Chronic Asymptomatic Carriers Research Articles

Early host immune responses in a human organoid-derived gallbladder monolayer to Salmonella Typhi strains from patients with acute and chronic infections: a comparative analysis.

Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen, invades the host through the gut to cause typhoid fever. Recent calculations of the typhoid fever burden estimated that more than 10 million new typhoid fever cases occur in low and middle-income countries, resulting in 65,400-187,700 deaths yearly. Interestingly, if not antibiotic-treated, upon the resolution of acute disease, 1%-5% of patients become asymptomatic chronic carriers. Chronically infected hosts are not only critical reservoirs of infection that transmit the disease to naive individuals but are also predisposed to developing gallbladder carcinoma. Nevertheless, the molecular mechanisms involved in the early interactions between gallbladder epithelial cells and S. Typhi remain largely unknown. Based on our previous studies showing that closely related S. Typhi strains elicit distinct innate immune responses, we hypothesized that host molecular pathways activated by S. Typhi strains derived from acutely and chronically infected patients would differ. To test this hypothesis, we used a novel human organoid-derived polarized gallbladder monolayer model, and S. Typhi strains derived from acutely and chronically infected patients. We found that S. Typhi strains derived from acutely and chronically infected patients differentially regulate host mitogen-activated protein kinase (MAPK) and S6 transcription factors. These variations might be attributed to differential cytokine signaling, predominantly via TNF-α and IL-6 production and appear to be influenced by the duration the isolate was subjected to selective pressures in the gallbladder. These findings represent a significant leap in understanding the complexities behind chronic S. Typhi infections in the gallbladder and may uncover potential intervention targets.

Differential responses of monocyte-derived macrophages from Theileria orientalis infected carrier cattle to Pasteruella multocida B:2 infection and latex beads: A preliminary study

This study aims to evaluate the responses of peripheral blood monocyte-derived macrophages (PBMDMs) from Theileria orientalis carrier cattle following exposure to Pasteruella multocida B:2 (PM B:2) and latex beads. Twenty-six male crossbred Kedah-Kelantan (KK) cattle were sampled for this study and quantitative PCR (qPCR) was employed in the detection of T. orientalis MPSP gene. Bactericidal assay using a 10:1 multiplicity of infection was performed to measure the phagocytosis and intracellular killing of PM B:2 by PBMDMs. The cell cultures were inoculated with 107 cfu/mL of PM B:2 and incubated in a humidified incubator. The absence of clinical signs, previous history of T. orientalis infection and an MPSP gene copy number below 15,000 GC/μL suggest that the cattle were asymptomatic chronic carriers. A non-significant phagocytic and mean cell death rates were observed in the PBMDMs of T. orientalis positive cattle relative to clinically healthy cattle (CHC) (p > 0.05). The PBMDMs of T. orientalis positive cattle had the lowest mean rate of intracellular killing relative to the CHC at the 30th minute post-infection only (p < 0.05). Exposure to latex beads caused an increase in the appearance of multinucleated macrophages following incubation of PBMDMs from T. orientalis positive cattle. Furthermore, the phagocytic index of PBMDMs of T. orientalis positive cattle were low or poor compared to that of CHC (p = 0.000). Therefore, our findings suggest that PBMDMs from cattle with chronic T. orientalis infection can efficiently phagocytise and kill PM: B2 but exhibited poor phagocytosis ability for foreign bodies despite appearance of multinucleated macrophages.

Phenotypes of peripheral CD4+ T helper cell subsets in pregnant women with HBeAg-negative chronic asymptomatic HBV carriers.

Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide, and mother-to-child transmission is the key mode of HBV infection. CD4+ T helper (Th) cells play a critical role in the immune microenvironment of specific maternal tolerance to the foetus during pregnancy. However, the roles of Th cell subsets in pregnant women (PW) with chronic asymptomatic HBV carriers (ASCs) remain completely unclear. Here, we aimed to characterize CD4+ T-cell immunity in PW with hepatitis Be antigen (HBeAg)-negative chronic ASCs. Human peripheral blood mononuclear cells (PBMCs) from PW without HBV infection or with chronic ASCs and healthy controls (HC) were isolated, and CD4+ Th cell subsets were detected by flow cytometry in addition to serum cytokines. Serological HBV markers, liver function and hormone levels of these individuals were also tested. The frequencies of circulating T follicular helper (Tfh) type 2 (Tfh2) cells were significantly evaluated, but Tfh1 cell frequencies were notably decreased in PW compared to HC. Moreover, the frequencies of Th22 cells were only notably increased in PW with chronic ASCs in comparison with PW. Additionally, increased levels of serum IL-4 were positively correlated with Tfh2 cell frequencies in healthy PW. Interestingly, serum P4 levels were positively associated with the frequencies of circulating Tfh2 or Th2 cells but were negatively related to the frequencies of circulating Tfh17 or Th17 cells in healthy PW. Although there were some changes in the other CD4+ Th cell frequencies and cytokine levels or other references, significant differences were not found among HC, healthy PW, PW with HBeAg-negative chronic ASCs. CD4+ Th cell subsets played a critical role in the immune microenvironment of PW, and these findings provided potential evidence for why PW with chronic ASCs did not receive antenatal antiviral prophylaxis.

