scholarly journals Genetic recombination in fast-spreading coxsackievirus A6 variants: a potential role in evolution and pathogenicity

2020 ◽  
Vol 6 (2) ◽  
Author(s):  
Yang Song ◽  
Yong Zhang ◽  
Zhenzhi Han ◽  
Wen Xu ◽  
Jinbo Xiao ◽  
...  

Abstract Hand, foot, and mouth disease (HFMD) is a common global epidemic. From 2008 onwards, many HFMD outbreaks caused by coxsackievirus A6 (CV-A6) have been reported worldwide. Since 2013, with a dramatically increasing number of CV-A6-related HFMD cases, CV-A6 has become the predominant HFMD pathogen in mainland China. Phylogenetic analysis based on the VP1 capsid gene revealed that subtype D3 dominated the CV-A6 outbreaks. Here, we performed a large-scale (near) full-length genetic analysis of global and Chinese CV-A6 variants, including 158 newly sequenced samples collected extensively in mainland China between 2010 and 2018. During the global transmission of subtype D3 of CV-A6, the noncapsid gene continued recombining, giving rise to a series of viable recombinant hybrids designated evolutionary lineages, and each lineage displayed internal consistency in both genetic and epidemiological features. The emergence of lineage –A since 2005 has triggered CV-A6 outbreaks worldwide, with a rate of evolution estimated at 4.17 × 10−3 substitutions site-1 year−1 based on a large number of monophyletic open reading frame sequences, and created a series of lineages chronologically through varied noncapsid recombination events. In mainland China, lineage –A has generated another two novel widespread lineages (–J and –L) through recombination within the enterovirus A gene pool, with robust estimates of occurrence time. Lineage –A, –J, and –L infections presented dissimilar clinical manifestations, indicating that the conservation of the CV-A6 capsid gene resulted in high transmissibility, but the lineage-specific noncapsid gene might influence pathogenicity. Potentially important amino acid substitutions were further predicted among CV-A6 variants. The evolutionary phenomenon of noncapsid polymorphism within the same subtype observed in CV-A6 was uncommon in other leading HFMD pathogens; such frequent recombination happened in fast-spreading CV-A6, indicating that the recovery of deleterious genomes may still be ongoing within CV-A6 quasispecies. CV-A6-related HFMD outbreaks have caused a significant public health burden and pose a great threat to children’s health; therefore, further surveillance is greatly needed to understand the full genetic diversity of CV-A6 in mainland China.

2013 ◽  
Vol 66 (3) ◽  
pp. 260-261 ◽  
Author(s):  
Masaaki Kobayashi ◽  
Tomohiko Makino ◽  
Nozomu Hanaoka ◽  
Hiroyuki Shimizu ◽  
Miki Enomoto ◽  
...  

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
Y Song ◽  
Y Zhang ◽  
W B Xu

Abstract Hand, foot, and mouth disease (HFMD) had the highest yearly incidence, with over 10 million cases of HFMD annually reported in China. Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) have been regarded as the leading pathogens of HFMD outbreaks worldwide and in China; however, in recent years, the leading pathogens have been changing, as large outbreaks of CV-A6-associated HFMD have been reported worldwide. Since 2013, repeated large-scale HFMD outbreaks caused by CV-A6 happened in mainland China, where, as a result, CV-A6 has surpassed EV-A71 and CV-A16 as the leading HFMD pathogen in most Chinese provinces. We sequenced the whole genomes of 158 CV-A6 clinical samples that were isolated between 2010 and 2018 from the HFMD Surveillance Network established in our laboratory. Our results showed that: seven recombination forms (RFs) of Chinese CV-A6 were detected; different CV-A6 RFs showed distinct virulence and transmissibility; VP1283T may play an important role in the virulence of Chinese CV-A6. HFMD epidemics in China have become a serious public health problem over the past decade. In this research, we have attempted to explore the causes of the high transmissibility of the emerging CV-A6 in mainland China on the basis of CV-A6 evolution based on 336 whole-genome sequences, and we have yielded some fruitful results for the future research and surveillance of HFMD in China. Key messages HFMD epidemics in China have become a serious public health problem over the past decade. CV-A6 has surpassed EV-A71 and CV-A16 as the leading HFMD pathogen in most Chinese provinces.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Si Xian Ho ◽  
Nyo Min ◽  
Emmerie Phaik Yen Wong ◽  
Chia Yin Chong ◽  
Justin Jang Hann Chu

AbstractWhile the underlying determinants are unclear, hand, foot and mouth disease (HFMD) presents a wide spectrum of clinical manifestations with varying severity in different individuals. Recently, many studies identified the human microbiome as a critical factor in the pathogenesis of various diseases. Therefore, we here investigated the ecological dynamics of the oral microbiome changes during the HFMD infection. After targeted enrichment of all known vertebrate viruses, the virome profiles of symptomatic and asymptomatic HFMD patients were examined and revealed to be significantly altered from those of healthy individuals, with nine discriminative viruses detected. Further characterization of the prokaryotic microbiome revealed an elevated level of Streptococcus sp. as the most important signature of the symptomatic HFMD cohort, positively correlating to the level of enterovirus A RNA. In addition, we found that while coxsackievirus A5 is detected in saliva RNA of all asymptomatic cases, coxsackievirus A6 dominates the majority of the symptomatic cohort.


