title: Lipoarabinomannan, and its related glycolipids, induce divergent and opposing immune responses to Mycobacterium tuberculosis depending on structural diversity and experimental variations.
abstract: Exposure to Mycobacterium tuberculosis (Mtb) may lead to active or latent tuberculosis, or clearance of Mtb, depending essentially on the quality of the host's immune response. This response is initiated through the interaction of Mtb cell wall surface components, mostly glycolipids, with cells of the innate immune system, particularly macrophages (Mφs) and dendritic cells (DCs). The way Mφs and DC alter their cytokine secretome, activate or inhibit different microbicidal mechanisms and present antigens and consequently trigger the T cell-mediated immune response impacts the host immune response against Mtb. Lipoarabinomannan (LAM) is one of the major cell wall components of Mtb. Mannosyl-capped LAM (ManLAM), and its related cell wall-associated types of glycolipids/lipoglycans, namely phosphatidylinositol mannosides (PIMs) and lipomannan (LM), exhibit important and distinct immunomodulatory properties. The structure, internal heterogeneity and abundance of these molecules vary between Mtb strains exhibiting distinct degrees of virulence. Thus ManLAM, LM and PIMs may be considered crucial Mtb-associated virulence factors in the pathogenesis of tuberculosis. Of particular relevance for this review, there is controversy about the specific immunomodulatory properties of these distinct glycolipids, particularly when tested as purified molecules in vitro. In addition to the variability in the glycolipid composition conflicting reports may also result from differences in the protocols used for glycolipid isolation and for in vitro experiments including immune cell types and procedures to generate them. Understanding the immunomodulatory properties of these cell wall glycolipids, how they differ between distinct Mtb strains, and how they influence the degree of Mtb virulence, is of utmost relevance to understand how the host mounts a protective or otherwise pathologic immune response. This is essential for the design of preventive strategies against tuberculosis. Thus, since clarifying the controversy on this matter is crucial we here review, summarize and discuss reported data from in vitro stimulation with the three major Mtb complex cell wall glycolipids (ManLAM, PIMs and LM) in an attempt to conciliate the conflicting findings.
authors.affiliation: Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, 118 83 Stockholm, Sweden. Electronic address: gunilla.kallenius@ki.se.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Källenius
authors.affiliation: Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, 118 83 Stockholm, Sweden; Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Correia-Neves
authors.affiliation: Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, 118 83 Stockholm, Sweden; Department of Medical Microbiology, School of Biomedical Sciences, College of Health Sciences, Makerere University, P.O Box 7072, Kampala, Uganda.
authors.forename: Helen
authors.initials: H
authors.lastname: Buteme
authors.affiliation: Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, 118 83 Stockholm, Sweden.
authors.forename: Beston
authors.initials: B
authors.lastname: Hamasur
authors.affiliation: Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, 118 83 Stockholm, Sweden.
authors.forename: Stefan B
authors.initials: SB
authors.lastname: Svenson
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D006017:Glycolipids / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D015398:Signal Transduction; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology*; D037521:Virulence Factors / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D006017:Glycolipids; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D037521:Virulence Factors; C050016:lipoarabinomannan
keywords: Glycolipids; Lipoarabinomannan; Mycobacterium; Tuberculosis