Abstract:
:Whole-genome sequencing analysis of ∼800 strains of group A Streptococcus (GAS) found that the gene encoding the multiple virulence gene regulator of GAS (mga) is highly polymorphic in serotype M59 strains but not in strains of other serotypes. To help understand the molecular mechanism of gene regulation by Mga and its contribution to GAS pathogenesis in serotype M59 GAS, we constructed an isogenic mga mutant strain. Transcriptome studies indicated a significant regulatory influence of Mga and altered metabolic capabilities conferred by Mga-regulated genes. We assessed the phosphorylation status of Mga in GAS cell lysates with Phos-tag gels. The results revealed that Mga is phosphorylated at histidines in vivo. Using phosphomimetic and nonphosphomimetic substitutions at conserved phosphoenolpyruvate:carbohydrate phosphotransferase regulation domain (PRD) histidines of Mga, we demonstrated that phosphorylation-mimicking aspartate replacements at H207 and H273 of PRD-1 and at H327 of PRD-2 are inhibitory to Mga-dependent gene expression. Conversely, non-phosphorylation-mimicking alanine substitutions at H273 and H327 relieved inhibition, and the mutant strains exhibited a wild-type phenotype. The opposing regulatory profiles observed for phosphorylation- and non-phosphorylation-mimicking substitutions at H273 extended to global gene regulation by Mga. Consistent with these observations, the H273D mutant strain attenuated GAS virulence, whereas the H273A strain exhibited a wild-type virulence phenotype in a mouse model of necrotizing fasciitis. Together, our results demonstrate phosphoregulation of Mga and its direct link to virulence in M59 GAS strains. These data also lay a foundation toward understanding how naturally occurring gain-of-function variations in mga, such as H201R, may confer an advantage to the pathogen and contribute to M59 GAS pathogenesis.
journal_name
Infect Immunjournal_title
Infection and immunityauthors
Sanson M,Makthal N,Gavagan M,Cantu C,Olsen RJ,Musser JM,Kumaraswami Mdoi
10.1128/IAI.03023-14subject
Has Abstractpub_date
2015-06-01 00:00:00pages
2382-95issue
6eissn
0019-9567issn
1098-5522pii
IAI.03023-14journal_volume
83pub_type
杂志文章abstract::Ureaplasma urealyticum has previously been isolated from the cultured cerebrospinal fluid of 13 of 418 newborn infants; additional bloodstream isolates were obtained from the same population. Ten of the 13 cerebrospinal fluid and 3 bloodstream isolates were available for serotyping in the present study. By the use of ...
journal_title:Infection and immunity
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doi:10.1128/IAI.60.8.3472-3474.1992
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journal_title:Infection and immunity
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doi:
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journal_title:Infection and immunity
pub_type: 杂志文章
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journal_title:Infection and immunity
pub_type: 杂志文章
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journal_title:Infection and immunity
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.2.5.686-688.1970
更新日期:1970-11-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
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更新日期:1996-08-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.60.3.768-772.1992
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journal_title:Infection and immunity
pub_type: 杂志文章
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更新日期:1992-07-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.59.8.2727-2736.1991
更新日期:1991-08-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章,评审
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更新日期:2012-02-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.56.10.2743-2748.1988
更新日期:1988-10-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.14.1.163-167.1976
更新日期:1976-07-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
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更新日期:2000-08-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.14.4.1106-1108.1976
更新日期:1976-10-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Infection and immunity
pub_type: 杂志文章
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更新日期:1989-08-01 00:00:00
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pub_type: 杂志文章
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journal_title:Infection and immunity
pub_type: 杂志文章
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更新日期:2015-08-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
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更新日期:1978-02-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.27.2.455-460.1980
更新日期:1980-02-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
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更新日期:1998-12-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
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更新日期:1988-04-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
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更新日期:1983-09-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.57.11.3445-3451.1989
更新日期:1989-11-01 00:00:00
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pub_type: 杂志文章
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更新日期:2000-03-01 00:00:00