東華大學圖書館 |

Language: English

Help

回圖書館首頁

手機版館藏查詢

Back

Switch To: Labeled | MARC Mode | ISBD

Linked to FindBook

Google Book

Amazon

博客來

Improving and Understanding Macrophage Restriction of Mycobacterium tuberculosis Infection.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Improving and Understanding Macrophage Restriction of Mycobacterium tuberculosis Infection./
Author:	Babunovic, Gregory Hunter.
Description:	1 online resource (132 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 83-09, Section: B.
Contained By:	Dissertations Abstracts International83-09B.
Subject:	Microbiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28964591click for full text (PQDT)
ISBN:	9798209894773

Improving and Understanding Macrophage Restriction of Mycobacterium tuberculosis Infection.
Babunovic, Gregory Hunter.

Improving and Understanding Macrophage Restriction of Mycobacterium tuberculosis Infection. - 1 online resource (132 pages)

Source: Dissertations Abstracts International, Volume: 83-09, Section: B.

Thesis (Ph.D.)--Harvard University, 2022.

Includes bibliographical references

Tuberculosis, the disease caused by Mycobacterium tuberculosis (Mtb), is a leading cause of death due to infectious disease. New biomedical interventions are necessary to meet World Health Organization goals for tuberculosis control. However, the creation of these interventions is constrained by insufficient knowledge of how the human immune system fights infection with Mtb, which limits our tools for improving immunity. Macrophages are a protective replicative niche for Mtb but can kill the infecting bacterium when appropriately activated. We sought to identify compounds that best activate macrophage restriction, and elucidate the resulting mechanism of Mtb control.A host-side CRISPR screen during mycobacterial infection identified macrophage genes for which genetic and pharmacologic targeting each increased macrophage survival and Mtb restriction. In a complementary approach, we systematically compared bacterial restriction by human macrophages after treatment with 26 activators, including compounds currently in clinical trials for tuberculosis. Both approaches yielded pharmacological inducers of Mtb restriction that were robust across macrophage contexts.To understand mechanisms of macrophage restriction of Mtb infection we studied the compound all-trans-retinoic acid (ATRA), an active metabolite of vitamin A which most effectively increased Mtb control. By comparing ATRA to closely related yet non-restrictive compounds, we found that bacterial clearance was transcriptionally and functionally associated with macrophage cholesterol efflux; this limitation of macrophage cholesterol was necessary for restriction of Mtb. To determine how cholesterol efflux affected bacterial control, we performed the first Mtb CRISPR interference screen in an infection model, identifying Mtb genes specifically required to survive in ATRA-activated macrophages. These data showed that ATRA treatment starves Mtb of cholesterol and the downstream metabolite propionyl-CoA. Supplementation with sources of propionyl-CoA abrogated the restrictive effect of ATRA, and this effect was dependent on pathways that integrate propionate into central carbon metabolism.The data in this dissertation demonstrate that host genetic screening and systematic comparative analysis can each identify effective activators of Mtb restriction by macrophages, enabling future therapeutic development. They also show that targeting the coupled metabolism of Mtb and the macrophage improves control of infection, and that it is possible to genetically map the mode of bacterial death using CRISPR interference.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798209894773Subjects--Topical Terms:

536250
Microbiology.
Subjects--Index Terms:

CholesterolIndex Terms--Genre/Form:

542853
Electronic books.

Improving and Understanding Macrophage Restriction of Mycobacterium tuberculosis Infection.
LDR:03958nmm a2200397K 4500 001 2359724
005 20230917195227.5
006 m o d
007 cr mn ---uuuuu
008 241011s2022 xx obm 000 0 eng d
020 $a 9798209894773
035 $a (MiAaPQ)AAI28964591
035 $a AAI28964591
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Babunovic, Gregory Hunter. $3 3700344
245 1 0 $a Improving and Understanding Macrophage Restriction of Mycobacterium tuberculosis Infection.
264 0 $c 2022
300 $a 1 online resource (132 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 83-09, Section: B.
500 $a Advisor: Starnbach, Michael.
502 $a Thesis (Ph.D.)--Harvard University, 2022.
504 $a Includes bibliographical references
520 $a Tuberculosis, the disease caused by Mycobacterium tuberculosis (Mtb), is a leading cause of death due to infectious disease. New biomedical interventions are necessary to meet World Health Organization goals for tuberculosis control. However, the creation of these interventions is constrained by insufficient knowledge of how the human immune system fights infection with Mtb, which limits our tools for improving immunity. Macrophages are a protective replicative niche for Mtb but can kill the infecting bacterium when appropriately activated. We sought to identify compounds that best activate macrophage restriction, and elucidate the resulting mechanism of Mtb control.A host-side CRISPR screen during mycobacterial infection identified macrophage genes for which genetic and pharmacologic targeting each increased macrophage survival and Mtb restriction. In a complementary approach, we systematically compared bacterial restriction by human macrophages after treatment with 26 activators, including compounds currently in clinical trials for tuberculosis. Both approaches yielded pharmacological inducers of Mtb restriction that were robust across macrophage contexts.To understand mechanisms of macrophage restriction of Mtb infection we studied the compound all-trans-retinoic acid (ATRA), an active metabolite of vitamin A which most effectively increased Mtb control. By comparing ATRA to closely related yet non-restrictive compounds, we found that bacterial clearance was transcriptionally and functionally associated with macrophage cholesterol efflux; this limitation of macrophage cholesterol was necessary for restriction of Mtb. To determine how cholesterol efflux affected bacterial control, we performed the first Mtb CRISPR interference screen in an infection model, identifying Mtb genes specifically required to survive in ATRA-activated macrophages. These data showed that ATRA treatment starves Mtb of cholesterol and the downstream metabolite propionyl-CoA. Supplementation with sources of propionyl-CoA abrogated the restrictive effect of ATRA, and this effect was dependent on pathways that integrate propionate into central carbon metabolism.The data in this dissertation demonstrate that host genetic screening and systematic comparative analysis can each identify effective activators of Mtb restriction by macrophages, enabling future therapeutic development. They also show that targeting the coupled metabolism of Mtb and the macrophage improves control of infection, and that it is possible to genetically map the mode of bacterial death using CRISPR interference.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2023
538 $a Mode of access: World Wide Web
650 4 $a Microbiology. $3 536250
650 4 $a Immunology. $3 611031
650 4 $a Cellular biology. $3 3172791
653 $a Cholesterol
653 $a CRISPR
653 $a Macrophage
653 $a Propionate
653 $a Tuberculosis
655 7 $a Electronic books. $2 lcsh $3 542853
690 $a 0410
690 $a 0982
690 $a 0379
710 2 $a ProQuest Information and Learning Co. $3 783688
710 2 $a Harvard University. $b Medical Sciences. $3 3181716
773 0 $t Dissertations Abstracts International $g 83-09B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28964591 $z click for full text (PQDT)