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Complete genome of Pandoraea pnomenusa RB-38, an oxalotrophic bacterium isolated from municipal solid waste landfill site

Lim YL, Ee R, Yong D, Tee KK, Yin WF, Chan KG

J Biotechnol, 2015 Nov 20;214:83-4.
PMID: 26393955 DOI: 10.1016/j.jbiotec.2015.09.018

Pandoraea pnomenusa RB-38 is a bacterium isolated from a former sanitary landfill site. Here, we present the complete genome of P. pnomenusa RB38 in which an oxalate utilization pathway was identified. The genome analysis suggested the potential of this strain as an effective biocontrol agent against oxalate-producing phytopathogens.
Complete genome sequence of Serratia fonticola DSM 4576 T, a potential plant growth promoting bacterium

Lim YL, Yong D, Ee R, Krishnan T, Tee KK, Yin WF, et al.

J Biotechnol, 2015 Nov 20;214:43-4.
PMID: 26376471 DOI: 10.1016/j.jbiotec.2015.09.005

Here, we present the first complete genome sequence of Serratia fonticola DSM 4576(T), a potential plant growth promoting (PGP) bacterium which confers solubilization of inorganic phosphate, indole-3-acetic acid production, hydrogen cyanideproduction, siderophore production and assimilation of ammonia through the glutamate synthase (GS/GOGAT) pathway. This genome sequence is valuable for functional genomics and ecological studies which are related to PGP and biocontrol activities.
Complete genome sequence of Serratia multitudinisentens RB-25(T), a novel chitinolytic bacterium

Lim YL, Yong D, Ee R, Tee KK, Yin WF, Chan KG

J Biotechnol, 2015 Aug 10;207:32-3.
PMID: 25975625 DOI: 10.1016/j.jbiotec.2015.04.027

Serratia multitudinisentens RB-25(T) (=DSM 28811(T) =LMG 28304(T)) is a newly proposed type strain in the genus of Serratia isolated from a municipal landfill site. Here, we present the complete genome of S. multitudinisentens RB-25(T) which contains a complete chitinase operon and other chitin and N-acetylglucosamine utilisation enzymes. To our knowledge, this is the first report of the complete genome sequence of this novel isolate and its chitinase gene discovery.
Fulltext Comparative seasonalities of influenza A, B and 'common cold' coronaviruses - setting the scene for SARS-CoV-2 infections and possible unexpected host immune interactions

Liu Y, Lam TTY, Lai FYL, Krajden M, Drews SJ, Hatchette TF, et al.

J Infect, 2020 08;81(2):e62-e64.
PMID: 32360499 DOI: 10.1016/j.jinf.2020.04.032
Hepatitis B virus DNA methylation and its potential role in chronic hepatitis B

Low WF, Ngeow YF, Chook JB, Tee KK, Ong SK, Peh SC, et al.

Expert Rev Mol Med, 2022 Nov 16;25:e11.
PMID: 36380484 DOI: 10.1017/erm.2022.38

Hepatitis B virus (HBV) infection led to 66% liver deaths world-wide in year 2015. Thirty-seven per cent of these deaths were the result of chronic hepatitis B (CHB)-associated hepatocellular carcinoma (HCC). Although early diagnosis of HCC improves survival, early detection is rare. Methylation of HBV DNA including covalently closed circular DNA (cccDNA) is more often encountered in HCC cases than those in CHB and cirrhosis. Three typical CpG islands within the HBV genome are the common sites for methylation. The HBV cccDNA methylation affects the viral replication and protein expression in the course of infection and may associate with the disease pathogenesis and HCC development. We review the current findings in HBV DNA methylation that provide insights into its role in HCC diagnosis.
Description of the COVID-19 epidemiology in Malaysia

Md Nadzri MN, Md Zamri ASS, Singh S, Sumarni MG, Lai CH, Tan CV, et al.

