- Open Access
Whole-genome sequencing and characterization of an antibiotic resistant Neisseria meningitidis B isolate from a military unit in Vietnam
© The Author(s) 2019
- Received: 26 November 2018
- Accepted: 27 April 2019
- Published: 6 May 2019
Invasive meningococcal disease (IMD) persists in military units in Vietnam despite the availability of antibiotics and vaccines. A hindrance to reducing the incidence of IMD in Vietnam is a lack of molecular data from isolates of the causative agent, Neisseria meningitidis from this country. Here, we characterized key genetic and epidemiological features of an invasive N. meningitidis isolate from a military unit in Vietnam using whole-genome sequencing.
Neisseria meningitidis was isolated from a conscript admitted for meningitis and tested against seven antibiotics. DNA from the isolate was extracted and sequenced using the Illumina HiSeq platform. Denovo assembly and scaffolding were performed to construct a draft genome assembly, from which genes were predicted and functionally annotated. Genome analysis included epidemiological characterization, genomic composition and identification of antibiotic resistance genes.
Susceptibility testing of the isolate showed high levels of resistance to chloramphenicol and diminished susceptibility to ampicillin and rifampicin. A draft genome of ~ 2.1 Mb was assembled, containing 2451 protein coding sequences, 49 tRNAs and 3 rRNAs. Fifteen coding sequences sharing ≥ 84% identity with known antibiotic resistance genes were identified. Genome analysis revealed abundant repetitive DNAs and two prophages. Epidemiological typing revealed newly described sequence type, antigenic finetype and Bexsero® Antigen Sequence Typing (BAST). The BAST profile showed no coverage by either Bexsero® or Trumenba®.
Our results present the first genome assembly of an invasive N. meningitidis isolate from a military unit in Vietnam. This study illustrates the usefulness of whole genome sequencing (WGS) analysis for epidemiological and antibiotic resistance studies and surveillance of IMD in Vietnam.
- Neisseria meningitidis
- Next generation sequencing
- Epidemiological characterization
- Antibiotic resistance
- Antigen sequence typing
Invasive meningococcal disease (IMD) was first reported in the early 1800s as an emerging infectious disease . IMD starts without clear symptoms but progresses rapidly into meningitis with, at times, septic shock that can be fatal . Caused by the meningococcus bacterium, Neisseria meningitidis, IMD can generally be effectively prevented by vaccination and, given timely diagnosis, treated by appropriate antibiotics . However, due to the lack of molecular characterization and proper epidemiological surveillance, fatality rates and disease sequelae can be high and severe [4, 5]. Neisseria meningitidis asymptomatically colonizes the nasopharyngeal mucosa of about 10% of the human population , but this rate drastically increases in certain living environments such as college dormitories or military units [7, 8]. IMD is relatively frequent in military units Vietnam, where prophylaxis and case treatment is based mainly on the experience of on-site medical personnel, mostly without the aid of molecular characterization and diagnosis. The drug of choice for treatment of IMD used to be penicillin and chloramphenicol , however due to resistance to these and some other antibiotics , third-generation cephalosporins, such as ceftriaxone and cefotaxime, are now the most common choice of treatment. These drugs, however, are often not readily available in many medical units in Vietnam.
Immunologically, N. meningitidis is divided into 12 serogroups, with most invasive strains belonging to serogroup A, B, C, W, X and Y. Strains can be further divided into serotypes and serosubtypes based on their outer-membrane antigens PorB and PorA, respectively . A multi-locus sequence typing (MLST) scheme was first suggested by Maiden and colleagues in 1998  utilizing seven house-keeping genes abcZ, adk, aroE, fumC, gdh, pdhC and pgm is now widely used to classify N. meningitidis isolates into sequence types (STs). Closely related STs can then be clustered together into groups and clonal complexes (CCs), with hypervirulent isolates often falling into several distinct CCs . PubMLST is currently the biggest public database that catalogs genetic data and isolate provenance of the Neisseria genus .
Sanger sequencing provided the means for obtaining the initial genome sequence for a strain of Neisseria meningitidis . However, it wasn’t until next-generation sequencing technologies were developed and evolved to allow far more rapid and inexpensive genomic studies, including those focused on N. meningitidis, that a fundamental understanding of the nature of metabolism, gene expression, and genetic variability within and between species could be obtained . Recently, the number of available N. meningitidis genome sequences was reported to be 13 985 and still growing steadily . Genomic studies of N. meningitidis have revealed important mechanisms underlying metabolic pathways , outbreak detection  and disease surveillance .
