[Frontiers in Bioscience 1, e42-54, August 1,1996]
Reprints
PubMed
CAVEAT LECTOR



MYCOPLASMAS AND HIV INFECTION: FROM EPIDEMIOLOGY TO THEIR INTERACTION WITH IMMUNE CELLS

Catherine Brenner, Olivier Neyrolles, Alain Blanchard

Institut Pasteur, Unité d'Oncologie Virale, Département SIDA et Rétrovirus, 28, rue du Dr. Roux, 75724 Paris Cedex 15, France

Received 07/05/96; Accepted 07/09/96; On-line 08/01/96

7. MYCOPLASMA INTERACTIONS WITH THE IMMUNE SYSTEM

The level of immune activation is a key factor in HIV disease progression. Analysis of the mechanisms by which, and indeed whether, mycoplasmas modulate the host immune functions would therefore advance our understanding of their role, if any, as AIDS disease cofactors. Mycoplasma infections are generally chronic and the humoral arm of the immune host response includes in particular the production of antibodies against membrane lipoproteins. The persistence of these infections is probably due to mycoplasmas expressing two mechanisms: antigenic surface variation, a mechanism which would allow immune escape, and /or molecular mimicry of the host.

7.1. Immune cell activators

Numerous mycoplasmas, as whole organisms, are immune cells activators. They are mitogenic in vitro for lymphocytes, induce B-cell differentiation and trigger secretion of cytokines including interleukin-1 (IL-1), IL-2, IL-4, IL-6, tumor necrosis factor-a (TNF-a), interferons, and granulocyte macrophage-colony stimulating factor (GM-CSF). These results were obtained with cells from various host species including human, rat, mouse and guinea pig (for review and references see (62)).

Viable M. penetrans induces a complete cellular immune response, including proliferation, blastogenesis and expression of activation markers by T lymphocytes from healthy or HIV infected patients (63). Furthermore, heat-inactivated M. fermentans and M. penetrans retain some stimulating properties and various molecular components responsible for these effects have recently been or are being identified. Indeed, membrane extracts containing lipoproteins from these two mycoplasmas trigger cellular proliferation, secretion of cytokines, TNF-a, IL-1 and IL-6, and IgG and IgM secretion from mouse splenocytes (64), human myelomonocytic cell lines and monocytes (65-67). A mycoplasma extract highly enriched in lipoproteins can be prepared with Triton X-114. However free membrane lipids and capsule components are also co-extracted and therefore, the effects of such extracts cannot be exclusively attributed to lipoproteins unless appropriate control experiments are performed. A protein fraction from M. fermentans and M. penetrans kills non-differentiated myelomonocytic cells whereas no similar has been observed for similar extract from other mycoplasma species (65). This killing requires the presence of actinomycin D and resembles apoptosis. However, it differs from TNF-induced death and does not act via the cell surface receptor CD95/Fas/Apo-1. The physiological significance of this finding is unknown because the mycoplasmas by themselves have not been shown to induce apoptosis.

We have studied the molecular interactions between spiralin, a mycoplasma lipoprotein, and immune cells. Spiralin was chosen because of its availability in a highly pure form and free of detergent, in a micellar structure (68). Spiralin polyclonally stimulated B-cells from mouse splenocytes (69), similar to the B-cell activation by an LPS-independent pathway reported for various bacterial lipoproteins such as Braun's lipoprotein of E. coli, OspA and OspB of Borrelia burgdorferi or the Treponema pallidum lipoproteins (70-73). Mycoplasma lipoproteins are potent immunogens and are major components of the mycoplasmal membranes. This is consistent with the strong and specific humoral response that develops against them during natural infections (74, 51). Non-protein membrane components have also been shown to be involved in the mycoplasma-associated activation. They include M. fermentans-derived high-molecular-weight material (MDHM) and a recently identified M. penetrans glycolipid fraction (GLF). MDHM induces strong IL-6 secretion from murine and human macrophages, and a cytolysis in murine thymocytes but does not induce a proliferative response of murine splenic cells (75-77). GLF is a strong mitogenic and induces differentiation of B-cells, and release of IgG and IgM. It does not induce the secretion of pro-inflammatory cytokines (IL-1 and IL-6) from mouse splenocytes and thus differs from mycoplasmal lipoproteins (61).

7.2. Antigenic surface variation and immune escape

Various mycoplasma species undergo antigenic variation, a mechanism by which they alter their surface architecture to evade immune recognition (78). However, the relationship between antigenic variation and mycoplasmal virulence is unknown (79).

The best documented case of mycoplasmal antigen variation is the M. hyorhinis variable lipoproteins (Vlps). Vlps genes corresponding genes encode proteins with characteristic C-terminal regions, the size of which varies due to insertion or deletion of intragenic repeats (80). Some Vlps have also been identified in M. fermentans (81), but there is no evidence for such proteins in M. penetrans. The P35 gene region contains direct and inverted repeated sequences which could allow antigenic variation through homologous recombination (48). Highly variable surface structure is a property common to several mycoplasma species (79, 82). Antigenic variability may explain the chronicity of mycoplasmal infection and thus further information on this issue would be valuable.

7.3. Molecular mimicry

Another mechanism often involved in immune system escape is molecular mimicry by structures of the parasite for its host. In contrast with its strong mitogenic properties toward mouse splenocytes, M. penetrans GLF had no effect on human PBMCs* of 15 donors in vitro. This strongly suggests molecular mimicry of the GLF for the sugars exposed on human cell surfaces. Indeed, this is coherent with the lack of humoral response toward this compound in M. penetrans-infected patients, although GLF-immunized rabbits and macaques developed a humoral response (61). Possibly GLF, recently characterized as a capsule-like material, protects M. penetrans from host phagocytosis.

Another type of mycoplasmal molecular mimicry of eukaryote structures was proposed for the P1 adhesin of M. pneumoniae to evade the induction of adherence inhibiting antibodies, and this may influence the pathogenesis of the infection (83).

Altogether, there is various evidence for complex cellular and molecular activation of the immune system by mycoplasmas. Mycoplasma interactions with the immune cells involve proteins, lipoproteins and glycolipids, each having a particular effect on host cells to induce cellular and/or humoral responses. Moreover, lipoproteins were found in numerous mycoplasmal species, whereas MDHM and GLF have only been identified in M. fermentans and M. penetrans, respectively. Therefore, any conclusions about their influence on immune cells cannot be extended to all the mycoplasmas species.

[Table of Contents ] [Next Section] [Previous Section]