Virulence Plasmid with IroBCDN Deletion Promoted Cross-regional Transmission of ST11-KL64 Carbapenem-resistant Hypervirulent Klebsiella Pneumoniae in central China

doi:10.21203/rs.3.rs-4629987/v1

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Virulence Plasmid with IroBCDN Deletion Promoted Cross-regional Transmission of ST11-KL64 Carbapenem-resistant Hypervirulent Klebsiella Pneumoniae in central China

https://doi.org/10.21203/rs.3.rs-4629987/v1

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Background:Carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKP) caused infections of high mortality and brought a serious impact on public health. This study evaluated the transmissibility of CR-hvKP among different regions to provide corresponding advice for cross-regional prevention.

Methods: Clinical K. pneumoniae strains were collected from Jiujiang region and Nanchang region in Jiangxi province from November 2021 to June 2022. We characterized these strains for their genetic relatedness, virulence phenotype, and dissimilarities in virulence plasmid structures using PFGE, Galleria mellonella, Whole-genome sequencing.

Results: Among 609 strains, 45 (7.4%) CR-hvKP were identified, while the strains

isolated from Nanchang and Jiujiang accounted for 10.05% (36/358) and 3.59% (9/251). We observed that ST11-KL64 CR-hvKP had an overwhelming epidemic dominance in these two regions. Significant genetic diversity was identified among all ST11-KL64 CR-hvKP cross-regional transmission between Nanchang and Jiujiang serving as major drivers of clonal clusters. Virulence genes profile revealed that ST11-KL64 CR-hvKP might harbour incomplete pLVPK-like plasmids and primarily evolved from CRKP by acquiring the hypervirulence plasmid. We found the predominance of truncated-IncFIB/IncHI1B type virulence plasmids with a 25kb fragment deletion that encoded iroBCDN clusters.

Conclusion: ST11-KL64 is the most cross-regional prevalent type CR-hvKPs in Jiangxi province, which mainly evolved from CRKPs by acquiring a truncated-IncHI1B/IncFIB virulence plasmid with the deletion of iroBCDN. Stricter surveillance and control measures are urgently needed to prevent the epidemic transmission of ST11-KL64 CR-hvKP.

Carbapenem-resistant hypervirulent Klebsiella pneumoniae

Virulence plasmid

Whole genome sequencing

MLST

Capsular serotypes

Klebsiella pneumoniae can be divided into classical K. pneumoniae (cKp) and hypervirulent K. pneumoniae (hvKp) that causes various diseases [1, 2]. Classical K. pneumoniae strains have been implicated in a higher rate of resistance to multiple antimicrobial agents and are primarily restricted in causing infections among immunocompromised patients [3]. However, compared to the cKp strains, hvKp has a strong clinical pathogenicity and often carries a large virulence plasmid, which include iuc/iro, rmpA/rmpA2 and peg-344 [4]. It can cause not only nosocomial infections in patients with low immune function but also community-acquired infections in young people with normal immune function, and can present migratory spread.

In recent years, hypervirulent carbapenem-resistant Klebsiella pneumoniae (CR-hvKP) has been widely reported and poses a global threat, which may lead to even higher mortality and morbidity [5, 6]. These CR-hvKP strains may differentiate in two possible evolutionary pathways: (1) hvKP strains acquired carbapenem-resistance plasmids; (2) CRKP strains acquired pLVPK-like virulence plasmids [7, 8]. Several previous studies revealed that ST11 CR-hvKP was found to have evolved from ST11 CRKP via the acquisition of pLVPK-like virulence plasmid, which was mainly associated with rmpA/rmpA2, aerobactin (iucABCD and iutA) and salmochelin (iroBCDN gene cluster) [9, 10]. Since then, an increasing number of reports have described in Beijing [11, 12], Shenzhen [13], Hangzhou [14], Zhengzhou [15], and Nanchang [16] in China, with several current variant sequence types identified. Furthermore, it has been reported that ST11-KL64 has gradually displaced ST11-KL47 as the most prevalent clone in China [17, 18]. Resistance, virulence and prevalence due to CR-hvKP increases the failure rate of patient treatment. Therefore, to further investigate the potential for transmission of CR-hvKP, we investigated the genetic characteristics, plasmid content and clonal relationship of CR-hvKP strains isolated from Nanchang and Jiujiang, in central China. Our findings provide epidemiological data directly linking clinical isolates of CR-hvKP from different regions in China.