Immune Checkpoint Molecules Expressed on CD4+ T Cell Subsets in Chronic Asymptomatic Hepatitis B Virus Carriers With Hepatitis B e Antigen-Negative.

BackgroundChronic hepatitis B virus (HBV) infection remains a major public health problem worldwide. Immune checkpoint molecules expressed on CD4+ T cells play critical roles in chronic HBV infection. However, their roles in chronic asymptomatic HBV carriers (ASCs) with hepatitis B e antigen (HBeAg)-negative remain unclear. In this study, we explored the role of immune checkpoint molecules expressed on CD4+ T cell subsets in chronic ASCs with HBeAg-negative.MethodsHuman peripheral blood mononuclear cells (PBMCs) from the ASCs with HBeAg-negative and healthy controls (HC) were isolated, and immune checkpoint molecules expressed on CD4+ T cell subsets and serum cytokines were detected by flow cytometry. Moreover, the mRNA expressions of immune checkpoint molecules were analyzed by a real-time quantitative PCR assay.ResultsIn comparison with HC, CD4+ T cells highly expressed LAG-3, TIM-3, and PD-1 in PBMCs from chronic ASCs with HBeAg-negative. Interestingly, the expressions of TIM-3 and PD-1 on circulating follicular helper T (Tfh) cells in ASCs were significantly high. Moreover, high expressions of LAG-3, TIM-3, and PD-1 were different among Treg, Th1, Th2, and Th17 cells. In addition, the expressions of TIM-3 and CTLA-4 mRNA in PBMCs from ASCs were significantly elevated. However, the frequency of CTLA-4+CD4+ T cell subsets in PBMCs from ASCs was not different from HC. The levels of six cytokines in serum from ASCs were not clearly different from HC.ConclusionImmune checkpoint molecules highly expressed on CD4+ T cell subsets indicated an important role in chronic ASCs with HBeAg-negative, which provided potential therapeutic targets in the pathogenesis of chronic HBV infection.

An Uncommon Cause for Respiratory Failure in a Preterm Neonate.

An Uncommon Cause for Respiratory Failure in a Preterm Neonate.

Toward Typhoid Fever Elimination

Salmonella enterica serotype Typhi (S Typhi) causes typhoid fever and is responsible for an estimated 9 million cases and 110,000 deaths globally per annum. Typhoid fever is endemic in areas where water, sanitation, and hygiene (WaSH) infrastructure is poor. Serious complications develop in approximately 10%-15% of patients if left untreated, and this is driven by inadequate diagnostic methods and the high burden of antibiotic-resistant strains, complicating clinical management and ultimately prognosis. Asymptomatic chronic carriers, in addition to acutely infected patients, contribute to continued transmission through the shedding of the organism in the feces. The high morbidity and mortality of typhoid fever in low- and middle-income countries reinforce the need for an integrated control approach, which may ultimately lead to elimination of the disease in the 21st century. Here we discuss the challenges faced in pursuit of typhoid fever elimination.

Carrier Status ofLeptospiraspp. in Healthy Companion Dogs in Sri Lanka

Dogs are asymptomatic chronic carriers of Leptospira spp. and excrete these bacteria in their urine, resulting in environmental contamination and potentially leading to zoonotic transmission. Although a previous study in Sri Lanka detected anti-Leptospira antibodies in companion dogs, the urinary shedding of Leptospira spp. and the Leptospira species and serogroups prevalent in them remain unclear. Thus, the current study identified the prevalent Leptospira serogroups and the carrier status of Leptospira spp. in apparently healthy, client-owned dogs in the Kandy District of Sri Lanka. Serum and urine samples were collected from 96 unvaccinated and 82 vaccinated dogs. Anti-Leptospira antibodies and Leptospira DNA in urine were detected using the microscopic agglutination test (MAT) and nested PCR that targeted the pathogenic leptospiral gene, flaB. The flaB sequences were compared with those of Leptospira spp. using the public databases. MAT detected anti-leptospiral antibodies in 15.6% (15/96) of the unvaccinated dogs, and the reactive serogroups were observed to be Sejroe (11.5%), Canicola (2.1%), Icterohemorrhagiae (1.0%), and Javanica (1.0%). Furthermore, MAT results revealed that 11.0% (9/82) of the vaccinated dogs tested positive for the anti leptospira antibodies and the only reactive serogroup was Sejroe. Leptospira DNA was detected in 15.6% (15/96) and 15.9% (13/82) of urine samples collected from unvaccinated and vaccinated dogs, respectively, and phylogenetic analysis revealed that the animals were infected with L. borgpetersenii, L. interrogans, L. kmetyi, and L. weilii. The L. interrogans sequence detected in the canine sample was identical to the one that was previously reported in a human sample from the Kandy District. This study demonstrated that both unvaccinated and vaccinated dogs excrete various pathogenic Leptospira spp. in their urine, suggesting that they may play an important role in environmental contamination that poses a health risk to the dog owners and the general public.

