Saposin D acting on macrophage bacteriostatic function in experimental tuberculosis infection

The protection against tuberculosis infection is largely determined by the ability of host tissue macrophages to limit the growth and spread of mycobacteria. Able to multiply within the host macrophages, mycobacteria have developed a number of protective mechanisms preventing phagosome-lysosome fusi...

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Autores principales:	G. S. Shepelkova, V. V. Evstifeev, A. E. Ergeshov, V. V. Yeremeev
Formato:	article
Lenguaje:	RU
Publicado:	Sankt-Peterburg : NIIÈM imeni Pastera 2021
Materias:	tuberculosis macrophages saposin d artificial gene lentivirus glycolipoprotein Infectious and parasitic diseases RC109-216
Acceso en línea:	https://doaj.org/article/7c837d3104524d8388a10a3e8c4837e4
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spelling	oai:doaj.org-article:7c837d3104524d8388a10a3e8c4837e42021-11-22T07:09:54ZSaposin D acting on macrophage bacteriostatic function in experimental tuberculosis infection2220-76192313-739810.15789/2220-7619-TEO-1386https://doaj.org/article/7c837d3104524d8388a10a3e8c4837e42021-06-01T00:00:00Zhttps://www.iimmun.ru/iimm/article/view/1386https://doaj.org/toc/2220-7619https://doaj.org/toc/2313-7398The protection against tuberculosis infection is largely determined by the ability of host tissue macrophages to limit the growth and spread of mycobacteria. Able to multiply within the host macrophages, mycobacteria have developed a number of protective mechanisms preventing phagosome-lysosome fusion, thereby evading damaging effects of lysosomal enzymes. Saposins are small, acidic, thermostable, non-enzymatic glycoproteins that participate as co-fac-tors in degradation of short oligosaccharide head group glycosphingolipids. Saposins A, B, C and D are formed in acidic endosomes due to cleavage of initial prosaposin molecule. The effect of saposins on human immune response is mediated by their involvement in presenting mycobacterial antigens on CD1 molecules. Preliminary studies with electron microscopy allowed to uncover saposin D-bound damaging effect on Mycobacterium tuberculosis in acidic environment. These data allowed us to suggest that saposin D is an important protective component fighting against TB infection. The aim of the study was to explore how saposin D deficiency might affect formation of anti-tuberculosis immune response and ability of macrophages to inhibit M. tuberculosis growth. Materials and methods. Interstitial pulmonary macrophages and peritoneal macrophages were isolated from wild type C57BL/6 strain and saposin D deficient C57BL/6-SapD-/- mouse strains. Results. It was found that as compared to macrophages from mice, macrophages from wild type strain significantly better controlled mycobacteria growth in vitro. To study an opportunity of compensating for deficient saposin D in peritoneal macrophages from C57BL/6-SapD-/- mice, a saposin D gene-bearing lentiviral vector was created. Transfection of SAPD-deficient peritoneal macrophages with expression vector compensated for saposin D deficiency in such cells and restored bactericidal function. The mechanisms of action for current anti-TB drugs are mediated by various metabolic pathways in mycobacteria (inhibited biosynthesis of fatty acids, arabinogalactan, peptidoglycan and protein; inhibition of DNA-dependent processes, proton pumps and cytochrome P450-dependent monooxygenases). Conclusion. It was shown that saposin D deficiency affects activation of macrophage bactericidal function in vitro. Our study data may be a prerequisite for biologically substantiated potential of using a vector construct bearing natural human protein gene such as saposin D, as a new anti-tuberculosis drug.G. S. ShepelkovaV. V. EvstifeevA. E. ErgeshovV. V. YeremeevSankt-Peterburg : NIIÈM imeni Pasteraarticletuberculosismacrophagessaposin dartificial genelentivirusglycolipoproteinInfectious and parasitic diseasesRC109-216RUInfekciâ i Immunitet, Vol 11, Iss 3, Pp 473-480 (2021)
institution	DOAJ
collection	DOAJ
language	RU
topic	tuberculosis macrophages saposin d artificial gene lentivirus glycolipoprotein Infectious and parasitic diseases RC109-216