Specimen collection and identification

We collected 358 strains and 251 strains Klebsiella pneumoniae between November 2021 to June 2022 from Nanchang and Jiujiang regions in central China, respectively. The clinical data of the patients (Age, sex, acquisition of infection, and diagnosis) were collected from the electronic medical records. K. pneumoniae isolates were identified using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (Bruker Daltonics). Klebsiella pneumoniae isolates that tested positive for the virulence genes peg-344 and rmpA/rmpA2 using loop-mediated isothermal amplification (LAMP) [19]and showed positive results in the string test (5 mm) were defined as hvKP. The clinical isolates used in the present study were resistant to carbapenems (meropenem, imipenem, or ertapenem) according to the guidelines of the Clinical Laboratory Standards Institute (CLSI, 2022) [20]. The Ethics Committee determined that patient consent was not required because the present study was retrospective, and the identities of the patients were anonymized.

Determination of capsular serotyping, virulence, PCR-based replicon typing, and drug resistance genes of CR-hvKP

All of template DNAs were extracted by bacterial DNA Kit. The presence of capsular serotyping, virulence, and drug resistance genes were determined by PCR as previously described [21, 22]. The positive products were sequenced by Shanghai Sangon Biotechnology, and the results were analyzed by BLAST. To identify the replicons of incompatibility plasmid groups among K. pneumoniae, a series of primers recognizing the FIA, FIB, FIC, HI1, HI2, I1-Iγ, L/M, N, P, W, T, A/C, K, B/O, X, Y, F, and FIIA replicons were used [23].

Analysis of homologous gene families and phylogenetic construction

According to the database (https://bigsdb.pasteur.fr/klebsiella/) for multilocus sequence typing (MLST), seven housekeeping genes, gapA, infB, mdh, pgi, phoE, rpoB, and tonB, were used for K. pneumoniae typing. Pulsed-field gel electrophoresis (PFGE) was carried out following the standard operating procedure by PulseNet International. PFGE images were imported to Bionumerics software ver. 7.6 (AppliedMaths, Belgium) to identify image bands and construct UPGMA dendrogram. Genetic relatedness was interpreted using a cluster cutoff line set at

80% similarity.

Galleria mellonella infection model

The toxicity test was conducted using the model of the Galleria mellonella model. Ten larvae weighing between 250 and 350 mg (purchased from Tianjin Huiyude Biotech Company, Tianjin, China) were used for the assessment of the virulence of each isolate. Overnight cultures of K pneumoniae strains were washed with phosphate-buffered saline (PBS) and further adjusted with PBS to concentrations of 1×10⁶ CFU/ml. The insects were inoculated by injecting 1×10⁶ CFU per 10 µl aliquot into the hemocoel via the rear left proleg, followed by a recording of survival rate every 12 h for 4 days. All experiments were performed in triplicates. K. pneumoniae strain NTUH-K2044 and strain ATCC700603 were used as controls of high and low virulence strains, respectively.

Whole-genome sequencing

After genomic DNA extraction, the genomes of the CR-hvKP strains were sequenced using both the Illumina HiSeq platform (Illumina, San Diego, CA, USA) and Oxford Nanopore MinION platform (Nanopore, Oxford, UK). The genome sequence was automatically annotated using National Center for Biotechnology Information (NCBI) Prokaryotic Genome Annotation Pipeline (PGAP) (http://www.ncbi.nlm.nih.gov/genome/annotation_prok/). Antimicrobial resistance genes, virulence genes, plasmid incompatibility groups and capsular serotype were predicted by ResFinder database, virulence factor database (VFDB), PlasmidFinder database and Kleborate with the command line of kleborate -a ASSEMBLIES -k, respectively. Comparative genomics analysis was performed using hypervirulent K. pneumoniae NTUH-K2044 (GenBank accession no. AP006725) as a reference by BacWGSTdb server with 25 alleles difference threshold. Concerning the analysis of sequenced plasmids, insertion sequences (ISs) were identified using ISfinder. The plasmid structure was visualized by DNAplotter[24]. Plasmid comparisons were conducted using Easyfig and further visualized via Adobe Illustrator[25].

Demographics and Clinical Characteristics of CR-hvKP from Nanchang and Jiujiang

In this study, for the CR-hvKP from two regions, the wards most affected by these strains were basically intensive care units and respiratory departments. Most of the patients have a history of combination antibiotic treatments. There was a difference in clinical specimens between CR-hvKP in Nanchang and Jiujiang. The CR-hvKP strains in Nanchang were mainly isolated from blood samples, while the majority of CR-hvKP strains in Jiujiang were isolated from sputum samples (P < 0.05). The mean age of onset for CR-hvKP was 61.02 ± 14.30 years, with a higher prevalence observed in males. CR-hvKP infected patients in Nanchang were significantly healthier and younger than those in Jiujiang (P < 0.05). Other clinical characteristics of the patients are summarized in Table 1.

