<i>Leishmania</i>‐encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence

Holowka, Thomas; Castilho, Tiago Moreno; Garcia, Alvaro Baeza; Sun, Tiffany; McMahon-Pratt, Diane; Bucala, Richard

doi:10.1096/fj.201500189r

Cited by 25 publications

(31 citation statements)

References 54 publications

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“…We postulate that parasite MIFs may compete with Hu‐MIF to bind CD74 by establishing non‐bonded interactions with the host receptor thus occupying the MIF‐binding site. The fact that Hu‐MIF orthologs in certain pathogens can modulate the host immune responses against themselves is a mechanism that has been well described in protozoa . While L major MIF is able to prevent parasite destruction by host immune cells, Plasmodium MIF was demonstrated to have an immunomodulatory action by disrupting the establishment of protective immunity .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, nematode MIFs have been reported to induce alternatively activated macrophages in a Th2‐polarized environment indicating that, in dependency on the prevailing cytokine pattern, nematode MIFs may either have pro‐ or counter‐inflammatory effects on the immune response . Similarly, MIF from the protozoan Leishmania major has a role in promoting parasite persistence by manipulating the host response to increase the exhaustion and depletion of protective CD4 T cell . Of interest, MIF from the protozoan Trichomonas vaginalis was demonstrated to be an inductor factor of prostate cancer and more interestingly, such parasite MIF is able to bind to the human CD74 exacerbating the proliferation signal and malignancy trait .…”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16][17][18] Some MIF proteins from parasites modulate the host immune response by different mechanisms including the alteration of cytokine production and promoting B cell antibody response. [19][20][21][22] The MIF analogs derived from several species of parasites have been hypothesized that may act as host immune response modulators to allow survival of the parasite from the attack of host immune system. 14,21,23,24 Interestingly, nematode MIFs have been reported to induce alternatively activated macrophages in a Th2-polarized environment indicating that, in dependency on the prevailing cytokine pattern, nematode MIFs may either have pro-or counter-inflammatory effects on the immune response.…”

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confidence: 99%

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A computational assessment of the predicted structures of Human Macrophage Migration Inhibitory Factor 1 orthologs in parasites and its affinity to human CD74 receptor

Machicado

Marcos

2017

J Mol Recognit

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The human macrophage migration inhibitory factor 1 (Hu-MIF-1) is a protein involved in the inflammatory and immunology response to parasite infection. In the present study, the existence of Hu-MIF-1 from parasites have been explored by mining WormBase. A total of 35 helminths were found to have Hu-MIF-1 homologs, including some parasites of importance for public health. Physicochemical, structural, and biological properties of Hu-MIF-1 were compared with its orthologs in parasites showing that most of these are secretory proteins, with positive net charge and presence of the Cys-Xaa-Xaa-Cys motif that is critical for its oxidoreductase activity. The inhibitor-binding site present in Hu-MIF-1 is well conserved among parasite MIFs suggesting that Hu-MIF inhibitors may target orthologs in pathogens. The binding of Hu-MIF-1 to its cognate receptor CD74 was predicted by computer-assisted docking, and it resulted to be very similar to the predicted complexes formed by parasite MIFs and human CD74. More than 1 plausible conformation of MIFs in the extracellular loops of CD74 may be possible as demonstrated by the different predicted conformations of MIF orthologs in complex with CD74. Parasite MIFs in complex with CD74 resulted with some charged residues oriented to CD74, which was not observed in the Hu-MIF-1/CD74 complex. Our findings predict the binding mode of Hu-MIF-1 and orthologs with CD74, which can assist in the design of novel MIF inhibitors. Whether the parasite MIFs function specifically subvert host immune responses to suit the parasite is an open question that needs to be further investigated. Future research should lead to a better understanding of parasite MIF action in the parasite biology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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A computational assessment of the predicted structures of Human Macrophage Migration Inhibitory Factor 1 orthologs in parasites and its affinity to human CD74 receptor

Machicado

Marcos

2017

J Mol Recognit

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“…Lma-MIF-1 (Lm1740MIF) was found to exhibit tautomerase activity and activate the (ERK)1/2 pathway in a CD74-dependent manner thereby inhibiting the activation-induced apoptosis of macrophages (Kamir et al, 2008), which in turn may allow parasites to persist within the macrophages and avoid immune destruction. The immunomodulatory role of the two Lma-MIF proteins was verified recently by the creation of a Lma-MIF-KO strain of L. major (Holowka et al, 2016). This mutant strain replicated normally but showed a 2-fold increased susceptibility to macrophage clearance, while mice infected with Lma-MIF-deficient L. major, when compared to the wild-type strain, also showed a 3-fold reduction in parasite burden.…”

