Background and Aims
Hepatitis E virus (HEV) variants causing human infection predominantly belong to HEV species A (HEV‐A). HEV species C genotype 1 (HEV‐C1) circulates in rats and is highly ...divergent from HEV‐A. It was previously considered unable to infect humans, but the first case of human HEV‐C1 infection was recently discovered in Hong Kong. The aim of this study is to further describe the features of this zoonosis in Hong Kong.
Approach and Results
We conducted a territory‐wide prospective screening study for HEV‐C1 infection over a 31‐month period. Blood samples from 2,860 patients with abnormal liver function (n = 2,201) or immunosuppressive conditions (n = 659) were screened for HEV‐C1 RNA. In addition, 186 captured commensal rats were screened for HEV‐C1 RNA. Sequences of human‐derived and rat‐derived HEV‐C1 isolates were compared. Epidemiological and clinical features of HEV‐C1 infection were analyzed. HEV‐C1 RNA was detected in 6/2,201 (0.27%) patients with hepatitis and 1/659 (0.15%) immunocompromised persons. Including the previously reported case, eight HEV‐C1 infections were identified, including five in patients who were immunosuppressed. Three patients had acute hepatitis, four had persistent hepatitis, and one had subclinical infection without hepatitis. One patient died of meningoencephalitis, and HEV‐C1 was detected in cerebrospinal fluid. HEV‐C1 hepatitis was generally milder than HEV‐A hepatitis. HEV‐C1 RNA was detected in 7/186 (3.76%) rats. One HEV‐C1 isolate obtained from a rat captured near the residences of patients was closely related to the major outbreak strain.
Conclusions
HEV‐C1 is a cause of hepatitis E in humans in Hong Kong. Immunosuppressed individuals are susceptible to persistent HEV‐C1 infection and extrahepatic manifestations. Subclinical HEV‐C1 infection threatens blood safety. Tests for HEV‐C1 are required in clinical laboratories.
Rat hepatitis E virus (Orthohepevirus species C; HEV-C1) is an emerging cause of viral hepatitis in humans. HEV-C1 is divergent from other HEV variants infecting humans that belong to Orthohepevirus ...species A (HEV-A). This study assessed HEV-C1 antigenic divergence from HEV-A and investigated the impact of this divergence on infection susceptibility, serological test sensitivity, and vaccine efficacy.
Immunodominant E2s peptide sequences of HEV-A and HEV-C1 were aligned. Interactions of HEV-C1 E2s and anti-HEV-A monoclonal antibodies (mAbs) were modeled. Recombinant peptides incorporating E2s of HEV-A (HEV-A4 p239) and HEV-C1 (HEV-C1 p241) were expressed. HEV-A and HEV-C1 patient sera were tested using antibody enzymatic immunoassays (EIA), antigen EIAs, and HEV-A4 p239/HEV-C1 p241 immunoblots. Rats immunized with HEV-A1 p239 vaccine (Hecolin), HEV-A4 p239 or HEV-C1 p241 peptides were challenged with a HEV-C1 strain.
E2s sequence identity between HEV-A and HEV-C1 was only 48%. There was low conservation at E2s residues (23/53; 43.4%) involved in mAb binding. Anti-HEV-A mAbs bound HEV-C1 poorly in homology modeling and antigen EIAs. Divergence resulted in low sensitivity of commercial antigen (0%) and antibody EIAs (10–70%) for HEV-C1 diagnosis. Species-specific HEV-A4 p239/HEV-C1 p241 immunoblots accurately differentiated HEV-A and HEV-C1 serological profiles in immunized rats (18/18; 100%) and infected-patient sera (32/36; 88.9%). Immunization with Hecolin and HEV-A4 p239 was partially protective while HEV-C1 p241 was fully protective against HEV-C1 infection in rats.
Antigenic divergence significantly decreases sensitivity of hepatitis E serodiagnostic assays for HEV-C1 infection. Species-specific immunoblots are useful for diagnosing HEV-C1 and for differentiating the serological profiles of HEV-A and HEV-C1. Prior HEV-A exposure is not protective against HEV-C1. HEV-C1 p241 is an immunogenic vaccine candidate against HEV-C1.
Rat hepatitis E virus (HEV-C1) is a new cause of hepatitis in humans. Using a combination of methods, we showed that HEV-C1 is highly divergent from the usual cause of human hepatitis (HEV-A). This divergence reduces the capacity of existing tests to diagnose HEV-C1 and also indicates that prior exposure to HEV-A (via infection or vaccination) is not protective against HEV-C1.