Front Public Health, 2024;12:1289622.
PMID: 38544725 DOI: 10.3389/fpubh.2024.1289622

INTRODUCTION: Since the COVID-19 pandemic began, it has spread rapidly across the world and has resulted in recurrent outbreaks. This study aims to describe the COVID-19 epidemiology in terms of COVID-19 cases, deaths, ICU admissions, ventilator requirements, testing, incidence rate, death rate, case fatality rate (CFR) and test positivity rate for each outbreak from the beginning of the pandemic in 2020 till endemicity of COVID-19 in 2022 in Malaysia.
METHODS: Data was sourced from the GitHub repository and the Ministry of Health's official COVID-19 website. The study period was from the beginning of the outbreak in Malaysia, which began during Epidemiological Week (Ep Wk) 4 in 2020, to the last Ep Wk 18 in 2022. Data were aggregated by Ep Wk and analyzed in terms of COVID-19 cases, deaths, ICU admissions, ventilator requirements, testing, incidence rate, death rate, case fatality rate (CFR) and test positivity rate by years (2020 and 2022) and for each outbreak of COVID-19.
RESULTS: A total of 4,456,736 cases, 35,579 deaths and 58,906,954 COVID-19 tests were reported for the period from 2020 to 2022. The COVID-19 incidence rate, death rate, CFR and test positivity rate were reported at 1.085 and 0.009 per 1,000 populations, 0.80 and 7.57%, respectively, for the period from 2020 to 2022. Higher cases, deaths, testing, incidence/death rate, CFR and test positivity rates were reported in 2021 and during the Delta outbreak. This is evident by the highest number of COVID-19 cases, ICU admissions, ventilatory requirements and deaths observed during the Delta outbreak.
CONCLUSION: The Delta outbreak was the most severe compared to other outbreaks in Malaysia's study period. In addition, this study provides evidence that outbreaks of COVID-19, which are caused by highly virulent and transmissible variants, tend to be more severe and devastating if these outbreaks are not controlled early on. Therefore, close monitoring of key epidemiological indicators, as reported in this study, is essential in the control and management of future COVID-19 outbreaks in Malaysia.
Fulltext Characterization and Transcriptome Studies of Autoinducer Synthase Gene from Multidrug Resistant Acinetobacter baumannii Strain 863

Ng CK, How KY, Tee KK, Chan KG

Genes (Basel), 2019 04 08;10(4).
PMID: 30965610 DOI: 10.3390/genes10040282

Quorum sensing (QS) is a cell-to-cell communication system that uses autoinducers as signaling molecules to enable inter-species and intra-species interactions in response to external stimuli according to the population density. QS allows bacteria such as Acinetobacter baumannii to react rapidly in response to environmental changes and hence, increase the chances of survival. A. baumannii is one of the causative agents in hospital-acquired infections and the number of cases has increased remarkably in the past decade. In this study, A. baumannii strain 863, a multidrug-resistant pathogen, was found to exhibit QS activity by producing N-acyl homoserine lactone. We identified the autoinducer synthase gene, which we named abaI, by performing whole genome sequencing analysis of A. baumannii strain 863. Using high resolution tandem triple quadrupole mass spectrometry, we reported that abaI of A. baumannii strain 863 produced 3-hydroxy-dodecanoyl-homoserine lactone. A gene deletion mutant was constructed, which confirmed the functionality of abaI. A growth defect was observed in the QS-deficient mutant strain. Transcriptome profiling was performed to determine the possible genes regulated by QS. Four groups of genes that showed differential expression were discovered, namely those involved in carbon source metabolism, energy production, stress response and the translation process.
Fulltext HIV-1 transmission networks among men who have sex with men in Asia

Ng KT, Ng KY, Chen JH, Ng OT, Kamarulzaman A, Tee KK

Clin Infect Dis, 2014 Sep 15;59(6):910-1.
PMID: 24944233 DOI: 10.1093/cid/ciu480
Fulltext Phylodynamic profile of HIV-1 subtype B, CRF01_AE and the recently emerging CRF51_01B among men who have sex with men (MSM) in Singapore

Ng KT, Ng KY, Khong WX, Chew KK, Singh PK, Yap JK, et al.