In this study, we used whole-genome sequencing (WGS) to assemble the genome of an invasive N. meningitidis isolate from a conscript in a military unit in Vietnam. Sequences obtained from WGS were annotated to determine the genetic and epidemiological characteristics of this Vietnamese isolate, together with an investigation of antibiotic resistance and vaccine coverage. This type of molecular characterization is needed for accurate IMD monitoring and surveillance and effective vaccination and for developing recommendations not only for military units but also other environments and communities in Vietnam.
Bacterial isolation and typing
An invasive N. meningitidis strain was isolated at the Laboratory of Microbiology, Military Institute of Preventive Medicine, Hanoi from cerebrospinal fluid (CSF) of a conscript presenting to Military Hospital 108 with sepsis and meningitis symptoms in 2014. In total, 2 ml of cerebrospinal fluid was collected from the patient before administration of ceftriaxone, maintained at 35 °C and transferred to the laboratory within one hour. Sample was centrifuged at 5000 rpm for 10 min and sediment was spread on Mueller Hinton (MH) chocolate agar (Difco, USA). Gray colonies were observed after 24 h of incubation at 37 °C supplemented with 5% CO2. Two to three colonies were selected for Gram staining along with strain identification using Vitek® 2 Compact system (bioMerieux, France) as per manufacturer’s instructions. Identified isolates were maintained on MH chocolate agar for immediate testing or stored at − 70 °C.
Serogroup typing and multi-locus sequence typing (MLST) was done according to previously described standard methods from the CDC laboratory manual for the diagnosis of meningitis .
Antibiotic susceptibility assay
To determine antibiotic susceptibility, isolate stored at − 70 °C were transferred to MH chocolate agar and recovered at 37 °C and 5% CO2 for 24 h. A total of seven antibiotics were tested, consisting of ampicillin, ciprofloxacin, cefotaxime, ceftriaxone, rifampicin, meropenem and chloramphenicol. MIC values were determined using E-test strip (bioMerieux, France) following manufacturer’s guideline and susceptibility was interpreted according to CLSI 2018 breakpoints .
Genomic DNA extraction and sequencing
Genomic DNA from the N. meningitidis DuyDNT strain was extracted using GeneJET Genomic DNA Purification Kit (Thermofisher Scientific) in accordance with the manufacturer’s instruction. The quality of DNA was assessed using an Agilent Technologies 2100 Bioanalyzer and sequenced using the Illumina HiSeq 4000 system (Macrogen). Raw images for system control were generated by HCS (HiSeq Control Software v3.3) and bases were called by RTA software (Real Time Analysis. v2.7.3). The BCL (base calls) binary was converted into FASTQ utilizing Illumina package bcl2fastq (v126.96.36.199).
Genome assembly and annotation
Raw reads was preprocessed to remove adapters and low quality reads using Trimmomatic (parameters: ILLUMINACLIP:2:30:10 LEADING:3 TRAILING:3 SLIDINGWINDOW:10:30 MINLEN:100) . FASTQC was then used to determine sequence quality before and after preprocessing . Reads passed filtering were used for a de novo assembly using Velvet and VelvetOptimiser [24, 25], with contigs shorter than 500 bp being discarded. To assess the completeness of the genome, Benchmarking Universal Single-Copy Orthologs v.3.0.2 (BUSCO) was used  and scaffolds were roughly ordered and oriented using MeDuSa with genomic sequence of N. meningitidis MC58 strain served as the reference genome . The resulting scaffolds were submitted to PATRIC web server  for protein prediction and annotation.
Genomic DNA sequence were submitted to PubMLST for identification of sequence type, antigenic finetype and Bexsero Antigen Sequence Typing following the database’s criteria. Complete genome sequences of N. meningitidis MC58, N. lactamica Y92–1009 and N. gonorrhoeae NCCP11945 were retrieved from the NCBI public database. Tandem Repeats Finder  was used to identify total number of repetitive DNA motifs in the genome. Frequency of specific repetitive motifs were analyzed by fuzznuc package of EMBOSS server.
