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.

Skin microbiota–host interactions

“…The Corynebacterium cell wall features additional lipoglycans termed lipomannans and lipoarabinomannans, which are anchored to the plasma membrane and have long oligosaccharide chains that emanate from the cell surface. Lipomannans and lipoarabinomannans are ligands for host glycan receptors such as Toll-like receptors (TLRs) and C-type lectin receptors, driving either pro- or anti-inflammatory responses depending on their structure and the immunological context in which they are sensed 36–42 . In mycobacteria, lipomannans and lipoarabinomannans play important roles in immune recognition and evasion 43 .…”

Underestimated Manipulative Roles of Mycobacterium tuberculosis Cell Envelope Glycolipids During Infection

“…Overall, without discerning the type of PIMs used, these have been shown to participate in host cell recognition, phagocytosis, oxidant and cytokine production, regulating intracellular vesicular trafficking, regulating signaling pathways, apoptosis, and antigen presentation (158-160) ( Table 1). However, as pointed out, these intrinsic PIM properties, apart of being species-specific and depending on their heterogeneous nature, also may be derived from differences in the protocols used for PIM isolation and for in vitro experiments including immune cell types and procedures to generate them (160,161).…”

Immunological consequences of strain variation within the Mycobacterium tuberculosis complex

“…A wide range of pathogen recognition receptors (PRRs) are involved in the initial interaction between MTBC and host cells, including toll like receptors (TLRs), C‐type lectin receptors (CLRs), nod like receptors (NLRs) and scavenger proteins . The cell wall structure of MTBC is complex, including glycolipids and lipoproteins that are uniquely found in pathogenic mycobacterial species and can vary between lineages . Together with secreted effector proteins, cell wall components act as pathogen‐associated molecular patterns (PAMPs) that are recognized by host immune cells.…”

“…MTBC cell wall products such as lipoarabinomanan (LAM) and mannosylated‐lipoarabinomanan (Man‐LAM) are recognized by these receptors. Phagocytosis of MTBC via this pathway leads to a reduced inflammatory response thereby presenting an important route of entry from the perspective of the bacillus . Structural variation in LAM between virulent and attenuated Mtb laboratory strains results in lower macrophage uptake in vitro of the attenuated Mtb H37Ra strain when compared with more virulent H37Rv or Erdman strains .…”