Human adenovirus (HAdV-7) is a highly contagious pathogen that causes severe respiratory illnesses. However, the epidemic patterns and genetic variability of HAdV-7 circulating in mainland China have not been well elucidated. In this study, we used Chinese HAdV sentinel surveillance data obtained from 2012-2015 to investigate the clinical features of 122 HAdV-7-positive cases and performed amplification and sequence determination of three capsid genes (penton base, hexon, and fiber) from 69 isolated viruses covering from seven provinces of China. Additionally, we compared with data from representative sequences of 21 strains covering seven more provinces in China and 32 international HAdV-7 strains obtained from GenBank database to determine the phylogenetic, sequence variations, and molecular evolution of HAdV-7. The results indicated that HAdV-7 infection occurred throughout the year, and a high proportion of severe cases (27 cases, 22.1%) exhibited infantile pneumonia. Moreover, phylogenetic analysis showed that all HAdV-7 strains could be divided into two major evolutionary branches, including subtype 1 and subtype 2, and subtype 3 was also formed according to analysis of the penton base gene. Subtypes 1 and 2 co-circulated in China before 2008, and HAdV-7 strains currently circulating in China belonged to subtype 2, which was also the predominant strain circulating worldwide in recent years. Further sequence variation analysis indicated that three genes of HAdV-7 were relatively stable across time and geographic space, particularly for viruses within subtypes, which shared almost the same variation sites. Owing to continuous outbreaks caused by HAdV-7, resulting in increased illness severity and fatality rates in China, the establishment of a national HAdV surveillance system is urgently needed for the development of effective preventive and infection-control interventions for adenovirus respiratory infections in China.

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Genetic variability of human adenovirus type 7 circulating in mainland China.

Objective To analyze a possible promoting factor of the seasonality pattern of the hand foot and mouth disease(HFMD) in mainland China,and to estimate values of important parameters of HFMD.Methods We established an age-structured susceptible-infected-recoversed(SIR) model which divides the population into two age groups,0-9 years group(child group) and 10-75 years group(elder group).Based on the HFMD prevalence data in China from 2009 to2011,we estimated contact rates(β) and average forces of infection(λ) of the two age groups,and the basic reproduction number R0.The model was simulated to analyze the transmission dynamics of HFMD and the effect of the beginning of school year on the transmission patterns.Results The annual average force of infection of child group and elder group was0.42 and 0.11 respectively; the average contact rate per year was 1.28 × 10-6and 3.31 × 10-7respectively; the basic reproduction number was 8.86.With the external driving force(the beginning of school year),the system fluctuates and shows an annual pattern.Conclusions For children under 9 years old in China,the average force of infection of HFMD is higher than that of other childhood infectious diseases reported in the literature up to now.The average contact rate among children under 9 years old is higher than that among the population of 10 years and above.The beginning of school year can lead to the annual seasonality of HFMD.

Age-structured model and analysis of hand foot and mouth disease in China

Outbreaks of severe, acute hepatitis among children have recently attracted global attention. The pathogen causing the outbreak remains unknown, but there is growing evidence that it may be associated with human adenovirus (HAdV).A review of adenovirus-related clinical studies, epidemiological studies, etiological studies, and case reports was conducted by reviewers independently.HAdV can cause a wide variety of clinical symptoms. In the Mainland of China, HAdV infection accounts for 5.8%-13% of patients with acute respiratory infections, and these infections are mainly caused by species B, C, and E of HAdV. For acute conjunctivitis, 39.8%-74.9% of sporadic cases were infected by B and D species of HAdV. Outbreaks of keratoconjunctivitis and pharyngoconjunctival fever related to HAdV infection could be found throughout the country. In pediatric patients with acute gastroenteritis, HAdV-41 was the predominant HAdV type, followed by HAdV species B and C. Several types of HAdV, including HAdV-5, HAdV-7, HAdV-1, and HAdV-2, have previously been reported as potential pathogens associated with HAdV hepatitis in immunocompromised patients. However, few HAdV-related hepatitis cases have been reported in China to date.There are no systematic surveillance and clinical studies on HAdV hepatitis in China. Therefore, it is imperative to establish a nationwide HAdV virological surveillance system to collect relevant clinical, epidemiological and virological surveillance data and risk factor information as soon as possible to assess the potential risk of HAdV hepatitis among children. 