spellingShingle	tuberculosis macrophages saposin d artificial gene lentivirus glycolipoprotein Infectious and parasitic diseases RC109-216 G. S. Shepelkova V. V. Evstifeev A. E. Ergeshov V. V. Yeremeev Saposin D acting on macrophage bacteriostatic function in experimental tuberculosis infection
description	The protection against tuberculosis infection is largely determined by the ability of host tissue macrophages to limit the growth and spread of mycobacteria. Able to multiply within the host macrophages, mycobacteria have developed a number of protective mechanisms preventing phagosome-lysosome fusion, thereby evading damaging effects of lysosomal enzymes. Saposins are small, acidic, thermostable, non-enzymatic glycoproteins that participate as co-fac-tors in degradation of short oligosaccharide head group glycosphingolipids. Saposins A, B, C and D are formed in acidic endosomes due to cleavage of initial prosaposin molecule. The effect of saposins on human immune response is mediated by their involvement in presenting mycobacterial antigens on CD1 molecules. Preliminary studies with electron microscopy allowed to uncover saposin D-bound damaging effect on Mycobacterium tuberculosis in acidic environment. These data allowed us to suggest that saposin D is an important protective component fighting against TB infection. The aim of the study was to explore how saposin D deficiency might affect formation of anti-tuberculosis immune response and ability of macrophages to inhibit M. tuberculosis growth. Materials and methods. Interstitial pulmonary macrophages and peritoneal macrophages were isolated from wild type C57BL/6 strain and saposin D deficient C57BL/6-SapD-/- mouse strains. Results. It was found that as compared to macrophages from mice, macrophages from wild type strain significantly better controlled mycobacteria growth in vitro. To study an opportunity of compensating for deficient saposin D in peritoneal macrophages from C57BL/6-SapD-/- mice, a saposin D gene-bearing lentiviral vector was created. Transfection of SAPD-deficient peritoneal macrophages with expression vector compensated for saposin D deficiency in such cells and restored bactericidal function. The mechanisms of action for current anti-TB drugs are mediated by various metabolic pathways in mycobacteria (inhibited biosynthesis of fatty acids, arabinogalactan, peptidoglycan and protein; inhibition of DNA-dependent processes, proton pumps and cytochrome P450-dependent monooxygenases). Conclusion. It was shown that saposin D deficiency affects activation of macrophage bactericidal function in vitro. Our study data may be a prerequisite for biologically substantiated potential of using a vector construct bearing natural human protein gene such as saposin D, as a new anti-tuberculosis drug.
format	article
author	G. S. Shepelkova V. V. Evstifeev A. E. Ergeshov V. V. Yeremeev
author_facet	G. S. Shepelkova V. V. Evstifeev A. E. Ergeshov V. V. Yeremeev
author_sort	G. S. Shepelkova
title	Saposin D acting on macrophage bacteriostatic function in experimental tuberculosis infection
title_short	Saposin D acting on macrophage bacteriostatic function in experimental tuberculosis infection
title_full	Saposin D acting on macrophage bacteriostatic function in experimental tuberculosis infection
title_fullStr	Saposin D acting on macrophage bacteriostatic function in experimental tuberculosis infection
title_full_unstemmed	Saposin D acting on macrophage bacteriostatic function in experimental tuberculosis infection
title_sort	saposin d acting on macrophage bacteriostatic function in experimental tuberculosis infection
publisher	Sankt-Peterburg : NIIÈM imeni Pastera
publishDate	2021
url	https://doaj.org/article/7c837d3104524d8388a10a3e8c4837e4
work_keys_str_mv	AT gsshepelkova saposindactingonmacrophagebacteriostaticfunctioninexperimentaltuberculosisinfection AT vvevstifeev saposindactingonmacrophagebacteriostaticfunctioninexperimentaltuberculosisinfection AT aeergeshov saposindactingonmacrophagebacteriostaticfunctioninexperimentaltuberculosisinfection AT vvyeremeev saposindactingonmacrophagebacteriostaticfunctioninexperimentaltuberculosisinfection
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Saposin D acting on macrophage bacteriostatic function in experimental tuberculosis infection

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