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Fulltext TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

Amrun SN, Tan JJL, Rickett NY, Cox JA, Lee B, Griffiths MJ, et al.

Sci Rep, 2020 03 02;10(1):3810.
PMID: 32123257 DOI: 10.1038/s41598-020-60761-5

Hand, foot and mouth disease (HFMD), caused by enterovirus A71 (EV-A71), presents mild to severe disease, and sometimes fatal neurological and respiratory manifestations. However, reasons for the severe pathogenesis remain undefined. To investigate this, infection and viral kinetics of EV-A71 isolates from clinical disease (mild, moderate and severe) from Sarawak, Malaysia, were characterised in human rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher EV-A71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways triggered by all EV-A71 isolates, although the extent of activation varied. Importantly, several pathways were found to be specific to the severe isolate, including triggering receptor expressed on myeloid cells 1 (TREM-1) signalling. Depletion of TREM-1 in EV-A71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-inflammatory genes for the moderate and severe isolates. Mechanistically, this is the first report describing the transcriptome profiles during EV-A71 infections in primary human cells, and the potential involvement of TREM-1 in the severe disease pathogenesis, thus providing new insights for future treatment targets.
In vitro antiviral activity of medicinal mushroom Ganoderma neo-japonicum Imazeki against enteroviruses that caused hand, foot and mouth disease

Ang WX, Sarasvathy S, Kuppusamy UR, Sabaratnam V, Tan SH, Wong KT, et al.

Trop Biomed, 2021 Sep 01;38(3):239-247.
PMID: 34362866 DOI: 10.47665/tb.38.3.063

Hand, foot and mouth disease (HFMD) is a highly contagious viral disease that predominantly affects children younger than 5 years old. HFMD is primarily caused by enterovirus A71 (EVA71) and coxsackievirus A16 (CV-A16). However, coxsackievirus A10 (CV-A10) and coxsackievirus A6 (CV-A6) are being increasingly reported as the predominant causative of HFMD outbreaks worldwide since the past decade. To date, there are still no licensed multivalent vaccines or antiviral drugs targeting enteroviruses that cause HFMD, despite HFMD outbreaks are still being frequently reported, especially in Asia-Pacific countries. The high rate of transmission, morbidity and potential neurological complications of HFMD is indeed making the development of broad-spectrum antiviral drugs/agents against these enteroviruses a compelling need. In this study, we have investigated the in vitro antiviral effect of 4 Ganoderma neo-japonicum Imazeki (GNJI) crude extracts (S1-S4) against EV-A71, CV-A16, CV-A10 and CV-A6. GNJI is a medicinal mushroom that can be found growing saprophytically on decaying bamboo clumps in Malaysian forests. The antiviral effects of this medicinal mushroom were determined using cytopathic inhibition and virus titration assays. The S2 (1.25 mg/ml) hot aqueous extract demonstrated the highest broad-spectrum antiviral activity against all tested enteroviruses in human primary oral fibroblast cells. Replication of EV-A71, CV-A16 and CVA10 were effectively inhibited at 2 hours post-infection (hpi) to 72 hpi, except for CV-A6 which was only at 2 hpi. S2 also has virucidal activity against EV-A71. Polysaccharides isolated and purified from crude hot aqueous extract demonstrated similar antiviral activity as S2, suggesting that polysaccharides could be one of the active compounds responsible for the antiviral activity shown by S2. To our knowledge, this study demonstrates for the first time the ability of GNJI to inhibit enterovirus infection and replication. Thus, GNJI is potential to be further developed as an antiviral agent against enteroviruses that caused HFMD.
Fulltext SARS-CoV-2 genomic surveillance in Malaysia: displacement of B.1.617.2 with AY lineages as the dominant Delta variants and the introduction of Omicron during the fourth epidemic wave

Azami NAM, Perera D, Thayan R, AbuBakar S, Sam IC, Salleh MZ, et al.