PLoS One, 2013;8(12):e80884.
PMID: 24312505 DOI: 10.1371/journal.pone.0080884

HIV-1 subtype B and CRF01_AE are the predominant infecting subtypes among men who have sex with men (MSM) in Singapore. The genetic history, population dynamics and pattern of transmission networks of these genotypes remain largely unknown. We delineated the phylodynamic profiles of HIV-1 subtype B, CRF01_AE and the recently characterized CRF51_01B strains circulating among the MSM population in Singapore. A total of 105 (49.5%) newly-diagnosed treatment-naïve MSM were recruited between February 2008 and August 2009. Phylogenetic reconstructions of the protease gene (HXB2: 2239 - 2629), gp120 (HXB2: 6942 - 7577) and gp41 (HXB2: 7803 - 8276) of the env gene uncovered five monophyletic transmission networks (two each within subtype B and CRF01_AE and one within CRF51_01B lineages) of different sizes (involving 3 - 23 MSM subjects, supported by posterior probability measure of 1.0). Bayesian coalescent analysis estimated that the emergence and dissemination of multiple sub-epidemic networks occurred between 1995 and 2005, driven largely by subtype B and later followed by CRF01_AE. Exponential increase in effective population size for both subtype B and CRF01_AE occurred between 2002 to 2007 and 2005 to 2007, respectively. Genealogical estimates suggested that the novel CRF51_01B lineages were probably generated through series of recombination events involving CRF01_AE and multiple subtype B ancestors. Our study provides the first insight on the phylodynamic profiles of HIV-1 subtype B, CRF01_AE and CRF51_01B viral strains circulating among MSM in Singapore.
Fulltext Evolutionary history of HIV-1 subtype B and CRF01_AE transmission clusters among men who have sex with men (MSM) in Kuala Lumpur, Malaysia

Ng KT, Ong LY, Lim SH, Takebe Y, Kamarulzaman A, Tee KK

PLoS One, 2013;8(6):e67286.
PMID: 23840653 DOI: 10.1371/journal.pone.0067286

HIV-1 epidemics among men who have sex with men (MSM) continue to expand in developed and developing countries. Although HIV infection in MSM is amongst the highest of the key affected populations in many countries in Southeast Asia, comprehensive molecular epidemiological study of HIV-1 among MSM remains inadequate in the region including in Malaysia. Here, we reported the phylodynamic profiles of HIV-1 genotypes circulating among MSM population in Kuala Lumpur, Malaysia. A total of n = 459 newly-diagnosed treatment-naïve consenting subjects were recruited between March 2006 and August 2012, of whom 87 (18.9%) were self-reported MSM. Transmitted drug resistance mutations were absent in these isolates. Cumulatively, phylogenetic reconstructions of the pro-rt gene (HXB2∶2253-3275) showed that HIV-1 subtype B and CRF01_AE were predominant and contributed to approximately 80% of the total HIV-1 infection among MSM. In addition to numerous unique transmission lineages within these genotypes, twelve monophyletic transmission clusters of different sizes (2-7 MSM sequences, supported by posterior probability value of 1) were identified in Malaysia. Bayesian coalescent analysis estimated that the divergence times for these clusters were mainly dated between 1995 and 2005 with four major transmission clusters radiating at least 12 years ago suggesting that active spread of multiple sub-epidemic clusters occurred during this period. The changes in effective population size of subtype B showed an exponential growth within 5 years between 1988 and 1993, while CRF01_AE lineage exhibited similar expansion between 1993 and 2003. Our study provides the first insight of the phylodynamic profile of HIV-1 subtype B and CRF01_AE circulating among MSM population in Kuala Lumpur, Malaysia, unravelling the importance of understanding transmission behaviours as well as evolutionary history of HIV-1 in assessing the risk of outbreak or epidemic expansion.
Genome sequence of a novel HIV-1 circulating recombinant form 54_01B from Malaysia

Ng KT, Ong LY, Takebe Y, Kamarulzaman A, Tee KK

J Virol, 2012 Oct;86(20):11405-6.
PMID: 22997423

We report here the first novel HIV-1 circulating recombinant form (CRF) 54_01B (CRF54_01B) isolated from three epidemiologically unlinked subjects of different risk groups in Malaysia. These recently sampled recombinants showed a complex genome organization composed of parental subtype B' and CRF01_AE, with identical recombination breakpoints observed in the gag, pol, and vif genes. Such a discovery highlights the ongoing active generation and spread of intersubtype recombinants involving the subtype B' and CRF01_AE lineages and indicates the potential of the new CRF in bridging HIV-1 transmission among different risk groups in Southeast Asia.
Fulltext Genome sequence of the hepatitis C virus subtype 6n isolated from malaysia

Ng KT, Lee YM, Al-Darraji HA, Xia X, Takebe Y, Chan KG, et al.

