Keywords: Tuberculosis; latent infection; Antiretroviral Therapy; lipid antigen ; CD1 ; Vaccine
Tuberculosis (TB) is a disease in which traditional prophylactic approaches have been largely unsuccessful. A search for new therapeutic interventions is required in order to overcome the low compliance to complex chemo-antibiotic regimens and to avoid multidrug resistance.
The aim of this project is to produce new knowledge and insight that bear potential for new therapeutic or prophylactic interventions. Project partners will be focusing on one of the most critical immune evasion mechanism of Mycobacterium tuberculosis (Mtb): the capacity to switch to a dormant status of latency, which causes its persistence in the host.
The switch implies a reduction/abrogation of the synthesis of antigens required for activation of T lymphocytes primed in the early phase of infection, while new products are generated with possible antigenic properties. MILD-TB will analyse the variations in lipid metabolism and composition associated to dormancy. This represents advancement beyond the current state of knowledge, which is limited to proteins synthesized during dormancy. The immune response against mycobacterial lipid antigens represents an important mechanism of defence. However, no data are available on the antigenicity of lipids produced by dormant Mtb. MILD-TB will analyse the immunogenicity of lipids isolated from non-replicating Mtb produced in vitro, using a culture method resembling Mtb dormancy in vivo.
Lipids will be analysed in reference strains and clinical isolates from endemic areas and will be compared to those produced by replicating Mtb. The immunogenicity of lipids specifically isolated from dormant Mtb will be determined using pre-existing and newly established lipid-specific T cell clones and by immunizing CD1b transgenic mice.
Parallel analysis of susceptibility of dormant Mtb to T-dependent mechanisms of direct or indirect killing will be performed to explore the possibility of new therapeutic or prophylactic interventions based on vaccination with lipidantigens or on immune-modulation.
Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens and tuberculosis (TB) remains one of the major health threats to mankind. Key reasons for this are the unavailability of an efficacious vaccine for adult disease; the rise of multidrug-resistant strains, and the association of
Combination antiretroviral therapy has resulted in a dramatic decrease in mortality and HIV-associated morbidity in industrialised countries. Nevertheless, many serious issues and challenges – namely long term toxicity and HIV drug resistance - are problematic and important in the management of HIV infected individuals, even when treated according to the state-of-the-art. The need for further advances in clinical governance and management of HIV infection remains a high priority, both from a public health and from a medical research perspective. TB with human immunodeficiency virus (HIV) infection. During the early stages of Mtb infection, the majority of individuals mount an effective immune response leading to the control of the infection. Consequently, most of these individuals experience a mild disease (primary TB), often without clinical relevance.
However, the immune response that causes such a clinical cure does not clear the bacilli from infected individuals and after primary TB, Mtb persists causing a latent infection. In immunocompetent adults TB typically occurs as a reactivation of pre-existing foci. This suggests the existence of a dynamic balance between the host immune system and Mtb. In most cases, the host response is sufficient to forestall activation of the disease for a lifetime. Occasionally the immune response fails in some way and the infection reactivates to cause active disease. The immune factors contributing to the establishment of latent infection and the immunological components that are required to maintain such an infection and prevent reactivation are still unknown.
Regarding the adaptive response of mycobacteria to host antimicrobial defences, it is unclear how the bacilli survive in the face of a strong immune response, whereas it is now clear that they profoundly change several metabolic activities leading to a non replicating status (dormancy).
The main goal of immunointervention is the induction of active immunity that is capable of eradicating bacilli rather than just controlling Mtb infection. Most of the current approaches have addressed the control of primary infection. These vaccination approaches cannot be effective in latent TB, because dormant bacilli reduce their metabolic activity and to the immune system they appear very different to replicating bacilli. It is reasonable to hypothesize that if new antigens are produced during dormancy, the priming of specific T cells would be inefficient because these antigens would hardly reach secondary lymphoid organs. In addition, in latent infection there is a reduced macrophage death. Consequently, cross-presentation of antigen to MHC class I- and CD1-restricted T cells by dendritic cells (DC) would be greatly reduced. These phenomena could be responsible for the lack of a T cell response against dormant Mtb, which would maintain a latent infection. Therefore, it is of primary importance to identify the metabolic changes that have potential relevance for immunorecognition and to take advantage of them to design new immune intervention strategies capable of preventing TB reactivation.
The scientific and technological goals of MILD-TB are:
Production of non replicating Mtb for lipid extraction and identification; Identification of dormancy related lipids inducing stimulation of both the innate and acquired immunity; Identification and functional evaluation of dormancy related lipid-specific T cells both in vitro and in vivo.
The main immune evasion mechanism used by Mtb during primary TB is based on its capacity to switch to a dormancy status in macrophages or giant cells that are present in the granuloma. This capacity allows Mtb to survive until the weakened immune defences of the host do not allow its “resuscitation” to the replicating and highly invasive form. The lack of eradication of dormant Mtb is the cause for post-primary reactivation TB.
MILD-TB aims to assess the immunogenic potential of lipids produced by Mtb during dormancy and to exploit the lipid-specific immune response to eradicate dormant bacilli. The identification of immunogenic dormancy-related lipid would be central to the design of innovative vaccination approaches and novel diagnostic tools for active vs. latent infection.
Dipartimento di Malattie infettive Parassitarie e Immunomediate - Istituto Superiore di Sanità
Viale Regina Elena 299
Tel. +39 06 4990 2659
Fax. +39 06 4938 7112
|Official Address||Other Information|
|2||Germain Puzo||Laboratoire "Immunochimie
et Glycoconjugués Mycobactériens"
Département des mécanismes
moléculaires des infections
Institut de Pharmacologie
et Biologie Structurale
205 route de Narbonne
|Tel: +33 (0)5 61 17 55 04
Fax: +33 (0)5 61 17 55 05
|3||Gennaro De Libero||Experimental Immunology
Department of Research
University Hospital Basel
4031 Basel Switzerland.
|Tel: +41 61 265 2327
Fax: +41 61 265 2350
|4||Mireille Dosso||Istitut Pasteur de Côte d’Ivoire
Abidjan 07 / Abidjan
|Tel: +22 50 554 6761
Fax: +22 52 345 7623