Two putative glutamate decarboxylases of Streptococcus pneumoniae as possible antigens for the production of anti-GAD65 antibodies leading to type 1 diabetes mellitus

Abstract

Type 1 diabetes mellitus (T1DM) has been increasing in prevalence in the last decades and has become a global burden. Autoantibodies against human glutamate decarboxylase (GAD65) are among the first to be detected at the onset of T1DM. Diverse viruses have been proposed to be involved in the triggering of T1DM because of molecular mimicry, i.e., similarity between parts of some viral proteins and one or more epitopes of GAD65. However, the possibility that bacterial proteins might also be responsible for GAD65 mimicry has been seldom investigated. To date, many genomes of Streptococcus pneumoniae (the pneumococcus), a prominent human pathogen particularly prevalent among children and the elderly, have been sequenced. A dataset of more than 9000 pneumococcal genomes was mined and two different (albeit related) genes (gadA and gadB), presumably encoding two glutamate decarboxylases similar to GAD65, were found. The various gadA_Spn alleles were present only in serotype 3 pneumococci belonging to the global lineage GPSC83, although some homologs have also been discovered in two subspecies of Streptococcus constellatus (pharyngis and viborgensis), an isolate of the group B streptococci, and several strains of Lactobacillus delbrueckii. Besides, gadB_Spn alleles are present in > 10% of the isolates in our dataset and represent 16 GPSCs with 123 sequence types and 20 different serotypes. Sequence analyses indicated that gadA- and gadB-like genes have been mobilized among different bacteria either by prophage(s) or by integrative and conjugative element(s), respectively. Substantial similarities appear to exist between the putative pneumococcal glutamate decarboxylases and well-known epitopes of GAD65. In this sense, the use of broader pneumococcal conjugate vaccines such as PCV20 would prevent the majority of serotypes expressing those genes that might potentially contribute to T1DM. These results deserve upcoming studies on the possible involvement of S. pneumoniae in the etiopathogenesis and clinical onset of T1DM.

Keywords: Glutamate decarboxylases; Streptococcus pneumoniae; Type 1 diabetes mellitus.

Fig. 1

Schematic representation of the chromosomal region surrounding a gadA-like gene in several bacterial species. Genes are shown with arrows pointing in the direction of transcription. Homologous genes are represented by identical color and/or shading. Red arrows correspond to the gadA-like genes. Dark and light blue arrows represent genes putatively coding for a transporter of the major facilitator superfamily (MFS) and a transcriptional regulator of the Rgg/GadR/MutR family, respectively. Yellow arrows correspond to genes putatively encoding a nonribosomal peptide synthase. Thin arrows represent interrupted genes (pseudogenes). Insertion sequences are shown as black arrows. Open arrows represent genes that are irrelevant in this study. The corresponding genomic regions of S. pneumoniae D39 and SA_GPS_SP505_sc_1895675 (GPSC21 ST10619 serotype 19F; NZ_LR216035) are shown for comparison

Fig. 2

Mol % G + C content of genes included in the DNA region encompassing gadA-like genes. The G + C content of each chromosome is indicated by a red line and at the right of the figure. Panels A to E correspond respectively to S. pneumoniae D39, S. pneumoniae A66, S. agalactiae NNA022, L. delbrueckii subsp. lactis DSM 20072 ^T, and L. delbrueckii subsp. lactis KCCM 34717. The color code of genes is the same as in Fig. 1. The mol % G + C content was calculated for each gene

Fig. 3

Diagram showing the gene organization around the gadB gene in selected S. pneumoniae strains. A Gene content of the variable region located between SPD_RS11335 and SPD_RS05125 of strain D39 in other pneumococcal genomes. B The same region as that showed in panel A but in strains harboring a gadB_Spn gene (indicated by a red arrow). The cluster of seven genes that are conserved in all of the pneumococcal genomes studied is highlighted in an orange rectangle. The nucleotide sequence of the genome of the GPSC9 strain (CAAYNA010000008) at this region (between positions 28,233 and 93,432) is > 99% identical to that shown for strain FDAARGOS_1508 (GPSC8) (1,869,701–1,935,072). C The corresponding region in the genome of a S. suis isolate. In panels B and C, the gene organization of S. pneumoniae 70585 (NC_012468) and S. suis NCTC 10234 ^T (NZ_LS483418.1), respectively, is also shown for comparison