Table 1

CR-hvKP of infected patients from Nanchang and Jiujiang regions
Clinical features	Nanchang CR-hvKP(n = 36), n(%)	Jiujiang CR-hvKP(n = 9), n(%)	P value
Age, years	53.02 ± 19.34	74.22 ± 9.47
0–30	6(16.67)	0	0.188
31–50	8(22.22)	0	0.119
51–70	17(47.22)	6(66.67)	0.297
over 70	5(13.89)	3(33.33)	0.172
Gender
Male	29(80.56)	9(100)	0.150
Female	7(19.44)	0(0)	0.150
Samples
Sputum	11(30.56)	8(88.89)	0.002*
Urine	3(8.33)	0(0)	0.370
Blood	14(38.89)	0(0)	0.024*
Bronchoalveolar lavage fluid	0(0)	1(11.11)	0.200
Ascites	2(5.56)	0(0)	0.469
Pus	4(11.11)	0(0)	0.295
Drainage fluid	1(2.78)	0(0)	0.613
Venous catheter	1(2.78)	0(0)	0.613
Wards
ICU	21(58.33)	4(44.44)	0.667
Neurosurgical department	1(2.78)	0(0)	0.613
Neurological department	2(5.56)	1(11.11)	0.550
Respiratory department	1(2.78)	3(33.33)	0.004*
Rehabilitation department	2(5.56)	0(0)	0.469
Other ward	9(25)	1(11.11)	0.370
Drug combination
Yes	33(91.67)	8(88.89)	0.793
No	3(8.33)	1(11.11)	0.793
non-medication	0(0)	0(0)	na

Capsule Serotype, and Virulence of CR-hvKP strains from Nanchang and Jiujiang

There was no statistically significant difference in the capsule serotypes and MLST typing of CR-hvKP strains between Nanchang and Jiujiang regions (Table 2). Five capsular types with the predominance of K64 (25/36, 69.44%), K1 (6/36, 16.67%), K2 (3/36, 8.33%) were isolated from Nanchang, while the majority of K64 (6/9, 66.67%), K5 (2/9, 22.22%), K1 (1/9, 11.11%) were isolated from Jiujiang.

In the virulence genes analysis, the different markers of CR-hvKP isolates were as follows: magA (15.6%, n = 7/45), rmpA (86.7%, n = 39/45), fimH (100%, n = 45/45), rmpA2 (95.6%, n = 43/45), iucA (97.8%, n = 44/45), iroB (28.9%, n = 13/45), and peg344 (93.3%, n = 42/45). Furthermore, All CR-hvKP isolates were multidrug-resistant (MDR). The occurrence of resistance genes in 45 CR-hvKP isolates was as follows: bla_KPC (80.0%, n = 36/45), bla_NDM (6.7%, n = 3/45), bla_CTX−M (97.8%, n = 44/45), bla_SHV (100%, n = 45/45), bla_TEM (84.4%, n = 38/45), rmtB (15.6%, n = 7/45), qnrS (62.2%, n = 28/45), qnrB (2.2%, n = 1/45), acc(6’)-lb-cr (31.1%, n = 14/45), mphA (4.4%, n = 2/45), and sul (77.8%, n = 35/45). We infected G.mellonella larvae with 45 CR-hvKP isolates obtained from Nanchang and Jiujiang. We infected G. mellonella larvae with 45 CR-hvKP isolates obtained from Nanchang and Jiujiang. As shown in Fig. 1, all CR-hvKP isolates displayed greater virulence than ATCC 700603, and most isolates had similar or greater virulence than NTUH-K2044.

Table 2

Capsule Serotype and MLST typing of CR-hvKP strain
K/MLST	Nanchang CR-hvKP(n = 36), n(%)	Jiujiang CR-hvKP(n = 9), n(%)	P Value
Capsular serotypes
K1	6(16.67)	1(11.11)	0.681
K2	3(8.33)	2(22.22)	0.236
K5	1(2.78)	0(0)	0.613
K47	1(2.78)	0(0)	0.613
K64	25(69.44)	6(66.67)	0.872
MLST typing
ST11	26(72.22)	6(66.67)	0.742
ST23	6(16.67)	1(11.11)	0.681
ST65	2(5.56)	2(22.22)	0.116
ST86	1(2.78)	0(0)	0.633
ST485	1(2.78)	0(0)	0.633

Genetic analysis of CR-hvKP strains from Nanchang and Jiujiang

The PFGE dendrogram was analyzed using BioNumeric software to ascertain the relatedness of these isolates. CR-hvKP strains isolated from both Nanchang and Jiujiang were classified into six clusters, with cluster A (40%, 18/45) and cluster B (24.4%, 11/45) dominating, which were all ST11-KL64. However, the CR-hvKP strains that cross-regional transmitted between Nanchang and Jiujiang are mainly concentrated in cluster B and cluster E.

