Mycobacterium microti may protect itself from intracellular destruction by releasing cyclic AMP into phagosomes

Lowrie, Douglas B.; Jackett, P. S.; Ratcliffe, Norman A.

doi:10.1038/254600a0

Cited by 107 publications

(75 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, in one novel role for cAMP in mycobacterial pathogenesis, Mycobacterium microti, a member of the M. tuberculosis complex, has been reported to secrete cAMP during infection of macrophages. It is postulated that secreted cAMP may prevent phagolysosome formation and thereby protect bacilli from host-mediated destruction (Lowrie et al, 1975(Lowrie et al, , 1979. Recently, it has been observed that exogenous cAMP induced the expression of several biologically significant genes in M. bovis BCG, thus implicating cAMPmediated regulation of gene expression as an important mechanism in the M. tuberculosis complex (Gazdik & McDonough, 2005).…”

Section: Discussionmentioning

confidence: 99%

Regulation of the expression of whiB1 in Mycobacterium tuberculosis: role of cAMP receptor protein

2006

View full text Add to dashboard Cite

The wbl (whiB-like) genes encode putative transcription factors unique to actinomycetes. This study characterized the promoter element of one of the seven wbl genes of Mycobacterium tuberculosis, whiB1 (Rv3219c). The results reveal that whiB1 is transcribed by a class I-type cAMP receptor protein (CRP)-dependent promoter, harbouring a CRP-binding site positioned at "58?5 with respect to its transcription start point. In vivo promoter activity analysis and electrophoretic mobility shift assays suggest that the expression of whiB1 is indeed regulated by cAMP-dependent binding of CRP M (encoded by the M. tuberculosis gene Rv3676) to the whiB1 59 untranslated region (59UTR). b-Galactosidase gene fusion analysis revealed induction of the whiB1 promoter in M. tuberculosis on addition of exogenous dibutyric cAMP (a diffusible cAMP analogue) only when an intact CRP-binding site was present. These results indicate that M. tuberculosis whiB1 transcription is regulated in part by cAMP levels via direct binding of cAMP-activated CRP M to a consensus CRP-binding site in the whiB1 59UTR. INTRODUCTIONMycobacterium tuberculosis, the aetiological agent of tuberculosis, accounts for nearly 2 million human deaths every year. Approximately one-third of the world's population is latently infected with M. tuberculosis, and 7 to 8 million new TB cases occur annually (Dye et al., 1999). M. tuberculosis can survive in diverse surroundings ranging from the human host to droplet nuclei in the atmosphere. Adaptation to such diverse conditions requires controlled regulation of the expression of key genes that allow the bacillus to alter its physiology in response to changes in environmental stimuli. Sequencing of the M. tuberculosis genome has revealed the presence of more than 100 regulatory proteins, 13 sigma factors and 11 two-component systems (Cole et al., 1998), which provide the bacterium with a high degree of adaptability.The Wbl (WhiB-like) family of proteins is present throughout the actinomycetes but absent from all other organisms evaluated so far (Molle et al., 2000;Soliveri et al., 2000). Due to the presence of a conserved helix-turn-helix motif, these proteins are believed to function as DNA-binding transcription regulators. The first of these proteins, WhiB, was identified in Streptomyces coelicolor, a Gram-positive sporulating bacterium closely related to M. tuberculosis. S. coelicolor whiB mutants produce abnormally long, tightly coiled aerial hyphae that are completely blocked in their ability to form sporulation septa (Chater, 1972;Davis & Chater, 1992;Flardh et al., 1999). Studies of whiB orthologues in mycobacteria have shown that the M. smegmatis whiB2 gene (also called whmD) is essential ; M. tuberculosis whiB3 plays a role in virulence and its gene product may interact with a sigma factor of RNA polymerase (Steyn et al., 2002); whiB7 of M. tuberculosis is involved in multi-drug resistance (Morris et al., 2005). Each of the Wbl family of proteins contains four invariant cysteine residues, which are believed to be inv...