Int J Infect Dis, 2022 Dec;125:216-226.
PMID: 36336246 DOI: 10.1016/j.ijid.2022.10.044

OBJECTIVES: This study reported SARS-CoV-2 whole genome sequencing results from June 2021 to January 2022 from seven genome sequencing centers in Malaysia as part of the national surveillance program.
METHODS: COVID-19 samples that tested positive by reverse transcription polymerase chain reaction and with cycle threshold values <30 were obtained throughout Malaysia. Sequencing of SARS-CoV-2 complete genomes was performed using Illumina, Oxford Nanopore, or Ion Torrent platforms. A total of 6163 SARS-CoV-2 complete genome sequences were generated over the surveillance period. All sequences were submitted to the Global Initiative on Sharing All Influenza Data database.
RESULTS: From June 2021 to January 2022, Malaysia experienced the fourth wave of COVID-19 dominated by the Delta variant of concern, including the original B.1.617.2 lineage and descendant AY lineages. The B.1.617.2 lineage was identified as the early dominant circulating strain throughout the country but over time, was displaced by AY.59 and AY.79 lineages in Peninsular (west) Malaysia, and the AY.23 lineage in east Malaysia. In December 2021, pilgrims returning from Saudi Arabia facilitated the introduction and spread of the BA.1 lineage (Omicron variant of concern) in the country.
CONCLUSION: The changing trends of circulating SARS-CoV-2 lineages were identified, with differences observed between west and east Malaysia. This initiative highlighted the importance of leveraging research expertise in the country to facilitate pandemic response and preparedness.
High Prevalence of Rodent-Borne Bartonella spp. in Urbanizing Environments in Sarawak, Malaysian Borneo

Blasdell KR, Perera D, Firth C

Am J Trop Med Hyg, 2019 03;100(3):506-509.
PMID: 30526734 DOI: 10.4269/ajtmh.18-0616

Rodents are the most prominent animal host of Bartonella spp., which are associated with an increasing number of human diseases worldwide. Many rodent species thrive in urban environments and live in close contact with people, which can lead to an increased human risk of infection from rodent-borne pathogens. In this study, we explored the prevalence and distribution of Bartonella spp. in rodents in urban, developing, and rural environments surrounding a growing city in Sarawak, Malaysian Borneo. We found that although Bartonella spp. infection was pervasive in most rodent species sampled, prevalence was highest in urban areas and infection was most commonly detected in the predominant indigenous rodent species sampled (Sundamys muelleri). Within the urban environment, parks and remnant green patches were significantly associated with the presence of both S. muelleri and Bartonella spp., indicating higher localized risk of infection for people using these environments for farming, foraging, or recreation.
Fulltext First detection of a novel 'unknown host' flavivirus in a Malaysian rodent

Blasdell KR, Wynne JW, Perera D, Firth C

Access Microbiol, 2021;3(4):000223.
PMID: 34151174 DOI: 10.1099/acmi.0.000223

Current phylogenetic analysis of the flavivirus genus has identified a group of mosquito-borne viruses for which the vertebrate hosts are currently unknown. Here we report the identification of a novel member of this group from a peridomestic rodent species (Sundamys muelleri) collected in Sarawak, Malaysia in 2016. We propose to name this novel flavivirus Batu Kawa virus after the location in which it was identified, with the abbreviation BKWV. Characterization of the BKWV genome allowed identification of putative mature peptides, potential enzyme motifs and conserved structural elements. Phylogenetic analysis found BKWV to be most closely related to Nhumirim virus (from Brazil) and Barkedji virus (from Senegal and Israel). Both of these viruses have been identified in Culex mosquitoes and belong to a group of viruses with unknown vertebrate hosts. This is the first known report of a member of this group of viruses from a potential mammalian host.
Fulltext Association of rodent-borne Leptospira spp. with urban environments in Malaysian Borneo

Blasdell KR, Morand S, Perera D, Firth C

PLoS Negl Trop Dis, 2019 02;13(2):e0007141.
PMID: 30811387 DOI: 10.1371/journal.pntd.0007141

