Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection.

Trypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein (HDL) complex that, through the cation channel-forming protein apolipoprotein L-1 (APOL1), provides innate immunity to select kinetoplastid parasites. The immunoprotective effects of TLF have been extensively investigated...

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Autores principales:	Jyoti Pant, Marie Samanovic, Maria T Nelson, Mert K Keceli, Joseph Verdi, Stephen M Beverley, Jayne Raper
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3122d2551537448dafd74d30109fbcd5
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spelling	oai:doaj.org-article:3122d2551537448dafd74d30109fbcd52021-12-02T20:00:06ZInterplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection.1553-73661553-737410.1371/journal.ppat.1008768https://doaj.org/article/3122d2551537448dafd74d30109fbcd52021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1008768https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Trypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein (HDL) complex that, through the cation channel-forming protein apolipoprotein L-1 (APOL1), provides innate immunity to select kinetoplastid parasites. The immunoprotective effects of TLF have been extensively investigated in the context of its interaction with the extracellular protozoan Trypanosoma brucei brucei, to which it confers sterile immunity. We previously showed that TLF could act against an intracellular pathogen Leishmania, and here we dissected the role of TLF and its synergy with host-immune cells. Leishmania major is transmitted by Phlebotomine sand flies, which deposit the parasite intradermally into mammalian hosts, where neutrophils are the predominant phagocytes recruited to the site of infection. Once in the host, the parasites are phagocytosed and shed their surface glycoconjugates during differentiation to the mammalian-resident amastigote stage. Our data show that mice producing TLF have reduced parasite burdens when infected intradermally with metacyclic promastigotes of L. major, the infective, fly-transmitted stage. This TLF-mediated reduction in parasite burden was lost in neutrophil-depleted mice, suggesting that early recruitment of neutrophils is required for TLF-mediated killing of L. major. In vitro we find that only metacyclic promastigotes co-incubated with TLF in an acidic milieu were lysed. However, amastigotes were not killed by TLF at any pH. These findings correlated with binding experiments, revealing that labeled TLF binds specifically to the surface of metacyclic promastigotes, but not to amastigotes. Metacyclic promastigotes of L. major deficient in the synthesis of surface glycoconjugates LPG and/or PPG (lpg1- and lpg5A-/lpg5B- respectively) whose absence mimics the amastigote surface, were resistant to TLF-mediated lysis. We propose that TLF binds to the outer surface glycoconjugates of metacyclic promastigotes, whereupon it kills the parasite in the acidic phagosome of phagocytes. We hypothesize that resistance to TLF requires shedding of the surface glycoconjugates, which occurs several hours after phagocytosis by immune cells, creating a relatively short-lived but effective window for TLF to act against Leishmania.Jyoti PantMarie SamanovicMaria T NelsonMert K KeceliJoseph VerdiStephen M BeverleyJayne RaperPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1008768 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Jyoti Pant Marie Samanovic Maria T Nelson Mert K Keceli Joseph Verdi Stephen M Beverley Jayne Raper Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection.
description	Trypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein (HDL) complex that, through the cation channel-forming protein apolipoprotein L-1 (APOL1), provides innate immunity to select kinetoplastid parasites. The immunoprotective effects of TLF have been extensively investigated in the context of its interaction with the extracellular protozoan Trypanosoma brucei brucei, to which it confers sterile immunity. We previously showed that TLF could act against an intracellular pathogen Leishmania, and here we dissected the role of TLF and its synergy with host-immune cells. Leishmania major is transmitted by Phlebotomine sand flies, which deposit the parasite intradermally into mammalian hosts, where neutrophils are the predominant phagocytes recruited to the site of infection. Once in the host, the parasites are phagocytosed and shed their surface glycoconjugates during differentiation to the mammalian-resident amastigote stage. Our data show that mice producing TLF have reduced parasite burdens when infected intradermally with metacyclic promastigotes of L. major, the infective, fly-transmitted stage. This TLF-mediated reduction in parasite burden was lost in neutrophil-depleted mice, suggesting that early recruitment of neutrophils is required for TLF-mediated killing of L. major. In vitro we find that only metacyclic promastigotes co-incubated with TLF in an acidic milieu were lysed. However, amastigotes were not killed by TLF at any pH. These findings correlated with binding experiments, revealing that labeled TLF binds specifically to the surface of metacyclic promastigotes, but not to amastigotes. Metacyclic promastigotes of L. major deficient in the synthesis of surface glycoconjugates LPG and/or PPG (lpg1- and lpg5A-/lpg5B- respectively) whose absence mimics the amastigote surface, were resistant to TLF-mediated lysis. We propose that TLF binds to the outer surface glycoconjugates of metacyclic promastigotes, whereupon it kills the parasite in the acidic phagosome of phagocytes. We hypothesize that resistance to TLF requires shedding of the surface glycoconjugates, which occurs several hours after phagocytosis by immune cells, creating a relatively short-lived but effective window for TLF to act against Leishmania.
format	article
author	Jyoti Pant Marie Samanovic Maria T Nelson Mert K Keceli Joseph Verdi Stephen M Beverley Jayne Raper
author_facet	Jyoti Pant Marie Samanovic Maria T Nelson Mert K Keceli Joseph Verdi Stephen M Beverley Jayne Raper
author_sort	Jyoti Pant
title	Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection.
title_short	Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection.
title_full	Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection.
title_fullStr	Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection.
title_full_unstemmed	Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection.
title_sort	interplay of trypanosome lytic factor and innate immune cells in the resolution of cutaneous leishmania infection.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/3122d2551537448dafd74d30109fbcd5
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Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection.

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