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Human gene variants linked to enhanced NLRP3 activity limit intramacrophage growth of Mycobacterium tuberculosis
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
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2014 (Engelska)Ingår i: The Journal of infectious diseases, ISSN 1537-6613, Vol. 209, nr 5, s. 749-753Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Activation of the NLRP3 inflammasome and subsequent generation of IL-1β is initiated in macrophages upon recognition of several stimuli. In the present work, we show that gain-of-function gene variants of inflammasome components known to predispose individuals to inflammatory disorders have a host-protective role during infection with Mycobacterium tuberculosis. By isolation of macrophages from patients and healthy blood donors with genetic variants in NLRP3 and CARD8 and subsequently infecting the cells by virulent M. tuberculosis, we show that these gene variants, combined, are associated with increased control of bacterial growth in human macrophages.

Ort, förlag, år, upplaga, sidor
University of Chicago Press / Oxford University Press (OUP) , 2014. Vol. 209, nr 5, s. 749-753
Nationell ämneskategori
Klinisk medicin
Identifikatorer
URN: urn:nbn:se:liu:diva-100889DOI: 10.1093/infdis/jit572ISI: 000331873700016PubMedID: 24158955OAI: oai:DiVA.org:liu-100889DiVA, id: diva2:664167
Tillgänglig från: 2013-11-14 Skapad: 2013-11-14 Senast uppdaterad: 2015-04-10Bibliografiskt granskad
Ingår i avhandling
1. Mycobacterium tuberculosis and the human macrophage: shifting the balance through inflammasome activation
Öppna denna publikation i ny flik eller fönster >>Mycobacterium tuberculosis and the human macrophage: shifting the balance through inflammasome activation
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Mycobacterium tuberculosis is a very successful pathogen and tuberculosis constitutes a major threat to global health worldwide. The World Health Organization (WHO) estimates that almost nine million new cases and 1.5 million deaths occur annually and the situation is worsened by increased antibiotic resistance and an extreme synergism with the HIV pandemic. M. tuberculosis primarily affects the lungs where the infection can lead to either eradication of the bacteria or the initiation of an immune response that culminates in the formation of a large cluster of immune cells termed granulomas. In these granulomas, the bacteria can either replicate and cause disease with the ultimate goal of spreading to new hosts or cause latent tuberculosis, which can persist for decades. The tools available to manage the disease are currently suboptimal and include lengthy antibiotic treatments and an inefficient vaccine resulting in poor protection. On a cellular level, M. tuberculosis primarily infects the cell designed to recognize, ingest and eradicate bacteria, namely the human macrophage. Following recognition, the macrophage phagocytoses the bacterium and tries to kill it using an array of different effector mechanisms including acidification of the bacterium-containing vacuole, different degradative enzymes and the generation of radicals. However, the bacterium is able to circumvent many of these harmful effects, leading to a tug-of-war between the bacterium  and host macrophage. This thesis aims at studying the interaction between the human macrophage and M. tuberculosis to identify host factors critical for controlling growth of the bacteria. More specifically, it focuses on the role of an intracellular receptor protein called NLRP3 and its downstream effects. NLRP3 is activated in human macrophages infected by M. tuberculosis and upon activation it forms a multi-protein complex known as the inflammasome. This protein complex is known to induce the production of the proinflammatory cytokine IL-1β and specialized forms of macrophage cell death. We hypothesized that stimulating this pathway would have a beneficial effect for the host macrophage during infection with M. tuberculosis.

To allow us to follow interaction between M. tuberculosis and the human macrophage, we first developed a luminometry-based method of measuring bacterial numbers and following bacterial growth over several days in infected cells. With this new assay we showed that low numbers of bacteria induced very low levels of IL-1β and failed to induce any type of cell death in the macrophage. However, when a critical number of bacteria were reached, the infected macrophages underwent necrosis, which was accompanied by high levels of IL-1β. We were also able to show that addition of vitamin D, which has been implicated as an important factor for increased killing capacity of infected macrophages, increased the production of IL-1β, which coincided with increased killing of M. tuberculosis. This effect was seen specifically in cells from patients with active tuberculosis, suggesting that these cells are primed to respond to vitamin D and increased levels of IL-1β. Furthermore, we also showed that increasing production of IL-1β by stimulating infected macrophages with apoptotic neutrophils in turn drives the production of other proinflammatory cytokines. Lastly, we showed that gain-of-function polymorphisms in inflammasome components linked to increased inflammasome activation and IL-1β production promotes bacterial killing in human macrophages. In conclusion, the work presented in this thesis shows  that by enhancing the functions of the inflammasome, it is possible to tip the balance between the human macrophage and M. tuberculosis in favor of the host cell.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2013. s. 97
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1372
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-100890 (URN)10.3384/diss.diva-100890 (DOI)978-91-7519-558-2 (ISBN)
Disputation
2013-12-11, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2013-11-14 Skapad: 2013-11-14 Senast uppdaterad: 2013-11-14Bibliografiskt granskad

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Eklund, DanielWelin, AmandaAndersson, HenrikVerma, DeeptiSöderkvist, PeterStendahl, OlleSärndahl, EvaLerm, Maria

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