Although leptospirosis is traditionally considered a disease of rural, agricultural and flooded environments, Leptospira spp. are found in a range of habitats and infect numerous host species, with rodents among the most significant reservoirs and vectors. To explore the local ecology of Leptospira spp. in a city experiencing rapid urbanization, we assessed Leptospira prevalence in rodents from three locations in Malaysian Borneo with differing levels of anthropogenic influence: 1) high but stable influence (urban); 2) moderate yet increasing (developing); and 3) low (rural). A total of 116 urban, 122 developing and 78 rural rodents were sampled, with the majority of individuals assigned to either the Rattus rattus lineage R3 (n = 165) or Sundamys muelleri (n = 100). Leptospira spp. DNA was detected in 31.6% of all rodents, with more urban rodents positive (44.8%), than developing (32.0%) or rural rodents (28.1%), and these differences were statistically significant. The majority of positive samples were identified by sequence comparison to belong to known human pathogens L. interrogans (n = 57) and L. borgpetersenii (n = 38). Statistical analyses revealed that both Leptospira species occurred more commonly at sites with higher anthropogenic influence, particularly those with a combination of commercial and residential activity, while L. interrogans infection was also associated with low forest cover, and L. borgpetersenii was more likely to be identified at sites without natural bodies of water. This study suggests that some features associated with urbanization may promote the circulation of Leptospira spp., resulting in a potential public health risk in cities that may be substantially underestimated.
Fulltext Dengue virus serotype 2 from a sylvatic lineage isolated from a patient with dengue hemorrhagic fever

Cardosa J, Ooi MH, Tio PH, Perera D, Holmes EC, Bibi K, et al.

PLoS Negl Trop Dis, 2009;3(4):e423.
PMID: 19399166 DOI: 10.1371/journal.pntd.0000423

Dengue viruses circulate in both human and sylvatic cycles. Although dengue viruses (DENV) infecting humans can cause major epidemics and severe disease, relatively little is known about the epidemiology and etiology of sylvatic dengue viruses. A 20-year-old male developed dengue hemorrhagic fever (DHF) with thrombocytopenia (12,000/ul) and a raised hematocrit (29.5% above baseline) in January 2008 in Malaysia. Dengue virus serotype 2 was isolated from his blood on day 4 of fever. A phylogenetic analysis of the complete genome sequence revealed that this virus was a member of a sylvatic lineage of DENV-2 and most closely related to a virus isolated from a sentinel monkey in Malaysia in 1970. This is the first identification of a sylvatic DENV circulating in Asia since 1975.
Isolation of subgenus B adenovirus during a fatal outbreak of enterovirus 71-associated hand, foot, and mouth disease in Sibu, Sarawak

Cardosa MJ, Krishnan S, Tio PH, Perera D, Wong SC

Lancet, 1999 Sep 18;354(9183):987-91.
PMID: 10501361

In mid-1997, several children died in Sarawak, Malaysia, during an epidemic of enterovirus-71 (EV71) hand, foot, and mouth disease. The children who died had a febrile illness that rapidly progressed to cardiopulmonary failure and the cause was not satisfactorily resolved. We describe the isolation and identification of a subgenus B adenovirus from the children who died.
Molecular epidemiology of human enterovirus 71 strains and recent outbreaks in the Asia-Pacific region: comparative analysis of the VP1 and VP4 genes

Cardosa MJ, Perera D, Brown BA, Cheon D, Chan HM, Chan KP, et al.

Emerg Infect Dis, 2003 Apr;9(4):461-8.
PMID: 12702227

This study provides a comprehensive overview of the molecular epidemiology of human enterovirus 71 (HEV71) in the Asia-Pacific region from 1997 through 2002. Phylogenetic analysis of the VP4 and VP1 genes of recent HEV71 strains indicates that several genogroups of the virus have been circulating in the Asia-Pacific region since 1997. The first of these recent outbreaks, described in Sarawak (Malaysian Borneo) in 1997, was caused by genogroup B3. This outbreak was followed by large outbreaks in Taiwan in 1998, caused by genogroup C2, and in Perth (Western Australia) in 1999, where viruses belonging to genogroups B3 and C2 cocirculated. Singapore, Taiwan, and Sarawak had HEV71 epidemics in 2000, caused predominantly by viruses belonging to genogroup B4; however, large numbers of fatalities were observed only in Taiwan. HEV71 was identified during an epidemic of hand, foot and mouth disease in Korea; that epidemic was found to be due to viruses constituting a new genogroup, C3.
Fulltext Improving the Diagnosis, Management, and Outcomes of Children with Pneumonia: Where are the Gaps?