Annotated amino acid sequences from DuyDNT genome were submitted to ResFinder 3.0 (https://cge.cbs.dtu.dk/services/ResFinder/), CARD (https://card.mcmaster.ca/analyze/rgi), and ARDB (https://ardb.cbcb.umd.edu/) to detect coding sequences involved in antibiotic resistance. PSI-BLAST were then used to find homologues to each identified coding sequence.
Case description and isolate characterization
A 21-year old male conscript presented to his unit’s medical center with headache, tiredness and fever at midnight in June, 2014. One hundred and fifty minutes later, he developed meningitis symptoms including nausea, drowsiness, confusion, stiff neck and Kernig sign. He was given 1000 mg of Amoxicillin, 1000 mg of Paracetamol and an IV dose of Ringer’s lactate solution. By 9:30 A.M., he was transferred to the emergency department of Military Hospital 108 showing symptoms of blood sepsis. He was diagnosed with meningitis and sepsis, and was treated with ceftriaxone at the dose of 1 g, four times a day. His cerebrospinal fluid was collected and a N. meningitidis culture was grown in 12 h. The obtained N. meningitidis isolate, designated DuyDNT, was typed and identified to belong to serogroup B. The patient recovered successfully after treatment.
Epidemiological characterization of DuyDNT isolate and other related isolates worldwide
Antibiotic susceptibility testing
Antibiotic susceptibility result of N. meningitidis isolate from Vietnam
MIC breakpoints (μg/ ml)a
MIC value (μg/ ml)
Resulting MICs showed that the DuyDNT isolate was still susceptible to most broad-range antibiotics, such as ciprofloxacin, cefotaxime, ceftriaxone and meropenem. In contrast, diminished susceptibility was observed toward ampicillin and rifampicin. This might be due to the fact that ampicillin and rifampicin are available in almost all military units and widely used for treatment and prevention of all nasal and upper respiratory tract infections, while there are not enough stocks of ciprofloxacin, cefotaxime, ceftriaxone and meropenem in many units. In fact, ampicillin, or its alternative amoxicillin, is still recommended by the Military Medicine, Ministry of National Defense of Vietnam in an internal descriptive document released in 2008 as an accepted therapy for treatment and prevention of bacterial meningitis in military units at the dose of 1000 mg twice daily in five consecutive days when there is no immediately available stock of other recommended antibiotics.
Complete resistance was observed against chloramphenicol, notably to an extremely high MICs of 256. To our knowledge, MIC value at 256 μg/ml against chloramphenicol observed in DuyDNT isolate is the highest to date, about 33% higher than the highest MIC recorded before .
Sequencing, assembly and annotation
Identification of antibiotic resistance genes
Resistance-associated genes identified in N. meningitidis DuyDNT isolate
Besides these, variants with 84–100% identity to known mutations conferring resistance against other antibiotics such as elfamycin, erythromycin, fluoroquinolone, isoniazid, tetracycline or multi-drug target were identified from DuyDNT genome. All identified resistance genes have been previously reported in N. meningitidis and N. gonorrhoeae, however the variants of ngo1259 and mtrD found in DuyDNT genome were observed for the first time. The presence of such wide repertoire of sequences involved in antibiotic resistance in DuyDNT genome is likely the result of both the high transformable nature of meningococcal B and excessive use of antibiotics in Vietnam. Sequence of the identified variants might contribute important information to deduce antibiotic resistance mechanisms in N. meningitidis.
Epidemiological characterization of DuyDNT isolate
Additional antigenic typing of DuyDNT isolate were done using sequences extracted from WGS data. Antigenic determinants’ fine structure of was analyzed using PubMLST finetyping antigens scheme that included two variable regions of gene proA (VR1 and VR2) and another one of gene FetA (VR). The resulting profile for DuyDNT isolate was VR1: 22–25, VR2: 14–32, VR: F4-6 (Table 1), which was a novel sequence type that varied from other isolates in the database by at least two out of three tested alleles.
We then performed Bexsero Antigen Sequence Typing (BAST) to estimate the likelihood of DuyDNT isolate to be covered by the two recently developed vaccines against N. meningitidis B, Bexsero® and Trumenba® [39, 40]. Notably, all allelic variants found in DuyDNT’s BAST profile (fHBP: 31, NHBA: 16, NadA: 0, PorA VR1: 22–25, PorA VR2: 14–32) were predicted to have no reactivity with either Bexsero® or Trumenba®, suggesting the potential for no protectiveness of these vaccines against this isolate. Taken together, epidemiological characteristics inferred from genomic sequence of DuyDNT isolate showed significant distinctiveness from other global N. meningitidis strains. These results highlight the need for an update epidemiological surveillance of IMD to effectively support vaccination strategy in Vietnam.
