Goiania was evaluated. The isolate of M. massiliense used in this study was able to infect immunocompetent mice, which completely controlled the bacterial load before the 30 days of infection. The mechanisms by which these animals cleared the mycobacteria were: production of NO by peritoneal macrophages, presence of specific IgG1 and induction of mRNA for inflammatory cytokines, as well as regulatory cytokines in inflammation. / Micobactérias atípicas são microrganismos distintos dos agentes etiológicos responsáveis pela tuberculose e pela lepra (Hanseníase). São considerados atualmente como patógenos emergentes associados a procedimentos cirúrgicos simples, e são resistentes aos antibióticos convencionais. As infecções por micobacterias atípicas atingem três em cada 10 mil pessoas por ano, porém a incidência vem aumentando à medida que cresce o número de indivíduos infectados por HIV. A baixa virulência das micobactérias atípicas condiciona a sua patogenicidade à diminuiçäo da resistência do hospedeiro, por isso faz-se necessário uma melhor investigação da interação do microrganismo com o hospedeiro. Nesta dissertação, a resposta imune celular e humoral de camundongos BALB/c e C57BL/6 frente à infecção por M. massiliense isolada de surto hospitalar na cidade de Goiânia foi avaliada. O isolado de M. massiliense utilizado neste estudo foi capaz de infectar camundongos imunocompetentes, que controlaram completamente a carga bacteriana antes dos 30 dias de infecção. Os mecanismos pelos quais estes animais eliminaram as micobactérias foram: produção de NO por macrófagos peritoneais, presença de IgG1 específica e indução de mRNA para citocinas inflamatórias, assim como de citocinas reguladoras da inflamação.