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Mycobacterium tuberculosis and HIV coinfection: Effects on innate immunity and strategies to boost the immune response
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tuberculosis (TB) still remains a big threat today, being the leading cause of death by a single infectious agent. The TB epidemic is fueled by HIV along with the increasing drug-resistance which prolongs the already long treatment duration and decreases the success rate for curing TB. In most cases an infection results in latency but HIV patients have a 20-30 times higher risk of developing active TB. There are around 36.9 million people living with HIV globally, with the highest burden in Africa. Although there are effective treatments against the disease, there is no cure for AIDS and the availability of the lifelong treatment is limited in low-income countries were the burden is highest. HIV infection causes an immunodeficiency characterized by the progressive loss of CD4 T cells which increases the risk of opportunistic infections, and infection by Mycobacterium tuberculosis (Mtb), the causative agent of TB. Mtb spreads through aerosols from one person with active tuberculosis to a healthy person. Upon inhalation the bacteria are phagocytosed by alveolar macrophages that secrete cytokines and chemokines to recruit more cells, such as dendritic cells, macrophages and lymphocytes, leading to the formation of a granuloma. During a single TB infection the bacteria are usually contained within the granuloma, but HIV can disrupt the stable granuloma, causing a rupture and dissemination of Mtb. This inflammatory site is also beneficial to HIV since it promotes replication of the virus within infected cells. HIV and Mtb are two successful intracellular pathogens able to avoid immune defense mechanisms both of the innate and adaptive immunity in order to persist and replicate. Their virulence factors can manipulate or inhibit cell signaling, phagosome maturation, autophagy, ROS production, apoptosis and antigen presentation, to promote survival. Boosting of immune defenses with host-directed therapies (HDT) has been proposed as a treatment strategy against TB, either alone or adjunctive to the current regimen.

In this thesis, ways to boost the innate immune responses in Mtb and HIV coinfected macrophages were investigated, along with studies of the effect of HIV on Mtb antigen presentation in coinfected dendritic cells. The initial hypothesis was that autophagy induction through inhibition of mammalian target of rapamycin (mTOR) could suppress Mtb growth in HIV coinfected macrophages. However, during a low grade infection, autophagy induction increased Mtb replication due to a decreased autophagic flux and acidification of Mtb phagosomes. A general autophagic flux was induced, although not localized to the Mtb phagosomes, thus not inducing a xenophagy (autophagy of intracellular pathogens). Other ways of inducing autophagy or boosting the response in coinfected macrophages might be more beneficial and therefore the effect of efferocytosis was investigated. Uptake of apoptotic neutrophils by coinfected macrophages did not induce autophagy but enhanced the control of Mtb by other means. Upon efferocytosis, the macrophages acquired active myeloperoxidase (MPO) from the neutrophils that suppressed Mtb growth. The coinfected macrophages also produced more ROS after efferocytosis. The inhibition of Mtb growth could thus be mediated by MPO and the increased ROS production either directly or indirectly.

The possibility to boost the innate immunity could prove to be important during an HIV coinfection, when the adaptive immunity is deficient. In addition to the well-known decline in CD4 T cells during the course of HIV progression, we found that HIV infection of dendritic cells inhibited antigen presentation by suppressing the expression of HLA-DR and co-stimulatory molecules on coinfected dendritic cells. Furthermore, HIV reduced secretion of pro-inflammatory cytokines and suppressed antigen processing through inhibition of autophagy. This impaired antigen presentation in coinfected dendritic cells resulted in a decreased activation and response of Mtb-specific CD4 T cells.

In conclusion, this thesis shows how HIV can manipulate antigen presentation in Mtb coinfected dendritic cells and subsequently inhibit the adaptive immune response. It also contributes to insights on how efferocytosis of apoptotic neutrophils can boost the innate immune responses during coinfection. Lastly, autophagy induction through mTOR inhibition does not enhance protection against TB. Induction of autophagy should therefore be handled with care, particularly during HIV coinfection. 