The molecular typing showed that all CR-hvKP isolates were grouped into 5 different sequence types (STs). CR-hvKP distinct isolates from Nanchang belonged to 5 sequence types with the prevalence of ST11 (26/36, 72.22%), ST23 (6/36, 16.67%), ST65 (2/36, 5.56%), ST86 (1/36, 2.78%), and ST485 (1/36, 2.78%), while isolates from Jiujiang were ST11 (6/9, 66.67%), ST23 (1/9, 11.11%), ST65 (2/9, 22.22%).

The epidemiology of CR-hvKP in central China is a complex and evolving phenomenon attributed to the horizontal transfer and clonal spread of major clones, predominantly ST11-KL64. Additional 8 CR-hvKP isolates were collected from patients in ICU and respiratory departments in Jiujiang (Fig. 2), who had ICU stay history in Nanchang prior to transfer to their current wards where the isolates were recovered.

Genetic environment and Structural Analysis of the Virulence Plasmid of ST11-CR-hvKP Strain

The genetic context of the virulence plasmids exhibited considerable diversity from the whole-genome sequence through Illumina and Nanopore platforms, revealed representatives of plasmid incompatibility groups ColRNAI, IncHI1B, IncFIB, IncFII, IncR, IncQ, IncX3. Plasmid sequence analysis confirmed that all virulence plasmids belonged to the IncFIB/IncHIB type with different sizes ranging from 122.4 to 357.5 kb in length, with a GC content of 51.22–53.47% (Fig. 3). However, the predominant plasmid replicon types associated with the KPC and NDM genes were IncFII(k) (100%) and IncX3 (100%). The unweighted pair group method with arithmetic mean (UPGMA) revealed that the virulence plasmid in Nanchang and Jiujiang isolates might have the same origin as the virulence plasmid in central China.

Interestingly, a 25-kbp fragment including iroBCDN locus with IS110 transposase were absent in the IncFIB/IncHI1B type virulence plasmid harbored in ST11-KL64 CR-hvKP isolates from Nanchang and Jiujiang (Fig. 3). According to these results, we hypothesize that IS110 might be responsible for the deletion of iroBCDN, and then this fragment deletion might be more conducive to promote cross-regional transmission and maintain plasmid stability in ST11-KL64 CR-hvKP isolates. Furthermore, virulence plasmids harbored in ST11-KL64 CR-hvKP isolates from Nanchang and Jiujiang exhibited a high level of homology. Virulence plasmids also harbored several virulence genes, i.e., rmpA, rmpA2, peg344, iucA, and iutA (Fig. 4). Comparison of genetic surroundings of virulence gene indicated that it was flanked by a similar core structure.

The recent emergence of CR-hvKP, associated with considerable morbidity and mortality, poses a critical challenge to clinical and public health. ST11-KL64 was the most frequent clone for CR-hvKP globally, especially in China[26]. Virulence plasmids are demonstrated to readily convert an ST11 CRKP strain to a CR-hvKP strain via conjugation. Therefore, surveillance and tracking of ST11-KL64 CR-hvKP is critical for clinicians in various clinical settings and deserves more attention. This study investigated the origin and cross-regional transmission pattern of CR-hvKP in central China.

In the retrospective study, although the specimen origins of CR-hvKP belonging to the same genotype varied greatly between Nanchang and Jiujiang, the trend of virulence in CR-hvKP was similar in different regions of central China. In particular, we have identified the blood sample as an important specimen associated with invasive infection in Nanchang, while we identified a cluster of patients in the neurosurgery ward with sputum cultures positive for CR-hvKP from Jiujiang region. Our findings demonstrated that CR-hvKP from Jiujiang could colonize in the respiratory tract, suggesting the strong colonization adaptability of CR-hvKP to the host. We speculate that the difference in specimen origins of CR-hvKP from Nanchang and Jiujiang may be related to differences in the administration of antimicrobial and endemic strains in these areas. Nevertheless, there is no denying that the cross-regional transmission of CR-hvKP is a serious issue.