Genome Announc, 2013 Jan;1(1).
PMID: 23409272 DOI: 10.1128/genomeA.00168-12

We report the full genome sequence of hepatitis C virus (HCV) subtype 6n from Kuala Lumpur, Malaysia. Phylogenetic analysis of the isolate 10MYKJ032 suggests that Southeast Asia might be the origin for the HCV subtype 6n and highlights the possible spread of this lineage from Southeast Asia to other regions.
Fulltext Co-infections and transmission networks of HCV, HIV-1 and HPgV among people who inject drugs

Ng KT, Takebe Y, Chook JB, Chow WZ, Chan KG, Abed Al-Darraji HA, et al.

Sci Rep, 2015;5:15198.
PMID: 26459957 DOI: 10.1038/srep15198

Co-infections with human immunodeficiency virus type 1 (HIV-1) and human pegivirus (HPgV) are common in hepatitis C virus (HCV)-infected individuals. However, analysis on the evolutionary dynamics and transmission network profiles of these viruses among individuals with multiple infections remains limited. A total of 228 injecting drug users (IDUs), either HCV- and/or HIV-1-infected, were recruited in Kuala Lumpur, Malaysia. HCV, HIV-1 and HPgV genes were sequenced, with epidemic growth rates assessed by the Bayesian coalescent method. Based on the sequence data, mono-, dual- and triple-infection were detected in 38.8%, 40.6% and 20.6% of the subjects, respectively. Fifteen transmission networks involving HCV (subtype 1a, 1b, 3a and 3b), HIV-1 (CRF33_01B) and HPgV (genotype 2) were identified and characterized. Genealogical estimates indicated that the predominant HCV, HIV-1 and HPgV genotypes were introduced into the IDUs population through multiple sub-epidemics that emerged as early as 1950s (HCV), 1980s (HIV-1) and 1990s (HPgV). By determining the difference in divergence times between viral lineages (ΔtMRCA), we also showed that the frequency of viral co-transmission is low among these IDUs. Despite increased access to therapy and other harm reduction interventions, the continuous emergence and coexistence of new transmission networks suggest persistent multiple viral transmissions among IDUs.
Fulltext Outbreaks of enterovirus D68 in Malaysia: genetic relatedness to the recent US outbreak strains

Ng KT, Oong XY, Pang YK, Hanafi NS, Kamarulzaman A, Tee KK

Emerg Microbes Infect, 2015 Aug;4(8):e47.
PMID: 26421270 DOI: 10.1038/emi.2015.47
Genome sequencing and phylogenetic reconstruction reveal a potential fourth rhinovirus species and its worldwide distribution

Ng KT, Takebe Y, Kamarulzaman A, Tee KK

Arch Virol, 2021 Jan;166(1):225-229.
PMID: 33084935 DOI: 10.1007/s00705-020-04855-5

Genome sequences of members of a potential fourth rhinovirus (RV) species, provisionally denoted as rhinovirus A clade D, from patients with acute respiratory infection were determined. Bayesian coalescent analysis estimated that clade D emerged around the 1940s and diverged further around 2006-2007 into two distinctive sublineages (RV-A8-like and RV-A45-like) that harbored unique "clade-defining" substitutions. Similarity plots and bootscan mapping revealed a recombination breakpoint located in the 5'-UTR region of members of the RV-A8-like sublineage. Phylogenetic reconstruction revealed the distribution of clade D viruses in the Asia Pacific region and in Europe, underlining its worldwide distribution.
Fulltext Performance of a Taqman Assay for Improved Detection and Quantification of Human Rhinovirus Viral Load

Ng KT, Chook JB, Oong XY, Chan YF, Chan KG, Hanafi NS, et al.