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. , p. 58
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1659
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-154605DOI: 10.3384/diss.diva-154605ISBN: 9789176851425 (print)OAI: oai:DiVA.org:liu-154605DiVA, id: diva2:1293200
Public defence
2019-04-12, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2019-03-04 Created: 2019-03-04 Last updated: 2019-05-21Bibliographically approved
List of papers
1. Autophagy induction targeting mTORC1 enhances Mycobacterium tuberculosis replication in HIV co-infected human macrophages
Open this publication in new window or tab >>Autophagy induction targeting mTORC1 enhances Mycobacterium tuberculosis replication in HIV co-infected human macrophages
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 28171Article in journal (Refereed) Published
Abstract [en]

To survive and replicate in macrophages Mycobacterium tuberculosis (Mtb) has developed strategies to subvert host defence mechanisms, including autophagy. Autophagy induction has the potential to clear Mtb, but little is known about its effect during controlled tuberculosis and HIV co-infection. Mammalian target of rapamycin complex1 (mTORC1) inhibitors were used to induce autophagy in human macrophages pre-infected with HIV-1(BaL) and infected with a low dose of Mtb (co-infected), or single Mtb infected (single infected). The controlled Mtb infection was disrupted upon mTOR inhibition resulting in increased Mtb replication in a dose-dependent manner which was more pronounced during co-infection. The increased Mtb replication could be explained by the marked reduction in phagosome acidification upon mTOR inhibition. Autophagy stimulation targeting mTORC1 clearly induced a basal autophagy with flux that was unlinked to the subcellular environment of the Mtb vacuoles, which showed a concurrent suppression in acidification and maturation/flux. Overall our findings indicate that mTOR inhibition during Mtb or HIV/Mtb co-infection interferes with phagosomal maturation, thereby supporting mycobacterial growth during low-dose and controlled infection. Therefore pharmacological induction of autophagy through targeting of the canonical mTORC1-pathway should be handled with caution during controlled tuberculosis, since this could have serious consequences for patients with HIV/Mtb co-infection.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-132355 (URN)10.1038/srep28171 (DOI)000384609100002 ()27302320 (PubMedID)
Available from: 2016-11-12 Created: 2016-11-01 Last updated: 2019-03-28
2. HIV Interferes with Mycobacterium tuberculosis Antigen Presentation in Human Dendritic Cells
Open this publication in new window or tab >>HIV Interferes with Mycobacterium tuberculosis Antigen Presentation in Human Dendritic Cells
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2016 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 186, no 12, p. 3083-3093Article in journal (Refereed) Published
Abstract [en]

HIV coinfection is the most prominent risk factor for progression of Mycobacterium tuberculosis (Mtb) infection into active tuberculosis (TB) disease. The mechanisms behind the increased transition from latent to active TB in coinfected individuals have not been well elucidated at the cellular level. We hypothesized that HIV infection contributes to Mtb pathogenesis by interfering with the dendritic cell (DC) mediated immune control. Mtb-antigen processing and presentation are key events in the immune response against TB. Human immature DCs coinfected with HIV/Mtb had decreased expression of human leukocyte antigen antigen D related and the costimulatory molecules CD40, CD80, and CD86. In addition, Mtb-infected DCs triggered a significant release of the proinflammatory cytokines IL-6, IL-1 beta, and tumor necrosis factor-alpha, whereas coinfected DCs did not. To assess the DC antigen presentation capacity, we measured interferon-gamma from co-cultures of DCs and autologous Mtb antigen-specific CD4(+) T cells. Interferon-gamma release was significantly reduced when purified protein derivative- and Ag85B-specific CD4(+) T cells had been activated with coinfected DCs compared to Mtb-infected DCs, and this effect was attributed to Mtb antigen processing rather than peptide major histocompatibility complex class II loading. Evaluating autophagy as a measure of vesicular processing and maturation further revealed that HIV efficiently blocks initiation of this pathway during coinfection. Overall, our results demonstrate that HIV impairs Mtb antigen presentation in DCs, thereby suppressing an important cell linking innate and adaptive immune response in TB.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2016
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-133376 (URN)10.1016/j.ajpath.2016.08.003 (DOI)000389103800003 ()27746182 (PubMedID)
Note

Funding Agencies|Swedish Research Council [521-2012-1807, 348-2013-6588]; Swedish Heart-Lung Foundation [2014-0578]

Available from: 2016-12-27 Created: 2016-12-22 Last updated: 2019-03-28

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Andersson, Anna-Maria

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