A comprehensive characterization of chronic norovirus infection in immunodeficient hosts.
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ABSTRACT:
SUBMITTER: Brown LK
PROVIDER: S-EPMC6843911 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The noroviruses are a leading cause of gastroenteritis worldwide. Although the illness is normally mild and self-limiting, there is a growing literature documenting the chronic excretion of norovirus in the immunocompromised. The aim of the current study was to examine the molecular features of chronic norovirus excretion in an immunocompromised patient with a past history of Burkitt lymphoma. During the 241 day course of the study from December 2013 to August 2014, seven faecal specimens were collected from the patient, tested for norovirus by RT-PCR and further analysed in the open reading frame (ORF) 1 and ORF 2 regions. All seven specimens were positive for norovirus by RT-PCR. Molecular sequencing in the polymerase (ORF 1) and capsid (ORF 2) regions indicated that the norovirus could be classified as GII.4 (2006b)/GII.4 (unknown). No significant mutation was found in the ORF 1 or ORF 2 regions analysed over the period of the study. The current report appears to be the first to document chronic norovirus excretion in a patient with a past history of Burkitt lymphoma. It is also the first to indicate long term norovirus excretion in a given individual need not involve major genetic change in key regions of the genome.
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Project description:Noroviruses are a major cause of acute gastroenteritis worldwide and can establish chronic infection in immunocompromised individuals. To investigate the mechanisms of norovirus evolution during chronic infection, we selected seven representative patients from a National Institutes of Health study cohort who sustained norovirus infection for periods ranging from 73 to 1,492 days. Six patients shed viruses belonging to a single genotype (GII.2[PNA], GII.4 New Orleans[P4], GII.4 Den Haag[P4], GII.3[P21], GII.6[P7], or GII.14[P7]) over the period examined, while one patient sequentially shed two genotypes (GII.6[P7] followed by GII.4 Sydney[P31]). Norovirus genomes from consecutive stool samples were sequenced at high resolution (>3,300 reads/nucleotide position) using the Illumina platform and subjected to bioinformatics analysis. Norovirus sequences could be resolved into one or more discrete clonal RNA genomes that persisted within these patients over time. Phylogenetic analyses inferred that clonal populations originated from a single founder virus and not by reinfection with community strains. Estimated evolutionary rates of clonal populations during persistent infection were similar to those of noroviruses from acute infection in the global database, suggesting that inherently higher RNA-dependent polymerase error rates were not associated with the ability to persist. The high-resolution analysis of norovirus diversity and evolution at the population level described here should allow a better understanding of adaptive mutations sustained during chronic infection. IMPORTANCE Noroviruses are an important cause of chronic diarrhea in patients with compromised immune systems. Presently, there are no effective therapies to clear the virus, which can persist for years in the intestinal tract. The goal of our study was to develop a better understanding of the norovirus strains that are associated with these long-term infections. With the remarkable diversity of norovirus strains detected in the immunocompromised patient cohort we studied, it appears that most, if not all, noroviruses circulating in nature may have the capacity to establish a chronic infection when a person is unable to mount an effective immune response. Our work is the most comprehensive genetic data set generated to date in which near full-length genomes from noroviruses associated with chronic infection were analyzed by high-resolution next-generation sequencing. Analysis of this data set led to our discovery that certain patients in our cohort were shedding noroviruses that could be subdivided into distinct haplotypes or populations of viruses that were co-evolving independently. The ability to track haplotypes of noroviruses during chronic infection will allow us to fine-tune our understanding of how the virus adapts and maintains itself in the human host, and how selective pressures such as antiviral drugs can affect these distinct populations.
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