title: Dormant Mycobacterium tuberculosis fails to block phagosome maturation and shows unexpected capacity to stimulate specific human T lymphocytes.
abstract: Dormancy is defined as a stable but reversible nonreplicating state of Mycobacterium tuberculosis. It is currently thought that dormant M. tuberculosis (D-Mtb) is responsible for latent tuberculosis (TB) infection. Recently, D-Mtb was also shown in sputa of patients with active TB, but the capacity of D-Mtb to stimulate specific immune responses was not investigated. We observed that purified protein derivative-specific human CD4(+) T lymphocytes recognize mycobacterial Ags more efficiently when macrophages are infected with D-Mtb instead of replicating M. tuberculosis (R-Mtb). The different Ag recognition occurs even when the two forms of mycobacteria equally infect and stimulate macrophages, which secrete the same cytokine pattern and express MHC class I and II molecules at the same levels. However, D-Mtb but not R-Mtb colocalizes with mature phagolysosome marker LAMP-1 and with vacuolar proton ATPase in macrophages. D-Mtb, unlike R-Mtb, is unable to interfere with phagosome pH and does not inhibit the proteolytic efficiency of macrophages. We show that D-Mtb downmodulates the gene Rv3875 encoding for ESAT-6, which is required by R-Mtb to block phagosome maturation together with Rv3310 gene product SapM, previously shown to be downregulated in D-Mtb. Thus, our results indicate that D-Mtb cannot escape MHC class II Ag-processing pathway because it lacks the expression of genes required to block the phagosome maturation. Data suggest that switching to dormancy not only represents a mechanism of survival in latent TB infection, but also a M. tuberculosis strategy to modulate the immune response in different stages of TB.
authors.affiliation: Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mariotti
authors.forename: Manuela
authors.initials: M
authors.lastname: Pardini
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Gagliardi
authors.forename: Raffaela
authors.initials: R
authors.lastname: Teloni
authors.forename: Federico
authors.initials: F
authors.lastname: Giannoni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fraziano
authors.forename: Francesco
authors.initials: F
authors.lastname: Lozupone
authors.forename: Stefania
authors.initials: S
authors.lastname: Meschini
authors.forename: Roberto
authors.initials: R
authors.lastname: Nisini
mesh_terms: D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D055985:Latent Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology*; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000382:microbiology / Q000473:pathology