Potent inhibition of viral fusion by the lipophosphoglycan of Leishmania donovani

Miao, Liyan; Stafford, Alan R.; Nir, Shlomo; Turco, Salvatore J.; Flanagan, Thomas D.; Epand, Richard M.

doi:10.1021/bi00014a022

Cited by 60 publications

(56 citation statements)

References 38 publications

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“…For example, LPG can impair signal transduction mediated by PKC in macrophages, thereby facilitating intracellular survival of the parasites (36, 37). Additionally, LPG is known to change the shape of membranes, leading to steric repulsion between the phagosome and endosome, thus delaying phagolysosome maturation (38). However, it is of interest to note that although LPG is present on the surface of Leishmania, the , and splenocyte lysates were analyzed for the expression of A20 by immunoblotting at the time periods indicated.…”

Section: Discussionmentioning

confidence: 99%

Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

Srivastav

Kar

Chande

et al. 2012

The Journal of Immunology

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TLRs, which form an interface between mammalian host and microbe, play a key role in pathogen recognition and initiation of proinflammatory response thus stimulating antimicrobial activity and host survival. However, certain intracellular pathogens such as Leishmania can successfully manipulate the TLR signaling, thus hijacking the defensive strategies of the host. Despite the presence of lipophosphoglycan, a TLR2 ligand capable of eliciting host-defensive cytokine response, on the surface of Leishmania, the strategies adopted by the parasite to silence the TLR2-mediated proinflammatory response is not understood. In this study, we showed that Leishmania donovani modulates the TLR2-mediated pathway in macrophages through inhibition of the IKK–NF-κB cascade and suppression of IL-12 and TNF-α production. This may be due to impairment of the association of TRAF6 with the TAK–TAB complex, thus inhibiting the recruitment of TRAF6 in TLR2 signaling. L. donovani infection drastically reduced Lys 63-linked ubiquitination of TRAF6, and the deubiquitinating enzyme A20 was found to be significantly upregulated in infected macrophages. Small interfering RNA-mediated silencing of A20 restored the Lys 63-linked ubiquitination of TRAF6 as well as IL-12 and TNF-α levels with a concomitant decrease in IL-10 and TGF-β synthesis in infected macrophages. Knockdown of A20 led to lower parasite survival within macrophages. Moreover, in vivo silencing of A20 by short hairpin RNA in BALB/c mice led to increased NF-κB DNA binding and host-protective proinflammatory cytokine response resulting in effective parasite clearance. These results suggest that L. donovani might exploit host A20 to inhibit the TLR2-mediated proinflammatory gene expression, thus escaping the immune responses of the host.

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Section: Discussionmentioning

confidence: 99%

Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

Srivastav

Kar

Chande

et al. 2012

The Journal of Immunology

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“…Possibly, inhibition of fusion is just an ancillary effect of LPG peripheral to its other roles in parasite virulence, as seen with amphipathic molecules with structural features resembling LPG in a variety of contexts (37). Alternatively, transient inhibition of fusion may lead to effects downstream of the ''early'' acidification or hydrolytic processes, as suggested by the finding that lpg1 Ϫ parasites survive poorly in the phox Ϫ macrophages after 5 days, a time when LPG has largely disappeared (Fig.…”

Section: Discussionmentioning

confidence: 99%

The role(s) of lipophosphoglycan (LPG) in the establishment ofLeishmania majorinfections in mammalian hosts

Späth

Garraway

Turco

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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261

259

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The abundant cell surface glycolipid lipophosphoglycan (LPG) was implicated in many steps of the Leishmania infectious cycle by biochemical tests. The presence of other abundant surface or secreted glycoconjugates sharing LPG domains, however, has led to uncertainty about the relative contribution of LPG in vivo. Here we used an Leishmania major lpg1 ؊ mutant, which lacks LPG alone and shows attenuated virulence, to dissect the role of LPG in the establishment of macrophage infections in vivo. lpg1 ؊ was highly susceptible to human complement, had lost the ability to inhibit phagolysosomal fusion transiently, and was oxidant sensitive. Studies of mouse mutants defective in relevant defense mechanisms confirmed the role of LPG in oxidant resistance but called into question the importance of transient inhibition of phagolysosomal fusion for Leishmania macrophage survival. Moreover, the limited lytic activity of mouse complement appears to be an ineffective pathogen defense mechanism in vitro and in vivo, unlike human hosts. In contrast, lpg1 ؊ parasites bound C3b and resisted low pH and proteases normally, entered macrophages efficiently and silently, and continued to inhibit host-signaling pathways. These studies illustrate the value of mechanistic approaches focusing on both parasite and host defense pathways in dissecting the specific biological roles of complex virulence factors such as LPG.phosphoglycans ͉ trypanosomatid protozoan parasite ͉ oxidant resistance ͉ inhibition of macrophage activation ͉ adhesin

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“…It does so by inserting itself, within minutes, into the macrophage membrane at the immediate area of internalization of the promastigote (Tolson et al, 1990) and within the phagosomal membrane. Insertion of LPG stabilizes the bilayer against the formation of an inverted hexagonal structure (Miao et al, 1995). As a consequence, LPG gives rise to an effective`steric repulsion' between phagosomal and endosomal membranes or reduces the negative curvature strain in bilayers, increasing the energy barrier for forming highly curved fusion intermediates, and thereby preventing fusion.…”

Section: Discussionmentioning

confidence: 99%

Impaired recruitment of the small GTPase rab7 correlates with the inhibition of phagosome maturation by Leishmania donovani promastigotes

Scianimanico¹,

Desrosiers²,

Dermine³

et al. 1999

Cell Microbiol

158

145

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SummaryWe have shown recently that one of the survival strategies used by Leishmania donovani promastigotes during the establishment of infection in macrophages consists in inhibiting phagosome±endosome fusion. This inhibition requires the expression of lipophosphoglycan (LPG), the predominant surface glycoconjugate of promastigotes, as parasites expressing truncated forms of LPG reside in phagosomes that fuse extensively with endocytic organelles. In the present study, we developed a single-organelle¯uorescence analysis approach to study and analyse the intracellular traf®cking of`fusogenic' and`low-fusogenic' phagosomes induced by an LPG repeating unit-defective mutant (lpg2 KO) or by wild-type L. donovani promastigotes respectively. The results obtained indicate that phagosomes containing mutant parasites fuse extensively with endocytic organelles and transform into phagolysosomes by losing the early endosome markers EEA1 and transferrin receptor, and acquiring the late endocytic and lysosomal markers rab7 and LAMP1. In contrast, a majority of`low-fusogenic' phagosomes containing wild-type L. donovani promastigotes do not acquire rab7, wheres they acquire LAMP1 with slower kinetics. These results suggest that L. donovani parasites use LPG to restrict phagosome±endosome fusion at the onset of infection in order to prevent phagosome maturation. This is likely to permit the transformation of hydrolase-sensitive promastigotes into hydrolase-resistant amastigotes within a hospitable vacuole not displaying the harsh environment of phagolysosomes.

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Potent inhibition of viral fusion by the lipophosphoglycan of Leishmania donovani

Cited by 60 publications

References 38 publications

Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

The role(s) of lipophosphoglycan (LPG) in the establishment ofLeishmania majorinfections in mammalian hosts

Impaired recruitment of the small GTPase rab7 correlates with the inhibition of phagosome maturation by Leishmania donovani promastigotes

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