Section: Non-mammalian Mif Homologues Identified Throughout the Eumentioning

confidence: 92%

The non-mammalian MIF superfamily

et al. 2017

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Macrophage migration inhibitory factor (MIF) was first described as a cytokine 50 years ago, and emerged in mammals as a pleiotropic protein with pro-inflammatory, chemotactic, and growth-promoting activities. In addition, MIF has gained substantial attention as a pivotal upstream mediator of innate and adaptive immune responses and with pathologic roles in several diseases. Of less importance in mammals is an intrinsic but non-physiologic enzymatic activity that points to MIF's evolution from an ancient defense molecule. Therefore, it is not surprising that mif-like genes also have been found across a range of different organisms including bacteria, plants, protozoa, helminths, molluscs, arthropods, fish, amphibians and birds. While Genebank analysis identifying mif-like genes across species is extensive, contained herein is an overview of the non-mammalian MIF-like proteins that have been most well studied experimentally. For many of these organisms, MIF contributes to an innate defense system or plays a role in development. For parasitic organisms however, MIF appears to function as a virulence factor aiding in the establishment or persistence of infection by modulating the host immune response. Consequently, a combined targeting of both parasitic and host MIF could lead to more effective treatment strategies for parasitic diseases of socioeconomic importance.

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“…Recent studies revealed that homologues of the macrophage migratory inhibitory factor expressed by Leishmania major, LmMIF-1 and -2, can alter the leishmanicidal activity of macrophages, leading to T cell exhaustion and disease progression during in vivo infection (17,18). Similarly, another well-studied immunomodulatory molecule of Leishmania is its promastigote surface molecule lipophosphoglycan (LPG) (19,20), which delays the fusion of the phagosome with late endosomes or lysosomes in macrophages (21,22).…”

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confidence: 99%

Characterization of the Protein Tyrosine Phosphatase LmPRL-1 Secreted by Leishmania major via the Exosome Pathway

et al. 2017

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Similar to other intracellular pathogens, Leishmania parasites are known to evade the antimicrobial effector functions of host immune cells. To date, however, only a few virulence factors have been described for Leishmania major, one of the causative agents of cutaneous leishmaniasis. Here, we have characterized the expression and function of an L. major phosphatase, which we termed LmPRL-1. This enzyme shows a strong structural similarity to the human phosphatases of regenerating liver (PRL-1, -2, and -3) that regulate the proliferation, differentiation, and motility of cells. The biochemical characterization of the L. major phosphatase revealed that the enzyme is redox sensitive. When analyzing the subcellular localization of LmPRL-1 in promastigotes, amastigotes, and infected macrophages, we found that the phosphatase was predominantly expressed and secreted by promastigotes via the exosome route. Finally, we observed that ectopic expression of LmPRL-1 in L. major led to an increased number of parasites in macrophages. From these data, we conclude that the L. major phosphatase LmPRL-1 contributes to the intracellular survival of the parasites in macrophages.KEYWORDS Leishmania, exosome, macrophage, tyrosine phosphatase L eishmaniasis is an infectious disease prevalent worldwide that is caused by kinetoplastid protozoan parasites belonging to the genus Leishmania (1). In nature, this heteroxenous parasite is transmitted by the bites of sand flies. Following the inoculation of flagellated promastigotes into the dermis of the host, the parasites are rapidly endocytosed by phagocytic cells, in which they differentiate into amastigotes, multiply, and reach inner compartments and organs, such as draining lymph nodes, spleen, liver, and bone marrow. The life cycle of the parasite is completed after ingestion of amastigote-infected cells by sand flies during their blood meal. In the digestive tract of their vector, parasites transform back into extracellular promastigotes that develop into infectious metacyclics (2). Depending on the status of the host immune system and the Leishmania species, the infection of mammals leads either to mostly self-healing skin lesions (cutaneous leishmaniasis [CL]) or to a systemic disease, termed visceral leishmaniasis (VL) or kala-azar, that is lethal if untreated (3-5).To survive in their hosts, Leishmania parasites need to quickly adapt their growth, metabolism, and mechanisms of protection to their new environment. Interestingly, only a few genes are differentially expressed during this adaptive process, suggesting an important role for the regulation of protein translation (6). Leishmania speciesspecific gene diversity also participates in the adaptation of the parasite to its organ-

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Leishmania‐encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence

Cited by 25 publications

References 54 publications

A computational assessment of the predicted structures of Human Macrophage Migration Inhibitory Factor 1 orthologs in parasites and its affinity to human CD74 receptor

A computational assessment of the predicted structures of Human Macrophage Migration Inhibitory Factor 1 orthologs in parasites and its affinity to human CD74 receptor

The non-mammalian MIF superfamily

Characterization of the Protein Tyrosine Phosphatase LmPRL-1 Secreted by Leishmania major via the Exosome Pathway

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