Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV

Tuberculosis owes its resurgence as a major global health threat mostly to the emergence of drug resistance and coinfection with HIV. The synergy between HIV and Mycobacterium tuberculosis (Mtb) modifies the host immune environment to enhance both viral and bacterial replication and spread. In the l...

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Autores principales:	David Pires, Marta Calado, Tomás Velez, Manoj Mandal, Maria João Catalão, Olivier Neyrolles, Geanncarlo Lugo-Villarino, Christel Vérollet, José Miguel Azevedo-Pereira, Elsa Anes
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	cystatins cathepsins tuberculosis HIV/Mtb coinfection host-directed therapies Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/9fde2304a0ec4cf187d7bb11ce29acfd
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spelling	oai:doaj.org-article:9fde2304a0ec4cf187d7bb11ce29acfd2021-11-18T09:01:59ZModulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV1664-322410.3389/fimmu.2021.742822https://doaj.org/article/9fde2304a0ec4cf187d7bb11ce29acfd2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.742822/fullhttps://doaj.org/toc/1664-3224Tuberculosis owes its resurgence as a major global health threat mostly to the emergence of drug resistance and coinfection with HIV. The synergy between HIV and Mycobacterium tuberculosis (Mtb) modifies the host immune environment to enhance both viral and bacterial replication and spread. In the lung immune context, both pathogens infect macrophages, establishing favorable intracellular niches. Both manipulate the endocytic pathway in order to avoid destruction. Relevant players of the endocytic pathway to control pathogens include endolysosomal proteases, cathepsins, and their natural inhibitors, cystatins. Here, a mapping of the human macrophage transcriptome for type I and II cystatins during Mtb, HIV, or Mtb-HIV infection displayed different profiles of gene expression, revealing cystatin C as a potential target to control mycobacterial infection as well as HIV coinfection. We found that cystatin C silencing in macrophages significantly improves the intracellular killing of Mtb, which was concomitant with an increased general proteolytic activity of cathepsins. In addition, downmodulation of cystatin C led to an improved expression of the human leukocyte antigen (HLA) class II in macrophages and an increased CD4+ T-lymphocyte proliferation along with enhanced IFN-γ secretion. Overall, our results suggest that the targeting of cystatin C in human macrophages represents a promising approach to improve the control of mycobacterial infections including multidrug-resistant (MDR) TB.David PiresMarta CaladoTomás VelezManoj MandalMaria João CatalãoOlivier NeyrollesGeanncarlo Lugo-VillarinoChristel VérolletJosé Miguel Azevedo-PereiraElsa AnesFrontiers Media S.A.articlecystatinscathepsinstuberculosisHIV/Mtb coinfectionhost-directed therapiesImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cystatins cathepsins tuberculosis HIV/Mtb coinfection host-directed therapies Immunologic diseases. Allergy RC581-607
spellingShingle	cystatins cathepsins tuberculosis HIV/Mtb coinfection host-directed therapies Immunologic diseases. Allergy RC581-607 David Pires Marta Calado Tomás Velez Manoj Mandal Maria João Catalão Olivier Neyrolles Geanncarlo Lugo-Villarino Christel Vérollet José Miguel Azevedo-Pereira Elsa Anes Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV
description	Tuberculosis owes its resurgence as a major global health threat mostly to the emergence of drug resistance and coinfection with HIV. The synergy between HIV and Mycobacterium tuberculosis (Mtb) modifies the host immune environment to enhance both viral and bacterial replication and spread. In the lung immune context, both pathogens infect macrophages, establishing favorable intracellular niches. Both manipulate the endocytic pathway in order to avoid destruction. Relevant players of the endocytic pathway to control pathogens include endolysosomal proteases, cathepsins, and their natural inhibitors, cystatins. Here, a mapping of the human macrophage transcriptome for type I and II cystatins during Mtb, HIV, or Mtb-HIV infection displayed different profiles of gene expression, revealing cystatin C as a potential target to control mycobacterial infection as well as HIV coinfection. We found that cystatin C silencing in macrophages significantly improves the intracellular killing of Mtb, which was concomitant with an increased general proteolytic activity of cathepsins. In addition, downmodulation of cystatin C led to an improved expression of the human leukocyte antigen (HLA) class II in macrophages and an increased CD4+ T-lymphocyte proliferation along with enhanced IFN-γ secretion. Overall, our results suggest that the targeting of cystatin C in human macrophages represents a promising approach to improve the control of mycobacterial infections including multidrug-resistant (MDR) TB.
format	article
author	David Pires Marta Calado Tomás Velez Manoj Mandal Maria João Catalão Olivier Neyrolles Geanncarlo Lugo-Villarino Christel Vérollet José Miguel Azevedo-Pereira Elsa Anes
author_facet	David Pires Marta Calado Tomás Velez Manoj Mandal Maria João Catalão Olivier Neyrolles Geanncarlo Lugo-Villarino Christel Vérollet José Miguel Azevedo-Pereira Elsa Anes
author_sort	David Pires
title	Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV
title_short	Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV
title_full	Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV
title_fullStr	Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV
title_full_unstemmed	Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV
title_sort	modulation of cystatin c in human macrophages improves anti-mycobacterial immune responses to mycobacterium tuberculosis infection and coinfection with hiv
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/9fde2304a0ec4cf187d7bb11ce29acfd
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Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV

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