The serotypes KL64 and KL47 were commonly present in ST11 CR-hvKP strain[27], but the epidemiological trends suggested that KL64 is prevalent among ST11 strains[28]. However, ST11-KL64 CR-hvKP is becoming hypervirulent by acquiring various virulence genes or a pLVKP-like plasmid[29]. PFGE showed that ST11-KL64 CR-hvKP from Nanchang and Jiujiang regions exhibited a high degree of clonality, suggested that clonal cross-regional transmission had occurred in central China. The related epidemiological information showed that some patients with CR-hvKP infections from Jiujiang have a history of prior hospitalization in Nanchang region. However, some patients with CR-hvKP infections from Nanchang are residents of Jiujiang region who go to seek health care at Nanchang hospitals. Current findings indicate that the two regions have the same CR-hvKP clone circulating thus indicating the cross-transmission between the two regions in China. The study emphasizes the importance of phylogenetic analysis of CR-hvKP in the regions using genotyping surveillance[30, 31].

Previously, it has been common that ST11 K. pneumoniae is a widely occurring multidrug-resistant clonal lineage, including carbapenems, but not hypervirulent. In our study, carbapenemases, several extended-spectrum β-lactamase (ESBL) resistance genes, and other reistance genes, including rmtB, qnrS, qnrB, acc(6’)-lb-cr, mphA, and sul, were identified in the CR-hvKP isolates. Furthermore, kleborate analysis revealed that all CR-hvKP strains harbored hypermucoviscous phenotype regulators and aerobactin synthesis, showed hypervirulent phenotype. Our data revealed a high prevalence of ST11-KL64 CR-hvKPs carrying the IncHI1B/IncFIB virulence plasmids with a 25-kbp fragment deletion including the salmonellin genes (iroBCDN). These results revealed virulence plasmid with iroBCDN deletion might promote cross-regional transmission of ST11-KL64 CR-hvKP in Jiangxi province, China. Further genomic epidemiology analysis and targeted surveillance at the national scale are urgently needed.

Our study identified the cross-regional transmission of ST11-KL64 CR-hvKP in China. The transmission threat of virulence plasmid with iroBCDN deletion in CR-hvKP makes it a new crucial super bacterium. Therefore, strengthening the clinical monitoring of CR-hvKP strains and taking adequate infection control measures to avoid transmission and prevent their further dissemination in cross-region.

Acknowledgements

We acknowledge the National Natural Youth Science Foundation of China (82102411, 82200194); The Natural Science Key Project of Jiangxi Province (20202ACBL206025 and 20202ACBL206023); the Project of Science and Technology Innovation Talents in Jiangxi (JSXQ2019201102); Jiangxi Provincial Department of Science and Technology (20202ZDB01016); the Science and technology plan of Jiangxi Health Committee (SKJP-220212554); the Clinical Research Nurture Project of the First Affiliated Hospital of Nanchang University (YFYLCYJPY202001); and Youth Scientific Research Foundation of the First Affiliated Hospital of Nanchang University (YFYPY202115), and the Science and Technology Plan of Jiangxi Provincial Health Commission (202130137).

Author contributions

HH, BH, and YX contributed equally. TX conceived and designed the research. HH, BH, and YX conducted experiments and wrote the manuscript. DW, and QH analyzed the data. PL contributed to analytical tools. YL acquired the funding and revised the manuscript. All the authors contributed to the article and approved the final manuscript.

Funding

Not applicable.

Data availability

All sequencing data have been uploaded to NCBI, with the following accession numbers: PRJNA1139312, PRJNA1139306, PRJNA1139303, PRJNA1139259, PRJNA1139256, PRJNA1139243, PRJNA1139242, PRJNA1139239, PRJNA1139237, PRJNA1139232, PRJNA1139245, PRJNA1139252, PRJNA1139253, PRJNA1139309, PRJNA1139310.

Ethics approval and consent to participate

Based on the rules of the Ethical Committee of our institute, this study did not require informed consent statement, because all isolates were recovered from clinical specimens during routine diagnostic procedures and these isolates were not specific to this study. In addition, the patients were not available to us. Based on the points mentioned above, the Ethical Committee of the First Affiliated Hospital of Nanchang University approved our project with reference number (2023)CDYFYYLK(01-011) and allowed this study to be conducted without informed consent statement.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Virulence Plasmid with IroBCDN Deletion Promoted Cross-regional Transmission of ST11-KL64 Carbapenem-resistant Hypervirulent Klebsiella Pneumoniae in central China

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