Proteomics of Toxigenic Corynebacteria

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This entry is adapted from the peer-reviewed paper 10.3390/proteomes12010002

Within the genus Corynebacterium, six species are potential carriers of the tox gene, which encodes the highly potent diphtheria exotoxin: Corynebacterium diphtheriae, Corynebacterium belfantii, Corynebacterium rouxii, Corynebacterium ulcerans, Corynebacterium pseudotuberculosis and Corynebacterium silvaticum. Based on their potential to infect different host species and cause either human infections, zoonotic diseases or infections of economically important animals, these bacteria are of high scientific and economic interest and different research groups have carried out proteome analyses. These showed that especially the combination of MS-based proteomics with bioinformatic tools helped significantly to elucidate the functional aspects of corynebacterial genomes and to handle the genome and proteome complexity.

caseous lymphadenitis Corynebacterium diphtheria exoproteome proteome complexity reverse vaccinology ulcerative lymphangitis zoonosis

1. Relevance and Properties of Toxigenic Corynebacteria

Corynebacteria belong to the phylum Actinobacteria, Gram-positive bacteria with a high G+C DNA content ^[1]. Within this phylum, they form the CMNR group together with the genera Mycobacterium, Nocardia and Rhodococcus based on a complex mycolic acids-containing cell wall structure, which is distinctive of these four genera ^[2]. To date, 158 taxonomically valid Corynebacterium species are described ^[3]. More than half of these were isolated from human and animal material, indicating the considerable medical and veterinary importance of the genus ^[3]. This is especially true for the group of toxigenic corynebacteria initially formed by Corynebacterium diphtheriae, Corynebacterium ulcerans and Corynebacterium pseudotuberculosis ^[4]. These species can be lysogenized by tox gene-encoding corynebacteriophages and subsequently express and secrete the potent diphtheria exotoxin ^[5]. The recently described new species Corynebacterium belfantii, Corynebacterium rouxii and Corynebacterium silvaticum are also potential carriers of the diphtheria toxin-encoding tox gene and may therefore be included in this group ^[6]^[7].

1.1. Corynebacterium diphtheriae

C. diphtheriae is the etiological agent of diphtheria, a putatively fatal infection of the upper respiratory tract characterized by sore throat, fever and pseudomembrane formation ^[8]. In addition to respiratory diphtheria, C. diphtheriae can cause skin lesions and systemic infections such as arthritis, bacteremia and endocarditis. While the diphtheria toxin is responsible for the often fatal outcome of the infection, additional virulence factors influence adhesion and invasion as well as the survival of the bacteria in macrophages ^[9].

Almost twenty years ago, Hansmeier and co-workers ^[10] started a proteomic approach to identifying the secreted proteins of C. diphtheriae based on the idea that these are especially important for pathogen–host interaction. Using protein separation via two-dimensional gel electrophoresis to separate the proteins by means of the isoelectric point and apparent molecular mass, tryptic digestion of excised spots and peptide mass fingerprint analysis, 85 different secreted proteins were identified in the extracellular and cell surface proteome fraction, including different putative virulence factors. Partially based on the work, these proteins were further characterized in independent studies, e.g., the neuraminidase/exo-alpha sialidase NanH ^[11], the invasion-associated protein DIP1281 ^[12]^[13] or the fimbrial protein-associated sortase SrtC ^[14].

To characterize the function of such virulence factors, often host–pathogen interaction studies using murine or human cell lines are carried out. For this kind of experiment, infection has to be carried out in cell culture media. To address the question of the putative influence of the cell culture media and their respective components, the C. diphtheriae strain ISS3319 was cultivated in a standard bacteriology medium, cell culture medium and fetal calf serum. The proteins were alkylated, digested and purified using C18 stage tips. Subsequent mass spectrometric analyses in combination with label-free protein quantification using the total protein approach (TPA) method ^[15] indicated the influence of the growth medium on the cell envelope and an increase in pathogenicity when bacteria were grown in the cell culture medium ^[15]. Pathogenicity-connected proteins, such as the multifunctional protein DIP0733, the conserved hypothetical protein DIP1546 and the resuscitation promoting factor RpfB (DIP0874), were induced in cell culture medium or serum even without host cell contact. Furthermore, the cell culture conditions led to the preadaptation of C. diphtheriae to host cell contact via the induction of iron starvation, cell envelope changes as well as oxidative and nitrosative stress response mechanisms ^[15].

