title: The phenolic glycolipid of Mycobacterium tuberculosis differentially modulates the early host cytokine response but does not in itself confer hypervirulence.
abstract: Mycobacterium tuberculosis possesses a diversity of potential virulence factors including complex branched lipids such as the phenolic glycolipid PGL-tb. PGL-tb expression by the clinical M. tuberculosis isolate HN878 has been associated with a less efficient Th1 response and increased virulence in mice and rabbits. It has been suggested that the W-Beijing family is the only group of M. tuberculosis strains with an intact pks1-15 gene, required for the synthesis of PGL-tb and capable of producing PGL-tb. We have found that some strains with an intact pks1-15 do not produce PGL-tb while others may produce a variant of PGL-tb. We examined the early host cytokine response to infection with these strains in vitro to better understand the effect of PGL-tb synthesis on immune responses. In addition, we generated a PGL-tb-producing H37Rv in order to determine the effect of PGL-tb production on the host immune response during infection by a strain normally devoid of PGL-tb synthesis. We observed that PGL-tb production by clinical M. tuberculosis isolates affected cytokine production differently depending on the background of the strain. Importantly, while ectopic PGL-tb production by H37Rv suppressed the induction of several pro- and anti-inflammatory cytokines in vitro in human monocytes, it did not lead to increased virulence in infected mice and rabbits. Collectively, our data indicate that, while PGL-tb may play a role in the immunogenicity and/or virulence of M. tuberculosis, it probably acts in concert with other bacterial factors which seem to be dependent on the background of the strain.
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, 225 Warren St., Newark, NJ 07103, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinsimer
authors.forename: Gaelle
authors.initials: G
authors.lastname: Huet
authors.forename: Claudia
authors.initials: C
authors.lastname: Manca
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Koo
authors.forename: Natalia
authors.initials: N
authors.lastname: Kurepina
authors.forename: Bavesh
authors.initials: B
authors.lastname: Kana
authors.forename: Barun
authors.initials: B
authors.lastname: Mathema
authors.forename: Salvatore A E
authors.initials: SA
authors.lastname: Marras
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilhot
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006017:Glycolipids / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000382:microbiology; D051379:Mice; D009000:Monocytes / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D011817:Rabbits; D013045:Species Specificity; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D016207:Cytokines; D006017:Glycolipids; C045169:phenolic glycolipid I, Mycobacterium leprae