Chang AB, Ooi MH, Perera D, Grimwood K

Front Pediatr, 2013;1:29.
PMID: 24400275 DOI: 10.3389/fped.2013.00029

Pneumonia is the greatest contributor to childhood mortality and morbidity in resource-poor regions, while in high-income countries it is one of the most common reasons for clinic attendance and hospitalization in this age group. Furthermore, pneumonia in children increases the risk of developing chronic pulmonary disorders in later adult life. While substantial advances in managing childhood pneumonia have been made, many issues remain, some of which are highlighted in this perspective. Multiple studies are required as many factors that influence outcomes, such as etiology, patient characteristics, and prevention strategies can vary between and within countries and regions. Also, outside of vaccine studies, most randomized controlled trials (RCTs) on pneumonia have been based in resource-poor countries where the primary aim is usually prevention of mortality. Few RCTs have focused on medium to long-term outcomes or prevention. We propose different tiers of primary outcomes, where in resource-rich countries medium to long-term sequelae should also be included and not just the length of hospitalization and readmission rates.
Cost-effective complete genome sequencing using the MinION platform for identification of recombinant enteroviruses

Chien YS, Chen FJ, Wu HC, Lin CH, Chang WC, Perera D, et al.

Microbiol Spectr, 2023 Oct 13.
PMID: 37831475 DOI: 10.1128/spectrum.02507-23

Enteroviruses (EVs) are a group of viruses that cause various human illnesses. While the CODEHOP (COnsensus-DEgenerate Hybrid Oligonucleotide Primer) method can generate VP1 gene fragments for enterovirus genotyping, it is unable to detect recombinant strains. Recent advances in viral genome sequencing using next-generation sequencing technologies have enabled comprehensive analyses. However, the high cost poses a challenge for widespread adoption. To address this issue, this study proposes a cost-effective approach for generating complete enterovirus genome sequences using the Oxford Nanopore MinION sequencer. This protocol not only facilitates the generation of accurate genome sequences for various enterovirus strains but also allows for the differentiation of co-infections from viral isolates. In addition, the method can generate polyprotein sequences as well as peptide sequences of the upstream ORF (uORF) whose expression can impact virus infection. Through the analysis of complete enterovirus genomes, this study successfully identified seven enterovirus A71 isolates obtained during the 2018 enterovirus outbreak in Malaysia and Taiwan as recombinants between enterovirus A71 and coxsackievirus A2. Furthermore, our study has made a significant discovery by establishing a strong correlation between uORF trees and the epidemics of EVA71. This finding highlights the potential of uORF sequences as valuable indicators for monitoring and understanding the spread of EVA71 infections. We also identified notable amino acid changes in the transmembrane domain of the uORF protein within a newly identified lineage. These findings provide crucial insights into the molecular characteristics and evolutionary dynamics of EVA71, offering valuable information for future research and intervention strategies. IMPORTANCE By employing a cost-effective approach for complete genome sequencing, the study has enabled the identification of novel enterovirus strains and shed light on the genetic exchange events during outbreaks. The success rate of genome sequencing and the scalability of the protocol demonstrate its practical utility for routine enterovirus surveillance. Moreover, the study's findings of recombinant strains of EVA71 and CVA2 contributing to epidemics in Malaysia and Taiwan emphasize the need for accurate detection and characterization of enteroviruses. The investigation of the whole genome and upstream ORF sequences has provided insights into the evolution and spread of enterovirus subgenogroups. These findings have important implications for the prevention, control, and surveillance of enteroviruses, ultimately contributing to the understanding and management of enterovirus-related illnesses.
Establishment of Asia-Pacific Network for Enterovirus Surveillance

Chiu ML, Luo ST, Chen YY, Chung WY, Duong V, Dussart P, et al.