Other proteome studies led to the identification of regulatory proteins, which are possibly involved in the coordination and control of NO stress in C. diphtheriae, i.e., DtxR and DIP1512 ^[16], and defined the role of S-mycothiolation in redox control under oxidative stress ^[17]. Using shotgun-proteomics, 26 S-mycothiolated proteins of the C. diphtheriae strain DSM43989 were identified in response to hypochlorite treatment. Post-translational thiol-modifications were identified by searching all the MS/MS spectra against the C. diphtheriae target–decoy protein sequence database using the Sorcerer-SEQUEST program package ^[17].

In contrast to the described in vitro studies, which focused on single strains, a number of in silico proteome studies were carried out, which are especially suited to address the proteome complexity of C. diphtheriae. In this organism, a restricted number of core genes are accompanied by strain-specific accessory genes often acquired via horizontal gene transfer. Already a first pangenome study with 13 isolates of this pathogen showed a number of gain and loss of function processes, and the authors concluded that these genome variations may reflect a strategy of C. diphtheriae to establish different host–pathogen interactions such as respiratory or systemic infections ^[18].

In addition to the described characterization of virulence factors, signaling pathways and genome variability, proteomics approaches were applied to discover new treatment and prevention methods. In silico approaches focused on strategies to identify essential proteins as targets to develop new preventive vaccines or drug targets. Already in 2008, Dass and Deepika showed that the scanning of immunologically relevant regions of bacterial protein sequences, i.e., membrane and membrane-associated proteins, is suitable for the identification of specific HLA-binding peptides for the design of putative vaccine candidates ^[19].

1.2. Corynebacterium belfantii and Corynebacterium rouxii

Recently, a number of former C. diphtheriae strains of biovar Belfanti were taxonomically newly described as separate species, Corynebacterium belfantii ^[20] and Corynebacterium rouxii ^[21]^[22]. While partially included in the former in silico studies of C. diphtheriae mentioned above, no separate proteome studies were carried out for these new species to date, while limited information is available for mass spectrometry-based identification.

1.3. Corynebacterium ulcerans

C. ulcerans was first isolated almost one hundred years ago from a case of a diphtheria-like respiratory infection ^[23], but it can also cause skin and systemic infections in humans. The bacteria colonize a wide variety of different domestic and wild animals, either as commensals or as pathogens (for a review, see ^[24]). For a long time, human infections were rare and mainly restricted to populations in direct contact with domestic livestock and to consumers of raw milk and unpasteurized dairy products as C. ulcerans is an etiological agent of mastitis in dairy cattle ^[25]^[26].

The virulence factors of this pathogen were not well-investigated and as a basis for pathogen–host interaction studies, surface-located proteins and the exoproteome of C. ulcerans strain 809, isolated from a fatal case of human respiratory tract infection, and BR-AD22, isolated from a nasal swap of an asymptomatic dog, were analyzed ^[27]^[28]. Cell surface proteins were isolated via tryptic shaving and proteins secreted into the medium were precipitated using trichloric acid ^[28]. After mass spectrometric analysis via nanoLC-MS/MS, an almost identical collection of virulence factors was detected in the culture supernatant and surface protein fractions of the two strains despite their isolation from different host organisms (human versus dog) and the different symptoms caused (fatal versus asymptomatic infection).

Unexpectedly, the study indicated that the canine isolate BR-AD22 is significantly less stable and less stress-resistant than the human isolate 809. During exponential growth, 38% of the predicted proteins encoded by the BR-AD22 genome were found, while only 17% of the proteins encoded in the genome sequence of strain 809 were detectable in the medium. The fact that a considerably high number of intracellular proteins are found at all is a rather rare observation in proteome studies of Corynebacterium species, since corynebacteria are typically very robust due to their complex cell wall structure ^[2]^[29]^[30] and significantly less proteins were found in the supernatant of other pathogenic corynebacteria in previous studies ^[10]^[31]^[32]^[33]^[34]^[35]^[36].