Salmonella Typhi Stool Shedding by Patients With Enteric Fever and Asymptomatic Chronic Carriers in an Endemic Urban Setting.

The burden of Salmonella enterica serotype Typhi (S. Typhi) shedding in stool and its contribution to transmission in endemic settings is unknown. During passive surveillance S. Typhi shedding was seen during convalescence in 332 bacteremic patient with typhoid, although none persisted at 1-year follow-up. Anti–virulence capsule (Vi)–immunoglobulin (Ig) G titers were measured in age-stratified cohort of serosurveillance participants. Systematic stool sampling of 303 participants with high anti–Vi-IgG titers identified 1 asymptomatic carrier with shedding. These findings suggest that ongoing S. Typhi transmission in this setting is more likely to occur from acute convalescent cases, although better approaches are needed to identify true chronic carriers in the community to enable typhoid elimination.

A dual-therapy approach for the treatment of biofilm-mediated Salmonella gallbladder carriage.

Asymptomatic carriage of Salmonella Typhi continues to facilitate the transmission of typhoid fever, resulting in 14 million new infections and 136,000 fatalities each year. Asymptomatic chronic carriage of S. Typhi is facilitated by the formation of biofilms on gallstones that protect the bacteria from environmental insults and immune system clearance. Here, we identified two unique small molecules capable of both inhibiting Salmonella biofilm growth and disrupting pre-formed biofilm structures without affecting bacterial viability. In a mouse model of chronic gallbladder Salmonella carriage, treatment with either compound reduced bacterial burden in the gallbladder by 1–2 logs resulting in bacterial dissemination to peripheral organs that was associated with increased mortality. Co-administration of either compound with ciprofloxacin not only enhanced compound efficacy in the gallbladder by a further 1–1.5 logs for a total of 3–4.5 log reduction, but also prevented bacterial dissemination to peripheral organs. These data suggest a dual-therapy approach targeting both biofilm and planktonic populations can be further developed as a safe and efficient treatment of biofilm-mediated chronic S. Typhi infections.

Investigating the Effect of Prompt Treatment on Malaria Prevalence in Children Aged below Five Years in Zambia: A Nested Case-Control Study in a Cross-Sectional Survey

Background. In a highly malaria endemic country like Zambia, prompt treatment of cases is known to reduce morbidity and mortality; however, it is not known whether it has a role as an effective prevention strategy because of the presence of asymptomatic chronic carriers who do not seek treatment and maintain the reservoirs of infection in the population. This study investigated the role of treatment of malaria cases as a prevention strategy in low, moderate, and high endemic settings. Methods. A nested case-control design was employed using datasets from a large countrywide national Malaria Indicator Survey of 2015. Self-reported malaria cases (n = 209) who took treatment in the two weeks preceding the survey were matched with controls (n = 511) who did not report malaria and did not take treatment during the same period using nearest neighbour propensity score matching for age, sex, and district. The data were analysed using conditional logistic regression in STATA version 15.1. Results. The malaria cases were more likely to be from rural areas (p=0.001), poorest households (p=0.049), and who lived in improvised housing structures (p=0.004) compared with the controls. Data from low and moderate malaria endemic areas did not have sufficient cases for the analysis to proceed; however, data from high endemic areas showed borderline evidence (p=0.054) that prompt treatment reduces the risk of malaria by almost half in the short-term aOR 0.057 (95% CI 0.32–1.01). Conclusion. We found borderline evidence which suggests that prompt treatment of malaria cases even in high endemic areas has potential to reduce the risk of malaria by almost half in the short term.

Natural history of liver-related disease in patients with chronic hepatitis C virus infection: An analysis using a Markov chain model.

