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Detection of human norovirus in intestinal biopsies from immunocompromised transplant patients.

ABSTRACT: Human noroviruses (HuNoVs) can often cause chronic infections in solid organ and haematopoietic stem cell transplant (HSCT) patients. Based on histopathological changes observed during HuNoV infections, the intestine is the presumed site of virus replication in patients; however, the cell types infected by HuNoVs remain unknown. The objective of this study was to characterize histopathological changes during HuNoV infection and to determine the cell types that may be permissive for HuNoV replication in transplant patients. We analysed biopsies from HuNoV-infected and non-infected (control) transplant patients to assess histopathological changes in conjunction with detection of HuNoV antigens to identify the infected cell types. HuNoV infection in immunocompromised patients was associated with histopathological changes such as disorganization and flattening of the intestinal epithelium. The HuNoV major capsid protein, VP1, was detected in all segments of the small intestine, in areas of biopsies that showed histopathological changes. Specifically, VP1 was detected in enterocytes, macrophages, T cells and dendritic cells. HuNoV replication was investigated by detecting the non-structural proteins, RdRp and VPg. We detected RdRp and VPg along with VP1 in duodenal and jejunal enterocytes. These results provide critical insights into histological changes due to HuNoV infection in immunocompromised patients and propose human enterocytes as a physiologically relevant cell type for HuNoV cultivation.

SUBMITTER: Karandikar UC

PROVIDER: S-EPMC5756488 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Detection of human norovirus in intestinal biopsies from immunocompromised transplant patients.

Karandikar Umesh C UC Crawford Sue E SE Ajami Nadim J NJ Murakami Kosuke K Kou Baijun B Ettayebi Khalil K Papanicolaou Genovefa A GA Jongwutiwes Ubonvan U Perales Miguel-Angel MA Shia Jinru J Mercer David D Finegold Milton J MJ Vinjé Jan J Atmar Robert L RL Estes Mary K MK

The Journal of general virology 20160712 9

Human noroviruses (HuNoVs) can often cause chronic infections in solid organ and haematopoietic stem cell transplant (HSCT) patients. Based on histopathological changes observed during HuNoV infections, the intestine is the presumed site of virus replication in patients; however, the cell types infected by HuNoVs remain unknown. The objective of this study was to characterize histopathological changes during HuNoV infection and to determine the cell types that may be permissive for HuNoV replica ...[more]

PMID: 27412790

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Project description:UnlabelledNoroviruses are the leading cause of acute gastroenteritis outbreaks worldwide. The majority of norovirus outbreaks are caused by genogroup II.4 (GII.4). Novel GII.4 strains emerge every 2 to 4 years and replace older variants as the dominant norovirus. Novel variants emerge through a combination of recombination, genetic drift, and selection driven by population immunity, but the exact mechanism of how or where is not known. We detected two previously unknown novel GII.4 variants, termed GII.4 UNK1 and GII.4 UNK2, and a diverse norovirus population in fecal specimens from immunocompromised individuals with diarrhea after they had undergone bone marrow transplantation. We hypothesized that immunocompromised individuals can serve as reservoirs for novel norovirus variants. To test our hypothesis, metagenomic analysis of viral RNA populations was combined with a full-genome bioinformatic analysis of publicly available GII.4 norovirus sequences from 1974 to 2014 to identify converging sites. Variable sites were proportionally more likely to be within two amino acids (P < 0.05) of positively selected sites. Further analysis using a hypergeometric distribution indicated that polymorphic site distribution was random and its proximity to positively selected sites was dependent on the size of the norovirus genome and the number of positively selected sites.In conclusion, random mutations may have a positive impact on driving norovirus evolution, and immunocompromised individuals could serve as potential reservoirs for novel GII.4 strains.ImportanceNorovirus is the most common cause of viral gastroenteritis in the United States. Every 2 to 3 years novel norovirus variants emerge and replace dominant strains. The continual emergence of novel noroviruses is believed to be caused by a combination of genetic drift, population immunity, and recombination, but exactly how this emergence occurs remains unknown. In this study, we identified two novel GII.4 variants in immunocompromised bone marrow transplant patients. Using metagenomic and bioinformatic analysis, we showed that most genetic polymorphisms in the novel variants occur near 0 to 2 amino acids of positively selected sites, but the distribution of mutations was random; clustering of polymorphisms with positively selected sites was a result of genome size and number of mutations and positively selected sites. This study shows that immunocompromised patients can harbor infectious novel norovirus variants, and although mutations in viruses are random, they can have a positive effect on viral evolution.