1.4. Corynebacterium silvaticum

C. silvaticum is a new species comprising bacteria formerly described as untypical C. ulcerans strains isolated from roe deer and wild boars in Germany and Austria ^[37]. Later, a broader distribution of the species with strains isolated in Portugal was reported ^[38]. A phylogenetic analysis showed that the species has diverged into two clades. Clade 1 is formed by toxigenic strains. In contrast, clade 2 contains non-toxigenic toxin gene-bearing (NTTB) strains, which cannot produce diphtheria toxin due to a frame shift in the tox gene or its promoter region ^[39].

While in principle less detrimental, even the NTTB strain W25 was cytotoxic to human epithelial cells and in the invertebrate model systems Caenorhabditis elegans and Galleria mellonella ^[40]. In the frame of a first proteome study of this species, the whole cell and cell surface fraction as well as the exoproteome of strain W25 were analyzed ^[41]. A total number of 1305 different proteins were detected, comprising 64.8% of the theoretical proteome of strain W25, when cells were grown in standard bacteriology medium. From the set of 15 virulence factors defined ^[42], 12 were identified in this study, namely phospholipase D, sialidase, a peptidoglycan endopeptidase, a cell wall peptidase, venom serin protease 2, a type VII secretion-associated serine protease, three proteins related to mycolic acid synthesis, a hydrolase and two resuscitation-promoting factors.

1.5. Corynebacterium pseudotuberculosis

Based on the highly effective mass vaccination strategy of the World Health Organization established in the 1970s, infections by C. diphtheriae became rare, although even today outbreaks are still reported, with a focus on countries with poor access to public health systems, e.g., Ethiopia, India, Indonesia, Madagascar, Nepal, Pakistan, Venezuela and Yemen ^[43].

The species is divided into two biovars based on the biochemical properties, infected host animals and evoked diseases. Biovar ovis is the causative agent of caseous lymphadenitis (CLA), a chronic contagious disease characterized by abscess formation in superficial lymph nodes and in subcutaneous tissues in small ruminants, especially sheep and goats. In addition, it can cause mastitis in dairy cattle ^[44]^[45]. Biovar equi is responsible for abscess formation as well as ulcerative lymphangitis in equines and edematous skin disease in buffalos ^[46]. Due to the negative economic impact of C. pseudotuberculosis infections, e.g., impaired wool, meat, milk and leather production, and the lack of efficient drugs, it is not astonishing that a considerably high number of proteomic studies was carried out for this zoonotic species.

As in the case of C. diphtheriae, C. ulcerans and C. silvaticum, a number of early studies focused on the protein inventory of C. pseudotuberculosis. Especially the exoproteome was analyzed based on the idea that this comprises the first pathogen proteins in contact with the host. A comparison was performed of the exoproteomes of different C. pseudotuberculosis strains isolated from goat and sheep.

Changes in protein abundance were also observed in bacterial isolates from a natural host ^[47], and a shift in the virulence potential of C. pseudotuberculosis biovar ovis after passage in a murine host model was observed ^[48]^[49]. Comparative proteome analyses of the laboratory reference strain Cptb_C231 and three field strains isolated from the lymph nodes of infected sheep were carried out and a total of 1358 proteins were identified, leading to a proteome coverage of approximately 65%. While the majority of proteins had a similar abundance, some of the identified proteins showed differences in the field isolates compared to the laboratory strain. The field isolates were characterized via the induction of proteins related to hypoxia, starvation and thiopeptide biosynthesis ^[47].

Label-free proteome analyses of culture supernatants were carried for C. pseudotuberculosis 1002_ovis grown under standard laboratory conditions and after the re-isolation of bacteria from the spleen of infected mice. In comparison, 118 proteins were found to be differentially expressed. The major virulence factors of C. pseudotuberculosis, i.e., the CP40 protease and phospholipase D, were exclusively found after murine passage, in addition to other proteins involved in the detoxification, pathogenesis and protein secretion pathways ^[48].

When C. pseudotuberculosis was grown in bovine fetal serum, analysis of the membrane-associated proteome via LC-MS/MS revealed 22 proteins with pathogenic potential differentially expressed by C. pseudotuberculosis. Based on the results obtained, it was assumed that pathogenesis may be connected to iron and oligopeptide uptake, protein secretion, bacterial resistance and adhesion ^[50].