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•Rat HEV (HEV-C1) is antigenically distinct from human HEV genotypes.•Human HEV-based antigen and antibody assays may not diagnose HEV-C1 infection.•Prior exposure to human HEV genotypes is not protective against HEV-C1 infection.•An HEV-C1 peptide can be used for specific HEV-C1 serodiagnosis and vaccination.
Abstract
Background
Hepatitis E virus (HEV) variants belonging to Orthohepevirus species A (HEV-A) are the primary cause of human hepatitis E. However, we previously reported that Orthohepevirus ...species C genotype 1 (HEV-C1), a divergent HEV variant commonly found in rats, also causes hepatitis in humans. Here, we present a clinical-epidemiological investigation of human HEV-C1 infections detected in Hong Kong, with an emphasis on outcomes in immunocompromised individuals.
Methods
A surveillance system for detecting human HEV-C1 infections was established in Hong Kong. Epidemiological and clinical characteristics of HEV-C1 cases identified via this system between 1 August 2019 and 31 December 2020 were retrieved. Phylogenetic analysis of HEV-C1 strain sequences was performed. Infection outcomes of immunocompromised individuals with HEV-A and HEV-C1 infections were analyzed.
Results
HEV-C1 accounted for 8 of 53 (15.1%) reverse-transcription polymerase chain reaction (RT-PCR)–confirmed HEV infections in Hong Kong during the study period, raising the total number of HEV-C1 infections detected in the city to 16. Two distinct HEV-C1 strain groups caused human infections. Patients were elderly and/or immunocompromised; half tested negative for HEV immunoglobulin M. Cumulatively, HEV-C1 accounted for 9 of 21 (42.9%) cases of hepatitis E recorded in immunocompromised patients in Hong Kong. Immunocompromised HEV-C1 patients progressed to persistent hepatitis at similar rates (7/9 77.8%) as HEV-A patients (10/12 75%). HEV-C1 patients responded to oral ribavirin, although response to first course was sometimes poor or delayed.
Conclusions
Dedicated RT-PCR–based surveillance detected human HEV-C1 cases that evade conventional hepatitis E diagnostic testing. Immunosuppressed HEV-C1–infected patients frequently progress to persistent HEV-C1 infection, for which ribavirin is a suitable treatment option.
Orthohepevirusspecies C (commonly known as rat hepatitis E virus) causes hepatitis in humans, with high rates of persistent infection in immunocompromised patients. Ribavirin is an effective antiviral for this condition, although suboptimal responses to the first course can occur.
Abstract
The first deep field images from the James Webb Space Telescope (JWST) of the galaxy cluster SMACS J0723.3-7327 reveal a wealth of new lensed images at uncharted infrared wavelengths, with ...unprecedented depth and resolution. Here we securely identify 14 new sets of multiply imaged galaxies totaling 42 images, adding to the five sets of bright and multiply imaged galaxies already known from Hubble Space Telescope data. We find examples of arcs crossing critical curves, allowing detailed community follow-up, such as JWST spectroscopy for precise redshift determinations, and measurements of the chemical abundances and of the detailed internal gas dynamics of very distant, young galaxies. One such arc contains a pair of compact knots that are magnified by a factor of hundreds, and features a microlensed transient. We also detect an Einstein cross candidate only visible thanks to JWST’s superb resolution. Our parametric lens model is available through the following link (
https://www.dropbox.com/sh/gwup2lvks0jsqe5/AAC2RRSKce0aX-lIFCc9vhBXa?dl=0
) and will be regularly updated using additional spectroscopic redshifts. The model is constrained by 16 of these sets of multiply imaged galaxies, three of which have spectroscopic redshifts, and reproduces the multiple images to better than an rms of 0.″5, allowing for accurate magnification estimates of high-redshift galaxies. The intracluster light extends beyond the cluster members, exhibiting large-scale features that suggest a significant past dynamical disturbance. This work represents a first taste of the enhanced power JWST will have for lensing-related science.