Vaccine, 2020 01 03;38(1):1-9.
PMID: 31679864 DOI: 10.1016/j.vaccine.2019.09.111

Enteroviruses (EV), the major pathogens of hand, foot, and mouth disease (HFMD) and herpangina, affect millions of children each year. Most human enteroviruses cause self-limited infections except polioviruses, enterovirus A71 (EV-A71), enterovirus D68 (EV-D68), and several echoviruses (Echo) and coxsackieviruses (CV). Especially, EV-A71 has repeatedly caused large-scale outbreaks in the Asia-Pacific region since 1997. Some Asian countries have experienced cyclical outbreaks of severe EV-A71 infections and initiated development of EV-A71 vaccines. Five EV-A71 vaccine candidates have been clinically evaluated and three of them were approved for marketing in China. However, none of the China-approved products seek marketing approval in other countries. This situation supports a role for collaboration among Asian countries to facilitate clinical trials and licensure of EV-A71 vaccines. Additionally, enterovirus D68 outbreaks have been reported in the US and Taiwan currently and caused severe complications and deaths. Hence, an Asia-Pacific Network for Enterovirus Surveillance (APNES) has been established to estimate disease burden, understand virus evolution, and facilitate vaccine development through harmonizing laboratory diagnosis and data collection. Founded in 2017, the APNES is comprised of internationally recognized experts in the field of enterovirus in Asian countries working to raise awareness of this potentially fatal and debilitating disease. This article demonstrated the summaries of the first expert meeting, 2017 International Workshop on Enterovirus Surveillance and Vaccine Development, held by APNES in Taipei, Taiwan, March 2017.
In enterovirus 71 encephalitis with cardio-respiratory compromise, elevated interleukin 1β, interleukin 1 receptor antagonist, and granulocyte colony-stimulating factor levels are markers of poor prognosis

Griffiths MJ, Ooi MH, Wong SC, Mohan A, Podin Y, Perera D, et al.

J Infect Dis, 2012 Sep 15;206(6):881-92.
PMID: 22829643 DOI: 10.1093/infdis/jis446

BACKGROUND: Enterovirus 71 (EV71) causes large outbreaks of hand, foot, and mouth disease (HFMD), with severe neurological complications and cardio-respiratory compromise, but the pathogenesis is poorly understood.
METHODS: We measured levels of 30 chemokines and cytokines in serum and cerebrospinal fluid (CSF) samples from Malaysian children hospitalized with EV71 infection (n = 88), comprising uncomplicated HFMD (n = 47), meningitis (n = 8), acute flaccid paralysis (n = 1), encephalitis (n = 21), and encephalitis with cardiorespiratory compromise (n = 11). Four of the latter patients died.
RESULTS: Both pro-inflammatory and anti-inflammatory mediator levels were elevated, with different patterns of mediator abundance in the CSF and vascular compartments. Serum concentrations of interleukin 1β (IL-1β), interleukin 1 receptor antagonist (IL-1Ra), and granulocyte colony-stimulating factor (G-CSF) were raised significantly in patients who developed cardio-respiratory compromise (P = .013, P = .004, and P < .001, respectively). Serum IL-1Ra and G-CSF levels were also significantly elevated in patients who died, with a serum G-CSF to interleukin 5 ratio of >100 at admission being the most accurate prognostic marker for death (P < .001; accuracy, 85.5%; sensitivity, 100%; specificity, 84.7%).
CONCLUSIONS: Given that IL-1β has a negative inotropic action on the heart, and that both its natural antagonist, IL-1Ra, and G-CSF are being assessed as treatments for acute cardiac impairment, the findings suggest we have identified functional markers of EV71-related cardiac dysfunction and potential treatment options.
Retraction Note: Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection

Gunaseelan S, Ariffin MZ, Khanna S, Ooi MH, Perera D, Chu JJH, et al.

Nat Commun, 2023 Feb 24;14(1):1053.
PMID: 36828847 DOI: 10.1038/s41467-023-36751-2
Fulltext Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection

Gunaseelan S, Ariffin MZ, Khanna S, Ooi MH, Perera D, Chu JJH, et al.