Besides the adaptation of metabolic and stress-related pathways to the host environment, biofilm formation is an important pathogenicity mechanism and some strains of C. pseudotuberculosis are forming biofilms already under laboratory conditions. In a comparative proteomic analysis of a biofilm-forming and a non-forming strain, cell wall synthesis and exopolysaccharide biosynthesis proteins were identified, which were either exclusively synthesized or upregulated in biofilm-forming C. pseudotuberculosis isolated from goats ^[51]. Biofilm-forming C. pseudotuberculosis CAPJ4 differentially expressed a penicillin-binding protein, which participates in the formation of peptidoglycans, and showed an increased expression of N-acetylmuramoyl-L-alanine amidase and galactose-1-phosphate uridylyltransferase, which are crucial for exopolysaccharide biosynthesis for biofilm formation ^[51].

While the approaches described above are of more general importance, a number of studies, especially from Brazilian research groups, were focusing on an integrative approach in order to discover putative targets for diagnosis and therapy, starting already with the availability of the first genome sequences. Advances in DNA sequencing techniques, analysis of C. pseudotuberculosis genome organization and software packages to analyze, e.g., pathogenicity islands or integrate RNA sequencing and proteome data were discussed ^[52].

In a complementary approach, immune-reactive exoproteins of two C. pseudotuberculosis strains were studied in a serological proteome analysis using blood sera from goats and sheep. With 13 immuno-reactive proteins identified from both strains, also this proteomic approach revealed putative targets for vaccine development ^[53]. Six of the identified proteins from the core immune-proteome were of unknown functions, surface layer protein A, cell-surface hemin receptor HtaA and two trehalose corynomycolyl transferases were related to cell envelope functions and resuscitation-promoting factor plays a role in the stress response and virulence.

2. Proteomics as a Diagnostic Tool

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been used as a fast and precise tool for the identification of bacteria, including corynebacteria. With this approach, mass spectra of tested organisms are compared to reference spectra in the databases to find the closest match. Before the introduction of proteomics, detection methods for the diagnosis of diphtheria and identification of potentially toxigenic corynebacteria were traditionally relying on a combination of basic species identification, biochemical differentiation approaches and molecular differentiation methods ^[54]^[55]. The criteria monitored included growth on selective media, colony color and form, hemolytic properties and a set of biochemical reactions (API Coryne) combined with fatty acid profile analysis and 16SrDNA sequencing as the gold standard. In addition, the expression of the diphtheria toxin was validated via real-time tox PCR and the Elek test ^[54]^[55]. In contrast to these time-consuming methods, an identification result from a single bacterial colony can be obtained via MALDI-TOF MS in less than 15 min. This is an immense advantage of proteomics, since especially in the case of potentially toxigenic Corynebacterium species, a rapid identification is crucial for appropriate antitoxin and antibiotic treatment. Already in 2010, a collection of 116 Corynebacterium strains from 18 species were examined via MALDI-TOF MS. All 90 potentially toxigenic C. diphtheriae, C. ulcerans and C. pseudotuberculosis strains were correctly identified by means of MALDI-TOF MS ^[56]. With improved databases, MALDI-TOF MS analysis showed superior performance compared to the identification of corynebacteria and is the backbone of laboratory diagnosis now ^[55].

3. Conclusions

Proteome studies of toxigenic corynebacteria show impressively that functional genomics studies are crucial to complement genome information. Especially the combination of MS-based proteomics with bioinformatic tools helped significantly to elucidate the functional aspects of corynebacterial genomes and to handle the genome and proteome complexity. The combination of proteomic and bioinformatic approaches has been a highly fruitful strategy to study proteome responses to environmental changes or host cell contact, and based on the technical advances in mass spectrometry, more complex samples from naturally infected host tissue material may be analyzed via proteomics, leading to a deeper understanding of the infection process. In addition, proteome studies have been used to discover new vaccine and drug targets, as especially exemplified for C. diphtheriae and C. pseudotuberculosis ^[42]^[57]^[58]^[59]^[60]^[61].

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