Abstract
The PASSAGES (Planck All-Sky Survey to Analyze Gravitationally-lensed Extreme Starbursts) collaboration has recently defined a sample of 30 gravitationally lensed dusty star-forming galaxies ...(DSFGs). These rare, submillimeter-selected objects enable high-resolution views of the most extreme sites of star formation in galaxies at cosmic noon. Here, we present the first major compilation of strong lensing analyses using
lenstool
for PASSAGES, including 15 objects spanning
z
= 1.1–3.3, using complementary information from 0.″6-resolution 1.1 mm Atacama Large Millimeter/submillimeter Array and 0.″4 5 cm Jansky Very Large Array continuum imaging, in tandem with 1.6
μ
m Hubble and optical imaging with Gemini-S. Magnifications range from
μ
= 2 to 28 (median
μ
= 7), yielding intrinsic infrared luminosities of
L
IR
= 0.2–5.9 × 10
13
L
⊙
(median 1.4 × 10
13
L
⊙
) and inferred star formation rates of 170–6300
M
⊙
yr
−1
(median 1500
M
⊙
yr
−1
). These results suggest that the PASSAGES objects comprise some of the most extreme known starbursts, rivaling the luminosities of even the brightest unlensed objects, further amplified by lensing. The intrinsic sizes of far-infrared continuum regions are large (
R
e
= 1.7–4.3 kpc; median 3.0 kpc) but consistent with
L
IR
–
R
e
scaling relations for
z
> 1 DSFGs, suggesting a widespread spatial distribution of star formation. With modestly high angular resolution, we explore if these objects might be maximal starbursts. Instead of approaching Eddington-limited surface densities, above which radiation pressure will disrupt further star formation, they are safely sub-Eddington—at least on global, galaxy-integrated scales.
Hepatitis E virus (HEV) variants infecting humans belong to two species:
(bHEV) and
(rat hepatitis E virus; rHEV).
is a ubiquitous rodent pathogen that has recently been recognized to cause hepatitis ...in humans. Transmission routes of rHEV from rats to humans are currently unknown. In this study, we examined rHEV exposure in cats and dogs to determine if they are potential reservoirs of this emerging human pathogen. Virus-like particle-based IgG enzymatic immunoassays (EIAs) capable of differentiating rHEV & bHEV antibody profiles and rHEV-specific real-time RT-PCR assays were used for this purpose. The EIAs could detect bHEV and rHEV patient-derived IgG spiked in dog and cat sera. Sera from 751 companion dogs and 130 companion cats in Hong Kong were tested with these IgG enzymatic immunoassays (EIAs). Overall, 13/751 (1.7%) dogs and 5/130 (3.8%) cats were sero-reactive to HEV. 9/751 (1.2%) dogs and 2/130 (1.5%) cats tested positive for rHEV IgG, which was further confirmed by rHEV immunoblots. Most rHEV-seropositive animals were from areas in or adjacent to districts reporting human rHEV infection. Neither 881 companion animals nor 652 stray animals carried rHEV RNA in serum or rectal swabs. Therefore, we could not confirm a role for cats and dogs in transmitting rHEV to humans. Further work is required to understand the reasons for low-level seropositivity in these animals.
HEV variants such as swine genotypes within Paslahepevirus species balayani (HEV-A) and rat HEV (Rocahepevirus ratti; HEV-C1) cause chronic hepatitis E in immunocompromised individuals. There are few ...reliable and accessible small animal models that accurately reflect chronic HEV infection. We aimed to develop an immunocompromised rat model of chronic hepatitis E infection.
In this animal model infection study, rats were immunosuppressed with a drug combination (prednisolone, tacrolimus, and mycophenolate mofetil) commonly taken by transplant recipients. Rats were challenged with human- and rat-derived HEV-C1 strains or a human-derived HEV-A strain. Viral load, liver function, liver histology, humoural, and cellular immune responses were monitored.
A high-dose (HD) immunosuppressive regimen consistently prolonged human- and rat-derived HEV-C1 infection in rats (up to 12 weeks post infection) compared with transient infections in low-dose (LD) immunosuppressant-treated and immunocompetent (IC) rats. Mean HEV-C1 viral loads in stool, serum, and liver tissue were higher in HD regimen-treated rats than in LD or IC rats (p <0.05). Alanine aminotransferase elevation was observed in chronically infected rats, which was consistent with histological hepatitis and HEV-C1 antigen expression in liver tissue. None (0/6) of the HD regimen-treated, 5/6 LD regimen-treated, and 6/6 IC rats developed antibodies to HEV-C1 in species-specific immunoblots. Reversal of immunosuppression was associated with clearance of viraemia and restoration of HEV-C1-specific humoural and cellular immune responses in HD regimen-treated rats, mimicking patterns in treated patients with chronic hepatitis E. Viral load suppression was observed with i.p. ribavirin treatment. HD regimen-treated rats remained unsusceptible to HEV-A infection.
We developed a scalable immunosuppressed rat model of chronic hepatitis E that closely mimics this infection phenotype in transplant recipients.