Sci Rep, 2016 10 10;6:34855.
PMID: 27721388 DOI: 10.1038/srep34855

Human rhinovirus (HRV) is the major aetiology of respiratory tract infections. HRV viral load assays are available but limitations that affect accurate quantification exist. We developed a one-step Taqman assay using oligonucleotides designed based on a comprehensive list of global HRV sequences. The new oligonucleotides targeting the 5'-UTR region showed high PCR efficiency (E = 99.6%, R2 = 0.996), with quantifiable viral load as low as 2 viral copies/μl. Assay evaluation using an External Quality Assessment (EQA) panel yielded a detection rate of 90%. When tested on 315 human enterovirus-positive specimens comprising at least 84 genetically distinct HRV types/serotypes (determined by the VP4/VP2 gene phylogenetic analysis), the assay detected all HRV species and types, as well as other non-polio enteroviruses. A commercial quantification kit, which failed to detect any of the EQA specimens, produced a detection rate of 13.3% (42/315) among the clinical specimens. Using the improved assay, we showed that HRV sheds in the upper respiratory tract for more than a week following acute infection. We also showed that HRV-C had a significantly higher viral load at 2-7 days after the onset of symptoms (p = 0.001). The availability of such assay is important to facilitate disease management, antiviral development, and infection control.
Viral Load and Sequence Analysis Reveal the Symptom Severity, Diversity, and Transmission Clusters of Rhinovirus Infections

Ng KT, Oong XY, Lim SH, Chook JB, Takebe Y, Chan YF, et al.

Clin Infect Dis, 2018 07 02;67(2):261-268.
PMID: 29385423 DOI: 10.1093/cid/ciy063

Background: Rhinovirus (RV) is one of the main viral etiologic agents of acute respiratory illnesses. Despite the heightened disease burden caused by RV, the viral factors that increase the severity of RV infection, the transmission pattern, and seasonality of RV infections remain unclear.
Methods: An observational study was conducted among 3935 patients presenting with acute upper respiratory illnesses in the ambulatory settings between 2012 and 2014.
Results: The VP4/VP2 gene was genotyped from all 976 RV-positive specimens, where the predominance of RV-A (49%) was observed, followed by RV-C (38%) and RV-B (13%). A significant regression in median nasopharyngeal viral load (VL) (P < .001) was observed, from 883 viral copies/µL at 1-2 days after symptom onset to 312 viral copies/µL at 3-4 days and 158 viral copies/µL at 5-7 days, before declining to 35 viral copies/µL at ≥8 days. In comparison with RV-A (median VL, 217 copies/µL) and RV-B (median VL, 275 copies/µL), RV-C-infected subjects produced higher VL (505 copies/µL; P < .001). Importantly, higher RV VL (median, 348 copies/µL) was associated with more severe respiratory symptoms (Total Symptom Severity Score ≥17, P = .017). A total of 83 phylogenetic-based transmission clusters were identified in the population. It was observed that the relative humidity was the strongest environmental predictor of RV seasonality in the tropical climate.
Conclusions: Our findings underline the role of VL in increasing disease severity attributed to RV-C infection, and unravel the factors that fuel the population transmission dynamics of RV.
Fulltext Cross-Neutralizing CRF01_AE-Infected Plasma from Malaysia Targets CD4-Binding Site of Human Immunodeficiency Virus Type-1 Envelope Glycoprotein

Ng QR, Tee KK, Binley JM, Tong T

AIDS Res Hum Retroviruses, 2022 Feb;38(2):162-172.
PMID: 34006141 DOI: 10.1089/AID.2020.0299

Human immunodeficiency virus type-1 (HIV-1) antigenic variation poses a great challenge for vaccine immunogen design to elicit broadly neutralizing antibodies (bNAbs). Over the last 10-15 years, great progress has been made to understand the conserved sites of sensitivity on HIV envelope glycoprotein spikes targeted by bNAbs. Plasma neutralization mapping and monoclonal antibody isolation efforts have revealed five major conserved epitope clusters. Most of this work has focused on subtype B and C-infected Caucasian or African donors. It is not clear if the same epitopes and epitope rank order preferences are also true in donors infected with different HIV-1 subtypes and with different racial backgrounds. To investigate this point, in this study we report the first attempt to profile the bNAb specificities of CRF01_AE-infected Malaysian plasmas. We first measured neutralization titers of 21 plasmas against a subtype A, B, and AE pseudovirus panel. This revealed that 14% (3 of 21) plasmas had cross-clade breadth. Focusing on the cross-neutralizing plasma P9, we used AE and JR-FL mutant pseudoviruses, gp120 monomer interference, and native polyacrylamide gel electrophoresis to better understand the neutralization specificity. P9 demonstrates CD4-binding-site specificity with trimer dependence and D368 independence.
Molecular diversity of HIV-1 and surveillance of transmitted drug resistance variants among treatment Naïve patients, 5 years after active introduction of HAART in Kuala Lumpur, Malaysia