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Current status of human adenovirus infection in China

In 2017, a survey of the molecular epidemiology of human adenovirus (HAdV) infections in Southern China based on hexon and fiber genotype demonstrated that the most prevalent genotypes of HAdV were HAdV-3 (n = 62), HAdV-2 (n = 21), and HAdV-7 (n = 16). In addition, two patients were co-infected with two genotypes of HAdV. Interestingly, a novel human adenovirus C recombinant genotype strain was isolated from one of the pneumonia patients in this survey. Phylogenetic, recombination, and proteotyping analysis showed that this novel pathogen originated from the recombination of parental viruses harboring the HAdV-1 penton and hexon gene, and the HAdV-2 fiber gene. It was named 'P1H1F2' and was assigned as HAdV-C104 based on the nomenclature protocol of using three major capsid proteins for characterization. Subsequent in vitro experiments demonstrated that HAdV-C104 had comparable proliferation capacity to HAdV-1, HAdV-2, and another recombination genotype P1H2F2. In addition, the HAdV-C104 infected patient was diagnosed with pneumonia and recovered after antiviral therapy. This report strengthens the hypothesis of recombination as a major pathway for the molecular evolution of HAdV-C species.

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Emergence and characterization of a putative novel human adenovirus recombinant HAdV-C104 causing pneumonia in Southern China

Human Adenoviruses (HAdVs) cause a wide array of illnesses in all age groups. They particularly cause frequent morbidity among children. In China, human adenovirus types 3, 4, 7, 11, 14, 21, and 55 have caused at least seven outbreaks since 2000. However, limited studies are available regarding the epidemiological patterns and diversity of HAdVs types among hospitalized patients with respiratory tract infections (RTIs). To understand the epidemiology and subtype distribution of HAdV infections associated with RTIs in China, nasal swab (NS) clinical samples were collected from 4129 patients in a Guangzhou hospital between August 2017 and October 2019. PCR, sequencing, and phylogenetic analysis were performed on these specimens to identify HAdV subtypes. HAdV was successfully sequenced in 99 (2.4%) of the 4129 NS specimens, with the highest HAdV prevalence (6.3%) found in children between the ages of 5 and 10 years. Among HAdV-positive specimens, the most prevalent genotypes identified were HAdV-B3 (55.6%) and HAdV-B7 (25.3%). The most common symptoms in the HAdV-infected patients were fever (100%), cough (80.8%), and rhinorrhea (71.8%). HAdV infections were detected throughout the year with a relatively higher prevalence in summer. All ages suffer adenovirus infections, but young children are at the greatest risk. This study data demonstrates that at least three species of HAdVs (species B, C, and E) are circulating in Guangzhou City, China. As antiviral therapies and type-specific vaccines become available, such epidemiological data will be useful in guiding therapy and public health interventions.

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Molecular typing of human adenoviruses among hospitalized patients with respiratory tract infections in a tertiary Hospital in Guangzhou, China between 2017 and 2019

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.

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

To date, at least three lineages (Lineage 1–3) that are related to recombinant human adenovirus species C (HAdV-C) have been identified in China. Among them, Lineage 1 includes two Chinese strains, strain KR699642-CHN-20093 (CBJ11) and strain MF315029-CHN-2013 (BJ09), which were collected in Beijing in 2009 and 2013, respectively. Herein, we performed genomic and bioinformatics analysis of two HAdV-C strains (strain SX-2000-140 and strain SX-2004-327) that were isolated from the feces of two healthy children in Shanxi province of China in 2000 and 2004, respectively. Results revealed that the genomes of both Shanxi strains had the highest homology to two Chinese HAdV-C strains belonging to Lineage 1 and harbored the genetic elements of these two strains, thereby presuming that Lineage1 has been circulated in mainland of China for decades. In addition, though the viruses in Lineage 1 showed slightly different recombinant patterns resulting from the recombinant events among the five types of HAdV-C, all the Lineage 1 viruses shared the highest sequence similarities with the HAdV-2 prototype strain (NC_001405-USA-1953) across the genome, especially in the major capsid genes including hexon, and fiber. These results indicated that Lineage 1 viruses that were associated with recombinants shared a common ancestor that is closely related to the HAdV-2 virus. Our current findings confirmed that frequent recombination among the different HAdV-C types might be an important driving force for the molecular evolution of HAdV-C. Therefore, there is a strong need for further comprehensive and systematic monitoring, detection, and research on HAdV-C.

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Jianfang Yang

Papers

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

Human adenovirus species C recombinant virus continuously circulated in China.

Multiple divergent Human mastadenovirus C co-circulating in mainland of China.