Convenient small animal models are required for the study of chronic hepatitis E in humans. We developed an animal model of chronic hepatitis E by suppressing immune responses of rats with drugs commonly taken by humans as organ transplant rejection prophylaxis. This model closely mimicked features of chronic hepatitis E in humans.
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•Chronic HEV infection is challenging to model with small animals.•Rats can be immunocompromised by transplant rejection drugs taken by patients.•This model supports chronic rat HEV infection robustly and consistently.•Immunosuppression in this model is scalable, reversible, and responsive to ribavirin.
Rat hepatitis E virus (Rocahepevirus ratti; HEV-C1) is an emerging cause of hepatitis E that is divergent from conventional human-infecting HEV variants (Paslahepevirus balayani; HEV-A). Validated ...serological assays for HEV-C1 are lacking. We aimed to develop a parallel enzymatic immunoassay (EIA) system that identifies individuals with HEV-C1 exposure. We also aimed to conduct the first HEV-C1 seroprevalence study in humans using this validated EIA system.
Expressed HEV-A (HEV-A4 p239) and HEV-C1 (HEV-C1 p241) peptides were characterised. Blood samples were simultaneously tested in HEV-A4 p239 and HEV-C1 p241 IgG EIAs. An optical density (OD) cut-off-based interpretation algorithm for identifying samples seropositive for HEV-A or HEV-C1 was validated using RT-PCR-positive infection sera. This algorithm was used to measure HEV-C1 seroprevalence in 599 solid organ transplant recipients and 599 age-matched immunocompetent individuals.
Both peptides formed virus-like particles. When run in HEV-A4 p239 and HEV-C1 p241 EIAs, HEV-A and HEV-C1 RT-PCR-positive samples formed distinct clusters with minimal overlap in a two-dimensional plot of optical density values. The final EIA interpretation algorithm showed high agreement with RT-PCR results (Cohen’s κ = 0.959) and was able to differentiate HEV-A and HEV-C1 infection sera with an accuracy of 94.2% (95% CI: 85.8–98.4%). HEV-C1 IgG seroprevalence was 7/599 (1.2%) among solid organ transplant recipients and 4/599 (0.7%) among immunocompetent individuals. Five of 11 (45.5%) of these patients had history of transient hepatitis of unknown cause.
HEV-C1 exposure was identified in 11/1198 (0.92%) individuals in Hong Kong indicating endemic exposure. This is the first estimate of HEV-C1 seroprevalence in humans. The parallel IgG EIA algorithm is a valuable tool for investigating epidemiology and risk factors for HEV-C1 infection.
Rat hepatitis E virus has recently been discovered to infect humans, but antibody tests for this infection are lacking, making it difficult to gauge how common this infection is. We developed an antibody test algorithm that can identify individuals with past rat hepatitis E virus exposure. We used this algorithm to estimate rat hepatitis E exposure rates in humans in Hong Kong and found that approximately 1% of all tested people had been exposed to this virus previously.
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•Rat hepatitis E virus (HEV-C1) is an emerging divergent cause of human hepatitis E.•HEV-A4 p239 and HEV-C1 p241 ORF2 truncated peptides form virus-like particles (VLPs).•An enzymatic immunoassay (EIA) for HEV-C1 was designed with these VLPs.•The EIA differentiates HEV-C1 and other hepatitis E variant serum antibody profiles.•The validated EIA was used for the first HEV-C1 seroprevalence estimate in humans.
Hepatitis E virus (HEV) is an important cause of hepatitis, which can be transmitted via the bloodborne route. However, risk of hepatitis E among persons who inject drugs (PWIDs) is poorly ...understood. This study aimed to elucidate whether PWIDs are at risk for hepatitis E. We performed HEV IgM, IgG and nucleic acid detection on a cohort of 91 PWIDs and 91 age- and sex-matched organ donors. Blood HEV IgG was measured using the WHO HEV antibody standard. The effects of age, gender and addictive injection use on HEV serostatus and concentration were assessed. HEV IgG seroprevalence was 42/91 (46.2%) in the PWID group and 20/91 (22%) in the donor group (odds ratio = 3.04 (1.59-5.79),
= 0.0006). The median HEV IgG concentration was 5.8 U/mL (IQR: 2.5-7.9) in the PWID group and 2.1 U/mL (IQR: 1.2-5.3) in the donor group (
= 0.005). Increasing age and addictive injection use were significantly associated with HEV IgG serostatus, but only addictive injection use was associated with HEV IgG concentration (
= 0.024). We conclude that PWIDs are at increased risk for hepatitis E and are prone to repeated HEV exposure and reinfection as indicated by higher HEV IgG concentrations.
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