Nat Commun, 2022 Feb 16;13(1):890.
PMID: 35173169 DOI: 10.1038/s41467-022-28533-z

Hand, foot and mouth disease (HFMD) caused by Human Enterovirus A71 (HEVA71) infection is typically a benign infection. However, in minority of cases, children can develop severe neuropathology that culminate in fatality. Approximately 36.9% of HEVA71-related hospitalizations develop neurological complications, of which 10.5% are fatal. Yet, the mechanism by which HEVA71 induces these neurological deficits remain unclear. Here, we show that HEVA71-infected astrocytes release CXCL1 which supports viral replication in neurons by activating the CXCR2 receptor-associated ERK1/2 signaling pathway. Elevated CXCL1 levels correlates with disease severity in a HEVA71-infected mice model. In humans infected with HEVA71, high CXCL1 levels are only present in patients presenting neurological complications. CXCL1 release is specifically triggered by VP4 synthesis in HEVA71-infected astrocytes, which then acts via its receptor CXCR2 to enhance viral replication in neurons. Perturbing CXCL1 signaling or VP4 myristylation strongly attenuates viral replication. Treatment with AZD5069, a CXCL1-specific competitor, improves survival and lessens disease severity in infected animals. Collectively, these results highlight the CXCL1-CXCR2 signaling pathway as a potential target against HFMD neuropathogenesis.
Fulltext Characterization of Three New Insect-Specific Flaviviruses: Their Relationship to the Mosquito-Borne Flavivirus Pathogens

Guzman H, Contreras-Gutierrez MA, Travassos da Rosa APA, Nunes MRT, Cardoso JF, Popov VL, et al.

Am J Trop Med Hyg, 2018 02;98(2):410-419.
PMID: 29016330 DOI: 10.4269/ajtmh.17-0350

Three novel insect-specific flaviviruses, isolated from mosquitoes collected in Peru, Malaysia (Sarawak), and the United States, are characterized. The new viruses, designated La Tina, Kampung Karu, and Long Pine Key, respectively, are antigenically and phylogenetically more similar to the mosquito-borne flavivirus pathogens, than to the classical insect-specific viruses like cell fusing agent and Culex flavivirus. The potential implications of this relationship and the possible uses of these and other arbovirus-related insect-specific flaviviruses are reviewed.
Importation and co-circulation of multiple serotypes of dengue virus in Sarawak, Malaysia

Holmes EC, Tio PH, Perera D, Muhi J, Cardosa J

Virus Res, 2009 Jul;143(1):1-5.
PMID: 19463715 DOI: 10.1016/j.virusres.2009.02.020

Although dengue is a common disease in South-East Asia, there is a marked absence of virological data from the Malaysian state of Sarawak located on the island of Borneo. From 1997 to 2002 we noted the co-circulation of DENV-2, DENV-3 and DENV-4 in Sarawak. To determine the origins of these Sarawak viruses we obtained the complete E gene sequences of 21 isolates. A phylogenetic analysis revealed multiple entries of DENV-2 and DENV-4 into Sarawak, such that multiple lineages co-circulate, yet with little exportation from Sarawak. Notably, all viral isolates were most closely related to those circulating in different localities in South-East Asia. In sum, our analysis reveals a frequent traffic of DENV in South-East Asia, with Sarawak representing a local sink population.
Coxsackievirus A16 in a 1-Day-Old Mouse Model of Central Nervous System Infection Shows Lower Neurovirulence than Enterovirus A71

Hooi YT, Ong KC, Tan SH, Perera D, Wong KT

J Comp Pathol, 2020 Apr;176:19-32.
PMID: 32359633 DOI: 10.1016/j.jcpa.2020.02.001

