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Deciphering mycobacterial subversion of early steps of adaptive immunity in vivo: A new approach to solve an old problem

Final Report Summary - IMAGING TB (Deciphering mycobacterial subversion of early steps of adaptive immunity in vivo: A new approach to solve an old problem)

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) and at the present time one third of the world’s population is latently infected with Mtb, in spite of the existence of a vaccine since 1921. This scenario is in part due to Mtb’s ability to adapt to current treatments, e.g. appearance of strains multi-resistant to antibiotics. However we also lack a proper understanding of the immunological mechanisms subverted by Mtb to establish a chronic infection in the majority of infected individuals. The use of mouse models of tuberculosis has demonstrated that an immune response against Mtb mediated by T cells is significantly delayed upon infection. Indeed, the migration of antigen presenting cells (APC) from the lung and into the lymph nodes that activate T cell immunity only occurs 8-10 days post-infection. In other pulmonary infections APC migration occurs within 24 hours after infection. In consequence, the host is not able to clear the initial infection and become chronically infected. In this fellowship we have aimed to identify the mechanisms by which Mtb subverts the initiation of T cell immunity and the migration of APCs. To this purpose we investigated the events that lead to dendritic cell migration to the draining lymph node, which is critical for the initiation of T cell immunity against Mtb.
In our work we have demonstrated that the delay in dissemination of Mtb towards the lymph node after infection (a readout of APC migration since bacilli are transported by these cells) is common to different strains of mycobacteria (M. tuberculosis, M. bovis-BCG and M. avium and M. cannetti). Hence this delay is not related to the virulence of Mycobacterium strains since M. bovis-BCG and M. avium are a vaccine strain or an opportunistic pathogen, respectively. This novel and unexpected result suggests that the vaccine strain has kept evasion mechanisms factors reminiscent of the virulent strain M. bovis, which might explain the poor immune response generated in vaccinated individuals. Moreover, a delay in T cell immunity is tissue dependent since intradermal infection by Mtb is not associated with a delay of APC migration from the site of infection towards the lymph nodes. The tissue dependent delay in initiation of T cell immunity upon Mtb infection was explained, in part, by a differential regulation of the onset of inflammation, a critical signal for triggering APC migration towards lymph nodes. At the present time we are validating the discovery of a cell wall component of Mtb that regulates APC migration. In the near future, we plan to exploit our findings to develop novel vaccination strategies that precisely target the virulence mechanisms revealed by our work. In this context, A. Peixoto was invited to participate in the Tuberculosis Vaccine Initiative, an independent non-profit organization that brings expertise to develop more effective and safer vaccines that will be globally accessible and affordable to fight Tuberculosis.

The promising results obtained during this fellowship were presented in an international symposium and have permitted the fellow, A. Peixoto, to establish himself as a team leader at the host institution. Furthermore, the fellow has obtained a prestigious grant from the French National of Research Agency (Chair of Excellence) to pursue the work initiated in this Marie Curie Fellowship. Altogether, this fellowship has permitted A. Peixoto to establish himself as an independent researcher and share his unique expertize to the benefit of the host institution and mentor the future generation of researchers. Moreover, the work performed during this fellowship has provided new insights into the evasion mechanisms of Mtb during infection that will significantly contribute to the development of new vaccines and treatments for the control of Tuberculosis.