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of the expression of whiB1 in Mycobacterium tuberculosis: role of cAMP receptor protein

2006

View full text Add to dashboard Cite

show abstract

“…Furthermore, bacterial toxins affecting small GTP-binding proteins via ADPribosylation or transfer of glucose from UDP-glucose have been identified in C. botulinum (57,58) and Clostridium difficile (59). Based on the local effects within MPC and the more generalized effects of M. bovis BCG preinfection on subsequently formed LBC, it is possible that some mycobacterial (51,52,60,61) or other putative activities directly or indirectly interfere with the regulation of membrane sorting processes.…”

Section: Discussionmentioning

confidence: 99%

Arrest of Mycobacterial Phagosome Maturation Is Caused by a Block in Vesicle Fusion between Stages Controlled by rab5 and rab7

Via

Deretic

Ulmer

et al. 1997

Journal of Biological Chemistry

503

439

View full text Add to dashboard Cite

Mycobacterium tuberculosis and the closely related organism Mycobacterium bovis can survive and replicate inside macrophages. Intracellular survival is at least in part attributed to the failure of mycobacterial phagosomes to undergo fusion with lysosomes. The transformation of phagosomes into phagolysosomes involves gradual acquisition of markers from the endosomal compartment. Members of the rab family of small GTPases which confer fusion competence in the endocytic pathway are exchanged sequentially onto the phagosomal membranes in the course of their maturation. To identify the step at which the fusion capability of phagosomes containing mycobacteria is compromised, we purified green fluorescent protein-labeled M. bovis BCG phagosomal compartments (MPC) and compared GTPbinding protein profiles of these vesicles with latex bead phagosomal compartments (LBC). We report that the MPC do not acquire rab7, specific for late endosomes, even 7 days postinfection, whereas this GTP-binding protein is present on the LBC within hours after phagocytosis. By contrast, rab5 is retained and enriched with time on the MPC, suggesting fusion competence with an early endosomal compartment. Prior infection of macrophages with M. bovis BCG also affected the dynamics of rab5 and rab7 acquisition by subsequently formed LBC. Selective exclusion of rab7, coupled with the retention of rab5 on the mycobacterial phagosome, may allow organisms from the M. tuberculosis complex to avert the usual physiological destination of phagocytosed material.

show abstract

“…the amount of cyclic AMP (Carrol et af., 1979) and the numbers of acid-fast bacteria (a.f.b.) per monolayer macrophage (Lowrie et al, 1975) were assessed. Monolayers were maintained in the absence of streptomycin.…”

Section: E T H O D Smentioning

confidence: 99%

“…In a preliminary report (Lowrie et a/., 1975), we showed that living M. microti caused an increase in cyclic adenosine 3' : 5'-monophosphate (cyclic AMP) in macrophages infected with this organism and that dead M . nzicroti, latex spheres or living M .…”

Section: Introductionmentioning

confidence: 99%

Phagosome-Lysosome Fusion and Cyclic Adenosine 3': 5'-Monophosphate in Macrophages Infected with Mycobacterium microti, Mycobacterium bovis BCG or Mycobacterium lepraemurium

Lowrie

Aber

Jackett

1979

Journal of General Microbiology

Self Cite

View full text Add to dashboard Cite

When ingested by mouse peritoneal macrophage monolayers, live Mycobacterium microti caused a sustained increase in monolayer cyclic AMP content and fusion of lysosomes with the bacterium-containing phagosomes was impaired. Ingested live M . bovis BCG caused a transient increase in cyclic AMP and the defect in phagolysosome formation was less pronounced. Dead mycobacteria and live M . lepraemurium neither enhanced monolayer cyclic AMP content nor inhibited phagolysosome formation, Mycobacterium microti and BCG exceeded M . lepraemurium in cyclic AMP-synthesizing activity in vitro but the question of whether bacterial cyclic AMP contributed substantially to the increments in infected macrophages was not resolved. Anti body-coated BCG retained the ability to synthesize cyclic AMP and to enhance monolayer cyclic AMP but lost the ability to inhibit phagolysosome formation in macrophages. The observations are discussed in terms of possible control of phagolysosome formation by cyclic nucleotides.

show abstract

Mycobacterium microti may protect itself from intracellular destruction by releasing cyclic AMP into phagosomes

Cited by 107 publications

References 13 publications

Regulation of the expression of whiB1 in Mycobacterium tuberculosis: role of cAMP receptor protein

Regulation of the expression of whiB1 in Mycobacterium tuberculosis: role of cAMP receptor protein

Arrest of Mycobacterial Phagosome Maturation Is Caused by a Block in Vesicle Fusion between Stages Controlled by rab5 and rab7

Phagosome-Lysosome Fusion and Cyclic Adenosine 3': 5'-Monophosphate in Macrophages Infected with Mycobacterium microti, Mycobacterium bovis BCG or Mycobacterium lepraemurium

Contact Info

Product

Resources

About