Project description:Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients.A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT.Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3-46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT.This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients.

Project description:MOLECULAR PROFILING IMPROVES DIAGNOSES OF REJECTION AND INFECTION IN TRANSPLANTED ORGANS. The monitoring of transplanted hearts is currently based on histological evaluation of endomyocardial biopsies, a method that is fairly insensitive and that does not always accurately discriminate between rejection and infection in the heart. Accurate diagnosis of rejection and infection is absolutely crucial, however, as the respective treatments are completely different. Using microarrays we analyzed gene expression in 76 cardiac biopsies from 40 heart recipients undergoing rejection, no rejection, or T. cruzi infection. We found a set of 98 genes whose expression patterns were typical of acute rejection, and 87 genes that discriminated between rejection and T. cruzi infection. These sets revealed acute rejection episodes up to two weeks earlier, and trypanosome infection up to two months earlier than did histological evaluation. When applied to raw data from other institutions, the two sets of predictive genes were also able to accurately pinpoint acute rejection of lung and kidney transplants, as well as bacterial infections in kidneys. In addition to their usefulness as diagnostic tools, the data suggest that there are similarities in the biology of the processes involved in rejection of different grafts and also in the tissue responses to pathogens as diverse as bacteria and protozoa. pre-rejection: GSM47949, GSM48048, GSM49625 non-rejection: GSM47957, GSM48045, GSM48049, GSM48057, GSM48072, GSM48089, GSM48092, GSM49624, GSM49654, GSM49656, GSM49657, GSM49658, GSM49661, GSM49666, GSM49748, GSM49750, GSM49751, GSM49752, GSM49754, GSM49756, GSM49757, GSM49758, GSM49762, GSM49765, GSM49766, GSM49767, GSM49769, GSM49771, GSM49773, GSM49774, GSM49781, GSM49782, GSM49783, GSM49784 acute rejection: GSM48040, GSM48043, GSM48046, GSM48047, GSM48050, GSM48053, GSM48056, GSM49655, GSM49747, GSM49749, GSM49755, GSM49759, GSM49761, GSM49763, GSM49764, GSM49780 pre-Chagas disease reactivation: GSM48089, GSM49756, GSM49757, GSM49758, GSM49767, GSM49769, GSM49771 Chagas disease reactivation: GSM49753, GSM49760, GSM49768, GSM49772, GSM49775, GSM49776, GSM49777, GSM49778 Toxoplasma myocarditis: GSM48058 first subset ("summer"): GSM47949, GSM47957, GSM48040, GSM48043, GSM48045, GSM48046, GSM48047, GSM48048, GSM48049, GSM48050, GSM48053, GSM48056, GSM48057, GSM48058, GSM48072, GSM48089, GSM48092, GSM49624, GSM49625, GSM49654, GSM49655, GSM49656, GSM49657, GSM49658, GSM49661, GSM49666, GSM49747, GSM49748, GSM49749, GSM49750, GSM49751, GSM49752 second subset ("winter"): GSM49753, GSM49754, GSM49755, GSM49756, GSM49757, GSM49758, GSM49759, GSM49760, GSM49761, GSM49762, GSM49763, GSM49764, GSM49765, GSM49766, GSM49767, GSM49768, GSM49769, GSM49770, GSM49771, GSM49772, GSM49773, GSM49774, GSM49775, GSM49776, GSM49777, GSM49778, GSM49780, GSM49781, GSM49782, GSM49783, GSM49784 Keywords = cardiac transplant Keywords = acute rejection Keywords = infection Keywords: repeat sample

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Dataset Information

Detection of human norovirus in intestinal biopsies from immunocompromised transplant patients.

Publications

Detection of human norovirus in intestinal biopsies from immunocompromised transplant patients.

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