Features of DuyDNT isolate’s genome
Repetitive DNA sequences are important features of N. meningitidis genomes. They result in genome modification and are involved in gene expression regulation, thus playing important roles in N. meningitidis virulence and host immune invasion [41, 42]. The top three most abundant repetitive DNA motifs of the Neisseria genus known to date are DNA uptake sequence (DUS), DSR3 elements and Correia (CE) elements . DUS is essential for DNA transformation, while DSR3 and CE are often found at phage integration sites and promoter sequences, respectively [41, 43–46].
Frequency of prominent repetitive DNA sequences in DuyDNT genome
N. meningitidis DuyDNT
N. meningitidis MC58
N. lactamica Y92–1009
N. gonorrhoeae NCCP11945
Prophage regions in genomes of DuyDNT and MC58
Region length (kb)
Closest known phage
Region length (kb)
Closest known phage
A Blast search revealed that two prophages PHAGE_Pseudo_YMC11/02/R656_NC_028657 and PHAGE_Burkho_BcepIL02_NC_012743 were commonly found in genomic sequences of meningococcus but no other species of Neisseria. Contrary, PHAGE_Haemop_SuMu_NC_019455 was found most prominently in N. meningitidis, but also in N. gonorrhoeae, N. polysaccharea and N. lactamica. Taken together, both repetitive DNA and prophage features highlighted the genome flexibility shared among N. meningitidis serotype B, while also emphasizing potential for genome modifications and expression modification observed only in the tested Vietnamese isolate.
In this study, we have described and analyzed for the first time the genome of a drug-resistant invasive N. meningitidis B isolate from a military unit in Vietnam. This isolate, designated DuyDNT, showed the highest MIC (256 μg/ml) against chloramphenicol known to date, while also displaying diminished susceptibility toward ampicillin and rifampicin, the latter is still widely used for prophylaxis in numerous clinical units in Vietnam. Multi-locus sequence typing for the isolate revealed a rare sequence type (ST 13074) found only in two other isolates from Vietnam identified by our laboratory. DuyDNT genome was sequenced and assembled into 6 scaffolds of 2,118,198 bps, yielding a total of 2451 protein coding sequences, as well as 49 tRNAs and 3 rRNAs. A search for genes involved in antibiotic resistances in the genome of DuyDNT recovered 15 coding sequences that might contribute to antibiotic resistance and reduced susceptibility. Among these some novel variants were found that potentially render the isolate even broader drug resistance. Additional epidemiologic characterization revealed DuyDNT has a unique antigenic finetype (VR1: 22–25, VR2: 14–32, VR: F4–6) and Bexero® BAST type (fHBP: 31, NHBA: 16, NadA: 0, PorA VR1: 22–25, PorA VR2: 14–32), the latter predicted this isolate was not covered by either Bexsero® or Trumenba®, the two most recently developed vaccines against meningococcal B. Genomic composition of DuyDNT isolate consisted of various repetitive DNA sequences and prophage regions with some features unique for just the Vietnamese isolate, pointing toward a flexible genome capable of exchanging DNA with other species of Neisseria. Altogether, our results illustrated the usefulness of WGS analysis for epidemiological and antibiotic resistance surveillance of IMD. Our study also highlights the need for a more comprehensive study of the diversity among N. meningitidis isolates in Vietnam and a standard molecular characterization scheme in order to accurately monitor antibiotic resistance of Neisseria species among military units as well as support an effective IMD vaccination strategy in Vietnam.
TXT performed genome assembly from raw reads, annotated the genome and other bioinformatics works. TTL performed serogroup and MLST typing, and extracted genomic DNA. LPT cultured the isolate, performed antibiotic susceptibility test and MIC determination. CMA supported genome assembly, sequence submission, and was a major contributor in revising and proofreading the manuscript. DVQ contributed to study design and manuscript drafting and revision. HMN designed experiments, interpreted data, wrote and revised the manuscript. All authors read and approved the final manuscript.
We are grateful for members of our laboratories for meaningful discussion and technical assistance.
The authors declare that they have no competing interests.
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This work is funded by the National Foundation for Science and Technology Development (NAFOSTED) via Grant Numbered 106-NN.02-2015.66.
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