Coxsackievirus A16 (CV-A16) and enterovirus A71 (EV-A71) are the major causes of hand, foot and mouth disease in young children. Although less so with CV-A16, both viruses are associated with serious neurological syndromes, but the differences between their central nervous system infections remain unclear. We conducted a comparative infection study using clinically-isolated CV-A16 and EV-A71 strains in a 1-day-old mouse model to better understand the neuropathology and neurovirulence of the viruses. New serotype-specific probes for in situ hybridization were developed and validated to detect CV-A16 and EV-A71 RNA in infected tissues. Demonstration of CV-A16 virus antigens/RNA, mainly in the brainstem and spinal cord neurons, confirmed neurovirulence, but showed lower densities than in EV-A71 infected animals. A higher lethal dose50 for CV-A16 suggested that CV-A16 is less neurovirulent. Focal virus antigens/RNA in the anterior horn white matter and adjacent efferent motor nerves suggested that neuroinvasion is possibly via retrograde axonal transport in peripheral motor nerves.
A novel orally infected hamster model for Coxsackievirus A16 hand-foot-and-mouth disease and encephalomyelitis

Hooi YT, Ong KC, Tan SH, Perera D, Wong KT

Lab Invest, 2020 Sep;100(9):1262-1275.
PMID: 32601355 DOI: 10.1038/s41374-020-0456-x

Coxsackievirus A16 (CV-A16) is one of the major causes of mild and self-limiting hand-foot-and-mouth disease (HFMD) in young children, which may occasionally leads to serious neurological complications. In this study, we had developed a novel, consistent, orally infected CV-A16 HFMD hamster model with encephalomyelitis. Four groups of 7-day-old hamsters in a kinetic study were orally infected with mouse-adapted CV-A16 strains and sacrificed at 1-4 days post infection (dpi), respectively. Tissues were studied by light microscopy, immunohistochemistry to detect viral antigens, in situ hybridization to detect viral RNA, and by viral titration. In a separate transmission experiment, orally infected index hamsters were housed together with contact hamsters to investigate oral and fecal viral shedding by virus culture and reverse transcription polymerase chain reaction (RT-PCR). At severe infection/death endpoints, index and contact hamster infection were also histopathologically analyzed. In the kinetic study, infected hamsters developed signs of infection at 4 dpi. Viral antigens/RNA were localized to brainstem (medulla/pons; reticular formation and motor trigeminal nucleus) and spinal cord anterior horn neurons, oral squamous epithelia and epidermis from 3 to 4 dpi. Salivary and lacrimal glands, myocardium, brown adipose tissue, intestinal smooth muscle, and skeletal muscle infection was also demonstrated. Viremia at 1 dpi and increasing viral titers in various tissues were observed from 2 dpi. In the transmission study, all contact hamsters developed disease 3-5 days later than index hamsters, but demonstrated similar histopathological findings at endpoint. Viral culture and RT-PCR positive oral washes and feces confirmed viral shedding. Our hamster model, orally infected by the natural route for human infection, confirmed CV-A16 neurotropism and demonstrated squamous epitheliotropism reminiscent of HFMD, attributes not found in other animal models. It should be useful to investigate neuropathogenesis, model person-to-person transmission, and for testing antiviral drugs and vaccines.
Fulltext Development and user testing study of MozzHub: a bipartite network-based dengue hotspot detector

Labadin J, Hong BH, Tiong WK, Gill BS, Perera D, Rigit ARH, et al.

Multimed Tools Appl, 2023;82(11):17415-17436.
PMID: 36404933 DOI: 10.1007/s11042-022-14120-3

Traditionally, dengue is controlled by fogging, and the prime location for the control measure is at the patient's residence. However, when Malaysia was hit by the first wave of the Coronavirus disease (COVID-19), and the government-imposed movement control order, dengue cases have decreased by more than 30% from the previous year. This implies that residential areas may not be the prime locations for dengue-infected mosquitoes. The existing early warning system was focused on temporal prediction wherein the lack of consideration for spatial component at the microlevel and human mobility were not considered. Thus, we developed MozzHub, which is a web-based application system based on the bipartite network-based dengue model that is focused on identifying the source of dengue infection at a small spatial level (400 m) by integrating human mobility and environmental predictors. The model was earlier developed and validated; therefore, this study presents the design and implementation of the MozzHub system and the results of a preliminary pilot test and user acceptance of MozzHub in six district health offices in Malaysia. It was found that the MozzHub system is well received by the sample of end-users as it was demonstrated as a useful (77.4%), easy-to-operate system (80.6%), and has achieved adequate client satisfaction for its use (74.2%).

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