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J Bacteriol ; 180(6): 1533-9, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9515923


The (alpha1-->6)-linked N-acetyl-D-mannosamine-1-phosphate meningococcal capsule of serogroup A Neisseria meningitidis is biochemically distinct from the sialic acid-containing capsules produced by other disease-associated meningococcal serogroups (e.g., B, C, Y, and W-135). We defined the genetic cassette responsible for expression of the serogroup A capsule. The cassette comprised a 4,701-bp nucleotide sequence located between the outer membrane capsule transporter gene, ctrA, and galE, encoding the UDP-glucose-4-epimerase. Four open reading frames (ORFs) not found in the genomes of the other meningococcal serogroups were identified. The first serogroup A ORF was separated from ctrA by a 218-bp intergenic region. Reverse transcriptase (RT) PCR and primer extension studies of serogroup A mRNA showed that all four ORFs were cotranscribed in the opposite orientation to ctrA and that transcription of the ORFs was initiated from the intergenic region by a sigma-70-type promoter that overlapped the ctrA promoter. The first ORF exhibited 58% amino acid identity with the UDP-N-acetyl-D-glucosamine (UDP-GlcNAc) 2-epimerase of Escherichia coli, which is responsible for the conversion of UDP-GlcNAc into UDP-N-acetyl-D-mannosamine. Polar or nonpolar mutagenesis of each of the ORFs resulted in an abrogation of serogroup A capsule production as determined by colony immunoblots and enzyme-linked immunosorbent assay. Replacement of the serogroup A biosynthetic gene cassette with a serogroup B cassette by transformation resulted in capsule switching from a serogroup A capsule to a serogroup B capsule. These data indicate that assembly of the serogroup A capsule likely begins with monomeric UDP-GlcNAc and requires proteins encoded by three other genes found in the serogroup A N. meningitidis-specific operon located between ctrA and galE.

DNA-Binding Proteins , Escherichia coli Proteins , Hexosamines/biosynthesis , Hexosamines/genetics , Neisseria meningitidis/genetics , Neisseria meningitidis/metabolism , Transcription Factors , UDPglucose 4-Epimerase/genetics , Bacterial Capsules/biosynthesis , Bacterial Capsules/genetics , Bacterial Capsules/immunology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Base Sequence , Carbohydrate Epimerases/genetics , Carbohydrate Epimerases/metabolism , Chromosomes, Bacterial , Cloning, Molecular , DNA, Bacterial/analysis , DNA, Bacterial/genetics , Genes, Bacterial , Hexosamines/immunology , Immunoblotting , Molecular Sequence Data , Mutagenesis, Insertional , Neisseria meningitidis/immunology , Open Reading Frames , Operon , Plasmids , Polymerase Chain Reaction , Promoter Regions, Genetic , RNA, Messenger/analysis , RNA, Messenger/metabolism , Sequence Analysis, DNA , Transcription, Genetic , Transformation, Genetic , UDPglucose 4-Epimerase/metabolism , Uridine Diphosphate N-Acetylglucosamine/metabolism , Uridine Diphosphate Sugars/metabolism
Am J Med Sci ; 313(2): 80-4, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9030672


Abnormalities of thyroid function are associated with hyperlipidemia, a risk factor for coronary artery disease that starts in childhood. We investigated the age-, race-, and sex-related differences in thyroid function and its relation to serum lipoprotein levels in children (n = 363) aged 6 to 18 years from the biracial (black/white) community of Bogalusa, Louisiana, using an ultrasensitive thyroid-stimulating hormone (TSH) assay. Serum levels of lipoprotein cholesterol fractions, triglycerides, triiodothyronine (T3), thyroxine (T4), and the Tanner stage of sexual development were determined. Serum T3 (P < 0.0001), T4 (P < 0.0001), and TSH (P < 0.0020) levels decreased significantly with Tanner stage. Serum T4 levels were significantly higher (P < 0.0001) in both black and white females than their male counterparts. An unexpected finding was a significantly increased mean serum TSH in whites (2.09 + 0.91; mean + standard error of mean) when compared to blacks (1.74 + 0.10; P = 0.0185). Overall, no significant correlation was noted between serum lipoprotein variables and TSH. However, those with the highest low-density lipoprotein to very low-density lipoprotein cholesterol fractions had a higher T4 and a T4/TSH ratio than those with the lowest low-density lipoprotein to very low-density lipoprotein cholesterol fractions. In summary, it is concluded that there is no simple relationship between lipoproteins and TSH or thyroid hormone levels in children.

Lipoproteins/metabolism , Thyroid Gland/metabolism , Adolescent , Age Factors , Child , Cholesterol/blood , Female , Humans , Lipoproteins/blood , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Lipoproteins, VLDL/blood , Louisiana , Male , Sex Factors , Thyroid Function Tests , Thyrotropin/blood , Thyroxine/blood , Triglycerides/blood , Triiodothyronine/blood
Proc Natl Acad Sci U S A ; 94(1): 271-6, 1997 Jan 07.
Article in English | MEDLINE | ID: mdl-8990198


The different sialic acid (serogroups B, C, Y, and W-135) and nonsialic acid (serogroup A) capsular polysaccharides expressed by Neisseria meningitidis are major virulence factors and are used as epidemiologic markers and vaccine targets. However, the identification of meningococcal isolates with similar genetic markers but expressing different capsular polysaccharides suggests that meningococcal clones can switch the type of capsule they express. We identified, except for capsule, isogenic serogroups B [(alpha2-->8)-linked polysialic acid] and C [(alpha2-->9)-linked polysialic acid] meningococcal isolates from an outbreak of meningococcal disease in the U. S. Pacific Northwest. We used these isolates and prototype serogroup A, B, C, Y, and W-135 strains to define the capsular biosynthetic and transport operons of the major meningococcal serogroups and to show that switching from the B to C capsule in the outbreak strain was the result of allelic exchange of the polysialyltransferase. Capsule switching was probably the result of transformation and horizontal DNA exchange in vivo of a serogroup C capsule biosynthetic operon. These findings indicate that closely related virulent meningococcal clones may not be recognized by traditional serogroup-based surveillance and can escape vaccine-induced or natural protective immunity by capsule switching. Capsule switching may be an important virulence mechanism of meningococci and other encapsulated bacterial pathogens. As vaccine development progresses and broader immunization with capsular polysaccharide conjugate vaccines becomes a reality, the ability to switch capsular types may have important implications for the impact of these vaccines.

Bacterial Capsules/genetics , Neisseria meningitidis/genetics , Sialic Acids/biosynthesis , Sialyltransferases/genetics , Base Sequence , Biological Transport/genetics , Disease Outbreaks , Gene Conversion , Genes, Bacterial , Genes, Switch , Meningococcal Infections/microbiology , Molecular Epidemiology , Molecular Sequence Data , Neisseria meningitidis/classification , Northwestern United States , Operon , Serotyping , Transformation, Genetic