Author(s):  
L.V. Butakova ◽  
O.E. Trotsenko ◽  
E.Yu. Sapega

The review presents data on epidemiological risks concerning worldwide spread of enterovirus infection due to intensified migration flows. Outbreak incidence of the most frequently registered forms of enterovirus infection – hand, foot and mouth disease (HFMD) –was analyzed. At the present time, Coxsackievirus A6 plays ever-greater significance in HFMD incidence. The article summarizes currently available scientific data on atypical Coxsackievirus A6-infection clinical manifestations. Details on the tense epidemiological situation concerning Enterovirus D68 that can be the cause of acute flaccid paralysis/myelitis are presented. According to latest recommendations, the molecular genetic techniques are the «golden standard» in diagnostics of enterovirus infection.


Author(s):  
Hae Ji Kang ◽  
Youngsil Yoon ◽  
Young-Pyo Lee ◽  
Hye-Jin Kim ◽  
Deog-Yong Lee ◽  
...  

Abstract Background Enteroviruses (EVs) occur frequently worldwide and are known to be associated with a broad spectrum of clinical manifestations from mild syndromes to neurological disease. To understand the epidemiology of EV in Korea, we characterized EV-infected cases during 2012–2019 based on national surveillance. Methods We collected specimens from patients with suspected EV infections and analyzed the data using real-time reverse-transcription polymerase chain reaction and VP1 gene sequencing. Results Among the 18 261 specimens collected, EVs were detected in 6258 (34.3%) cases. Although the most common EV types changed annually, EV-A71, echovirus 30, coxsackievirus B5, coxsackievirus A6, and coxsackievirus A10 were commonly identified. Among the human EVs, the case numbers associated with the 2 major epidemic species (EV-A and EV-B) peaked in the summer. While EV-A species affected 1-year-old children and were associated with herpangina and hand, foot, and mouth disease, EV-B species were mostly associated with neurologic manifestations. The highest incidence of EV-B species was observed in infants aged <12 months. Feces and respiratory specimens were the most predictive of EV infection. Specimens collected within 5 days of symptom onset allowed for timely virus detection. Conclusions EV-A and EV-B species co-circulating in Korea presented different epidemiologic trends in clinical presentation, affected subjects, and seasonality trends. This study could provide information for the characterization of EVs circulating in Korea to aid the development of EV antivirals and vaccines, as well as public health measures to control enteroviral diseases.


2020 ◽  
Author(s):  
Shanshan Xu ◽  
Huajun Li ◽  
Peng Qiao ◽  
Guofeng Xu ◽  
Dongying Zhao ◽  
...  

Abstract Background: Evidence of hand, foot, and mouth disease (HFMD) in neonates is limited. The aim of this study was to evaluate the clinical symptoms, pathogens, possible transmission routes, and prognosis of neonatal HFMD in Shanghai. Methods: This was a case-control study based on the HFMD registry surveillance system. All neonates and infected family members were enrolled between 2016 and 2017 in Shanghai. Neonates with HFMD were followed for at least half a year. Detailed questionnaires, medical history, and physical examination were recorded. Routine blood examination, liver and renal function, immunophenotypes of peripheral blood lymphocytes (CD3, CD4, and CD8 T-cells; NK cells), immunoglobulin (Ig) M, IgG, and IgA, and cytokine interleukin (IL-1β, IL-2R, IL-6, IL-8, IL-10, and TNF-α) levels were measured. All rectal swab specimens were collected and genotyped for enterovirus, and phylogenetic analysis based on the VP1 sequences of coxsackievirus A6 (CV-A6) was performed to investigate molecular and evolutionary characteristics. T-test or nonparametric test was used to evaluate the differences. Logistic analysis was applied to calculate the risk of clinical manifestations in the group of HFMD neonates and their paired siblings. Results: There were 16 neonates among the 12608 diagnosed patients with HFMD, accounting for 0.13%. All neonatal infections were transmitted by other members of the family, mainly the elder siblings, and were caused by CV-A6. CV-A6 was the emerging and predominant causative agent of HFMD in Shanghai. None of the neonates with HFMD experienced fever, onychomadesis, or severe complications. However, two elder sibling patients showed lethargy, and one developed hypoperfusion. In the elder siblings with HFMD, the proportion of white blood cells was generally higher than in neonates with HFMD. The immunologic function of the neonates with HFMD was basically normal. The levels of inflammatory markers were higher in both neonates and elder siblings with HFMD compared to age-matched controls. The clinical symptoms receded about one week after onset. None of the neonates had sequelae. Conclusions: In our study, CV-A6 infection in neonates was benign, but had the character of family clustering. Due to the two-child policy in China, elder siblings may be the main route of HFMD transmission.


