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Characterization of Tonsil Microbiota and Their Effect on Adenovirus Reactivation in Tonsillectomy Samples.

ABSTRACT: The adenoviral DNA is prevalent in adenotonsillectomy specimens from pediatric patients, though the virus seems to be in latent state. The tonsils are at the forefront of airway entry point and are the first line of defense against airway viral and bacterial infections. We hypothesized that tonsil microbiota plays a role in human adenovirus (HAdV) latency and reactivation. In this study, we surveyed the presence of HAdV in tonsillectomy samples from 81 patients and found that HAdV DNA was in 85.2% of the tonsil samples. We then determined the microbiota of the samples. Taxonomic profiling showed that Proteobacteria, Firmicutes, Fusobacteriota, and Bacteroidota accounted for approximately 70% of the total phyla in tonsil samples. A correlation analysis showed that the HAdV-positive samples had significantly higher abundance of Neisseria and Bifidobacterium and lower abundance of Streptococcus, Ochrobactrum, and Lactobacillus than that of the HAdV-negative samples. Culture-based isolation followed by 16S rRNA sequencing identified Staphylococcus aureus, Streptococcus pneumoniae, Veillonella, Prevotella, Capnocytophaga sputigena, Pseudomonas aeruginosa, Neisseria, and Moraxella catarrhalis from the samples. Gas chromatography-mass spectrometry (GC-MS) profiling of short-chain fatty acids in bacterial cultures of minced tonsillectomy tissues or representative isolates showed the cultures contained various amounts of short-chain fatty acids (SCFAs). Treatment of isolated tonsil lymphocytes with bacterial lipopolysaccharide (LPS) or with SCFAs promoted HAdV reactivation. The compounds also promoted HAdV reactivation in a xenograft model with implanted tonsil fragments. This study shows a potential interplay between tonsil microbiota and HAdV reactivation that may lead to recurrent virus infection of respiratory tract disease. IMPORTANCE Human adenovirus infection is common among pediatric patients and can be life-threatening among organ transplant recipients. Adenovirus is transmitted by close contact, but it is believed that a majority of invasive events appear to arise from viral reactivation. The human tonsil is a reservoir for virus latency and has a high prevalence of latently infected adenovirus. Also, tonsils are located at the gateway of the respiratory tracts and are commonly exposed to bacterial pathogens. Here, we uncovered adenoviral DNA-positive and -negative samples that appeared to harbor distinct distribution patterns of microorganisms. SCFAs, primary metabolites of microbiota on tonsils, could induce the adenovirus reactivation in tonsil lymphocytes, resulting in adenovirus replication and production of infectious virions. The study suggests that viral-bacterial interaction plays a role in virus reactivation from latency and could be a contributing factor for recurrent viral infection in pediatric patients.

SUBMITTER: Wang L

PROVIDER: S-EPMC8528100 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Adenovirus (HAdV) infection is a common cause of illness among young children, immunocompromised patients, and transplant recipients. The majority of HAdV infections are self-limited, but recurring infection is frequently encountered in young children and may require hospitalization. In this study, we surveyed the presence of HAdV in tonsillectomy samples and investigated epigenetic conditions that contributed to HAdV reactivation. HAdV DNA was detected from 86.7% donors. The lymphocytes isolated from the samples failed to produce infectious HAdV after incubation, suggesting the viruses remained in a latent status. To determine whether epigenetic factors played a role in HAdV reactivation, isolated lymphocytes were treated with a small compound library. Viral DNA replication and infectious HAdV production were assayed by PCR and by a secondary infection assay. We identified several compounds, mainly pan- and selective histone deacetylase (HDAC) inhibitors, which showed activity to reactivate HAdV from latency. The viruses were isolated and were determined as species C HAdV. Using a model of HAdV lytic infection, we showed that the compounds promoted histone-3 acetylation and association with viral early gene promoters. In addition to demonstrate the palatine tonsils as a reservoir of latent HAdV, this study uncovers a critical role of histone acetylation in HAdV reactivation, linking HAdV latency to recurrent HAdV infection.IMPORTANCE Respiratory tract infection by adenoviruses is among the most common diseases in children, attributing to approximately 20% of hospitalizations of children with acute respiratory infection (ARI). Adenovirus transmits by direct contact, but recurrent infection is common. Ever since its isolation, adenovirus has been known to have the ability to establish persistent or latent infection. We found 87.7% tonsillectomy specimens contained detectable amounts of adenoviral DNA. Isolated lymphocytes did not produce infectious adenoviruses without stimulation. By screening an epigenetic informer compound library, we identified several histone deacetylase inhibitors that promoted adenovirus reactivation that was evidenced by increased viral DNA replication and production of infectious viruses. The human tonsils are covered with bacterial pathogens that may utilize pathogen-associated pattern molecules or metabolites to cause epigenetic activation and proinflammatory gene transcription, which may lead to viral reactivation from latency. The study shows that recurrent adenovirus infection could arise from reactivation of residing virus from previous infections.

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Characterization of Tonsil Microbiota and Their Effect on Adenovirus Reactivation in Tonsillectomy Samples.

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