Ong LY, Razak SN, Lee YM, Sri La Sri Ponnampalavanar S, Syed Omar SF, Azwa RI, et al.

J Med Virol, 2014 Jan;86(1):38-44.
PMID: 24127302 DOI: 10.1002/jmv.23772

Expansion of antiretroviral treatment programs have led to the growing concern for the development of antiretroviral drug resistance. The aims were to assess the prevalence of drug resistant HIV-1 variants and to identify circulating subtypes among HAART-naïve patients. Plasma specimens from N = 100 HIV+ HAART-naïve adult were collected between March 2008 and August 2010 and viral RNA were extracted for nested PCR and sequenced. PR-RT sequences were protein aligned and checked for transmitted drug resistance mutations. Phylogenetic reconstruction and recombination analysis were performed to determine the genotypes. Based on the WHO consensus guidelines, none of the recruited patients had any transmitted drug resistance mutations. When analyzed against the Stanford guidelines, 35% of patients had at least one reported mutation that may reduce drug susceptibility to PI (24%), NRTI (5%), and NNRTI (14%). The commonly detected mutation that may affect current first line therapy was V179D (3%), which may lead to reduced susceptibility to NNRTI. The predominant circulating HIV-1 genotypes were CRF01_AE (51%) and CRF33_01B (17%). The prevalence of unique recombinant forms (URF) was 7%; five distinct recombinant structures involving CRF01_AE and subtype B' were observed, among them a cluster of three isolates that could form a novel circulating recombinant form (CRF) candidate. Transmitted drug resistance prevalence among HAART-naïve patients was low in this cohort of patients in Kuala Lumpur despite introduction of HAART 5 years ago. Owing to the high genetic diversity, continued molecular surveillance can identify the persistent emergence of HIV-1 URF and novel CRF with significant epidemiological impact.
Identification and evolutionary dynamics of two novel human coronavirus OC43 genotypes associated with acute respiratory infections: phylogenetic, spatiotemporal and transmission network analyses

Oong XY, Ng KT, Takebe Y, Ng LJ, Chan KG, Chook JB, et al.

Emerg Microbes Infect, 2017 Jan 04;6(1):e3.
PMID: 28050020 DOI: 10.1038/emi.2016.132

Human coronavirus OC43 (HCoV-OC43) is commonly associated with respiratory tract infections in humans, with five genetically distinct genotypes (A to E) described so far. In this study, we obtained the full-length genomes of HCoV-OC43 strains from two previously unrecognized lineages identified among patients presenting with severe upper respiratory tract symptoms in a cross-sectional molecular surveillance study in Kuala Lumpur, Malaysia, between 2012 and 2013. Phylogenetic, recombination and comparative genomic analyses revealed two distinct clusters diverging from a genotype D-like common ancestor through recombination with a putative genotype A-like lineage in the non-structural protein (nsp) 10 gene. Signature amino acid substitutions and a glycine residue insertion at the N-terminal domain of the S1 subunit of the spike gene, among others, exhibited further distinction in a recombination pattern, to which these clusters were classified as genotypes F and G. The phylogeographic mapping of the global spike gene indicated that the genetically similar HCoV-OC43 genotypes F and G strains were potentially circulating in China, Japan, Thailand and Europe as early as the late 2000s. The transmission network construction based on the TN93 pairwise genetic distance revealed the emergence and persistence of multiple sub-epidemic clusters of the highly prevalent genotype D and its descendant genotypes F and G, which contributed to the spread of HCoV-OC43 in the region. Finally, a more consistent nomenclature system for non-recombinant and recombinant HCoV-OC43 lineages is proposed, taking into account genetic recombination as an important feature in HCoV evolution and classification.

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