Author(s):  
Hongbo Liu ◽  
Ming Zhang ◽  
Changzeng Feng ◽  
Shanri Cong ◽  
Danhan Xu ◽  
...  

Coxsackievirus A6 (CVA6) is a key pathogen causing hand, foot and mouth disease (HFMD). However, there are currently no specific antiviral drugs or vaccines for treating infections caused by CVA6. In this study, human rhabdomyosarcoma (RD), African green monkey kidney (Vero), and human embryonic lung diploid fibroblast (KMB17) cells were used to isolate CVA6 from 327 anal swab and fecal samples obtained during HFMD monitoring between 2009 and 2017. The VP1 genes of the isolates were sequenced and genotyped, and the biological characteristics of the representative CVA6 strains were analyzed. A total of 37 CVA6 strains of the D3 gene subtypes were isolated from RD cells, all of which belonged to the epidemic strains in mainland China. Using the adaptive culture method, 10 KMB17 cell-adapted strains were obtained; however, no Vero cell-adapted strains were acquired. Among the KMB17 cell-adapted strains, only KYN-A1205 caused disease or partial death in suckling mice, and its virulence was stronger than its RD cell-adapted strain. The pathogenic KYN-A1205 strain caused strong tropism to the muscle tissue and led to pathological changes, including muscle necrosis and nuclear fragmentation in the forelimb and hindlimb. Sequence analysis demonstrated that the KYN-A1205 strain exhibited multiple amino acid mutations after KMB17 cell adaptation. Moreover, it showed strong pathogenicity, good immunogenicity and genetic stability, and could be used as an experimental CVA6 vaccine candidate.


2019 ◽  
Vol 6 (11) ◽  
Author(s):  
Kevin G Buell ◽  
Charles Whittaker ◽  
Cédric B Chesnais ◽  
Paul D Jewell ◽  
Sébastien D S Pion ◽  
...  

Abstract Background Loiasis is mostly considered a relatively benign infection when compared with other filarial and parasitic diseases, with Calabar swellings and eyeworm being the most common signs. Yet, there are numerous reports in the literature of more serious sequelae. Establishing the relationship between infection and disease is a crucial first step toward estimating the burden of loiasis. Methods We conducted a systematic review of case reports containing 329 individuals and detailing clinical manifestations of loiasis with a focus on nonclassical, atypical presentations. Results Results indicate a high proportion (47%) of atypical presentations in the case reports identified, encompassing a wide range of cardiac, respiratory, gastrointestinal, renal, neurological, ophthalmological, and dermatological pathologies. Individuals with high microfilarial densities and residing in an endemic country were at greater risk of suffering from atypical manifestations. Conclusions Our findings have important implications for understanding the clinical spectrum of conditions associated with Loa loa infection, which extends well beyond the classical eyeworm and Calabar swellings. As case reports may overestimate the true rate of atypical manifestations in endemic populations, large-scale, longitudinal clinico-epidemiological studies will be required to refine our estimates and demonstrate causality between loiasis and the breadth of clinical manifestations reported. Even if the rates of atypical presentations were found to be lower, given that residents of loiasis-endemic areas are both numerous and the group most at risk of severe atypical manifestations, our conclusions support the recognition of loiasis as a significant public health burden across Central Africa.


2020 ◽  
Vol 11 (SPL3) ◽  
pp. 952-955
Author(s):  
Nithyanandham Masilamani ◽  
Dhanraj Ganapathy

Hand, Foot and Mouth Disease (HFM) is often a potentially infectious condition primarily caused through enteroviruses. Clinical manifestations involve erythematous papules mostly on arms, legs, and even in the oral cavity, followed by prodromal effects such as myalgia, moderate fever, and abdominal distress. This survey was conducted to assess hand, foot, and mouth disease awareness among dental students. This was a questionnaire-based cross-sectional type of survey comprising 100 dental college students in Chennai. A self-designed questionnaire containing ten queries based on the knowledge and awareness about Hand, foot and mouth disease (HFMD) among dental college students. Questionnaires were distributed through an online website survey planet. After the responses were received from 100 participants, data were collected and analysed.47% are aware of HFMD. 34%are aware of the clinical manifestation of HFMD. 31%Are aware of the mode of transmission of HFMD. 26% are aware of the preventive measures against HFMD.18%. Are aware of the incubation period of HFMD. 24%aware of treatment measures for HFMD. This study found the dental students displayed less knowledge and understanding of HFMD. Even, there are few differences in knowledge and behaviours that require enhancement. Large-scale health awareness initiatives of HFMD should be implemented by professional associations in order to fill these gaps and improve awareness in order to positively impact their attitudes.


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