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Evasion of the macrophage apoptotic ...

Riendeau-Arnold, Carrie Judith.

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Evasion of the macrophage apoptotic response by virulent strains of Mycobacterium tuberculosis.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Evasion of the macrophage apoptotic response by virulent strains of Mycobacterium tuberculosis./
作者:	Riendeau-Arnold, Carrie Judith.
面頁冊數:	116 p.
附註:	Major Professor: Hardy Kornfeld.
Contained By:	Dissertation Abstracts International64-03B.
標題:	Biology, Microbiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3084506

Evasion of the macrophage apoptotic response by virulent strains of Mycobacterium tuberculosis.
Riendeau-Arnold, Carrie Judith.

Evasion of the macrophage apoptotic response by virulent strains of Mycobacterium tuberculosis. - 116 p.

Major Professor: Hardy Kornfeld.

Thesis (Ph.D.)--Boston University, 2003.

The goal of this work was to determine the virulence-associated mechanism(s) whereby <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>) evades the innate immune response of the infected host. Initial studies evaluated the potential for phorbol myristate acetate-differentiated THP-1 cells, a monocytic leukemia cell line, to mimic the apoptotic response of primary macrophages to mycobacterial infection. The development of a model system was undertaken to overcome the limitations associated with infection of primary alveolar macrophages, namely low cell numbers and the prohibitive cost of bronchoscopy on human volunteers. Consistent with the behavior of alveolar macrophages, differentiated THP-1 cells underwent apoptosis in response to infection with attenuated or avirulent strains of mycobacteria in a tumor necrosis factor (TNF)-dependent manner. High levels of macrophage apoptosis correlated with decreased viability of the bacilli. Contrastingly, virulent strains of <italic> Mtb</italic> did not induce apoptosis over background levels. These results demonstrate that THP-1 cells faithfully model alveolar macrophage responses to <italic>Mtb</italic> infection.Subjects--Topical Terms:

1017734
Biology, Microbiology.

Evasion of the macrophage apoptotic response by virulent strains of Mycobacterium tuberculosis.
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100 1 $a Riendeau-Arnold, Carrie Judith. $3 1251168
245 1 0 $a Evasion of the macrophage apoptotic response by virulent strains of Mycobacterium tuberculosis.
300 $a 116 p.
500 $a Major Professor: Hardy Kornfeld.
500 $a Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1168.
502 $a Thesis (Ph.D.)--Boston University, 2003.
520 $a The goal of this work was to determine the virulence-associated mechanism(s) whereby <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>) evades the innate immune response of the infected host. Initial studies evaluated the potential for phorbol myristate acetate-differentiated THP-1 cells, a monocytic leukemia cell line, to mimic the apoptotic response of primary macrophages to mycobacterial infection. The development of a model system was undertaken to overcome the limitations associated with infection of primary alveolar macrophages, namely low cell numbers and the prohibitive cost of bronchoscopy on human volunteers. Consistent with the behavior of alveolar macrophages, differentiated THP-1 cells underwent apoptosis in response to infection with attenuated or avirulent strains of mycobacteria in a tumor necrosis factor (TNF)-dependent manner. High levels of macrophage apoptosis correlated with decreased viability of the bacilli. Contrastingly, virulent strains of <italic> Mtb</italic> did not induce apoptosis over background levels. These results demonstrate that THP-1 cells faithfully model alveolar macrophage responses to <italic>Mtb</italic> infection.
520 $a Low-dose infection of THP-1 cells with avirulent <italic>Mtb</italic> activated caspases 8, 10, 9 and 3 while virulent mycobacteria failed to activate any of the caspases tested. This suggests a mycobacterial-induced blockade of apoptosis, both at the level of the TNF receptor (TNFR) and at the level of the mitochondria. Further experiments determined that virulent but not avirulent <italic>Mtb</italic> induced mRNA and protein expression of TNFR2, a subset of TNFRs linked to cell survival. This finding may explain the lack of early activation of receptor-associated caspases 8 and 10. Ribonuclease protection assays and western blots indicated an increase in Mcl-1 RNA and protein, a Bcl-2 family member that blocks mitochondrial apoptosis in THP-1 cells infected with virulent but not avirulent <italic>Mtb</italic>. Upregulation of this mediator may explain the blockade in activation of mitochondrial-associated caspase 9. Retroviral-induced overexpression of Mcl-1 in THP-1 cells rescued them from avirulent <italic>Mtb</italic>-induced apoptosis. Conversely, inhibiting expression of Mcl-1 by small inhibitory RNAs (siRNA) increased apoptosis in THP-1 cells infected with virulent <italic>Mtb</italic> strains. Taken together, these results suggest the virulent <italic>Mtb</italic> strains have evolved at least two mechanisms for evading host macrophage apoptosis: by upregulating surface TNFR2 and the mitochondrial protein Mcl-1.
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650 4 $a Health Sciences, Immunology. $3 1017716
650 4 $a Health Sciences, Pathology. $3 1017854
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