BackgroundLong‐term prognosis of patients with chronic hepatitis C infection (HCV) remains incompletely characterized. We investigated the long‐term prognosis of liver disease in patients with chronic HCV infection who have not received antiviral therapy.MethodsA total of 2304 patients with chronic HCV who were not received interferon‐based therapy were included.ResultsIn the assessment of 1‐year disease state of liver transition probabilities, progression to chronic hepatitis occurred in 12% to 14% of patients across all age groups in male asymptomatic carriers. In male patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (7.6%) and ≥70 age groups (9.6%). In addition, in male patients with cirrhosis, HCC development occurred in approximately 5% of patients over the age of 40. In female asymptomatic carriers, progression to chronic hepatitis was observed in 6% to 14% of patients across all age groups. In female patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (8.7%) and ≥70 (7.4%) age groups. In addition, in female patients with cirrhosis, HCC development occurred in 0.9% to 3.3% of patients over the age of 50. Under assumptions of either chronic hepatitis or asymptomatic carrier state at age 40 as the starting condition for simulation over the following 40 years, the probability of HCC gradually increased with age and was higher in male patients.ConclusionsThere is a risk of cirrhosis or HCC development in HCV patients with not only chronic hepatitis but the asymptomatic carrier state as well.

Deciphering fatigue factor in chronic hepatitis B infection

ABSTRACT Background: With success in treating hepatitis C disease, chronic hepatitis B infection will be given more attention here forward. Whereas prevention of late morbidity with chronic hepatitis B infection is an admirable goal, the benefit for treating chronic carriers who lack determinable advances in their liver disease remains a debate. Purpose: Fatigue, as a symptom, is one of several clinical complications that may be useful to assess the treatment of relatively asymptomatic chronic carriers. This narrative review assesses the current status for assessment of fatigue in this context. Methods: A literature review was conducted of citations intersecting fatigue and hepatitis B as found in PubMed, EMBASE, CINAHL Plus, and the Cochrane Library. Results: Fatigue measurement can be direct or indirect with the assistance of several survey instruments, but there is a lack of universal adoption of any one or more. Nevertheless, there appears to be a consensus that worse fatigue scores are associated with increased hepatitis B-associated morbidity. There is no clear consensus about which quality of life indicators will serve treatment studies best. Conclusion: Studies of treatment that assess fatigue and other clinical symptoms as outcomes must be properly matched and controlled. The combination of clinical and/or biochemical measures should have uniformity and consensus among scientists.

Corrigendum] Sequence analysis of the Pre‑S gene in chronic asymptomatic HBV carriers with low‑level HBsAg.

After the publication of the article, the authors realize that the grant funding number for the support that they received from Natural Science Foundation of Zhejiang Province appeared incorrectly in the Funding section of the paper: This should have been featured as grant no. LY15H200001 (i.e., with an 'L' at the start of the number). The authors regret that this error was not corrected prior to the publication of their paper, and apologize to the funders for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 42: 2689-2699, 2018; DOI:10.3892/ijmm.2018.3831].

Thioredoxin reductase gene expression and activity among human T-cell lymphotropic virus type 1-infected patients.

The thioredoxin (Trx) system is a reducing complex, consisting of Trx, Trx reductase (TrxR), and NADPH, that scavenges reactive oxygen species. The system is a natural protective mechanism to prevent apoptosis and progression of oxidative stress-related diseases. The present study was conducted to explore possible changes in TrxR activity and gene expression as a response to the oxidative stress during HTLV-1 infection. Blood samples were collected from 40 HTLV-1-infected patients and 40 age- and sex-matched healthy controls. The patient group consisted of chronic asymptomatic carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM-TSP) patients. A commercial kit was used to measure the TrxR enzyme activity, and real-time polymerase chain reaction was performed to evaluate TrxR gene expression in extracted peripheral blood mononuclear cells (PBMCs). A decreasing pattern of TrxR enzyme activity was observed among control, carrier, and HAM-TSP groups (mean ± SD; controls, 0.1734 ± 0.056; carriers, 0.134 ± 0.065; and HAM-TSP, 0.0928 ± 0.047 µmol/min/mL). Cellular TrxR gene expression showed the same decreasing trend. The fold differences of gene expression in carriers and HAM-TSP groups compared with healthy controls were 0.8 and 0.7 vs 1, respectively. We found a reduction in TrxR expression as well as serum enzyme activity in HTLV-1-infected individuals, particularly in HAM-TSP patients. The reduced TrxR activity during HTLV-1 infection may hamper the natural protective mechanisms, thereby contributes to virus-induced complications.

Analysis of clinical characteristics and S gene sequences in chronic asymptomatic HBV carriers with low-level HBsAg

During the natural hepatitis B virus (HBV) infection process, some infected subjects are characterized by a sustained low serum HBV surface antigen (HBsAg) expression level. Most members in this population are chronic asymptomatic HBV carriers (ASCs). To elucidate the mechanism underlying low-level HBsAg expression in ASCs, we sequenced the HBV S gene in these patients to reveal specific sequence characteristics. Overall, 1308 cases of chronic ASCs were grouped according to their HBsAg serum expression levels (10 IU/mL). The clinical characteristics of the population were analysed in detail. The HBV S gene was sequenced from 276 ASC cases with low-level HBsAg expression. Additionally, 100 of 1032 ASC cases with high-level HBsAg expression were randomly selected for HBV S gene sequencing based on age matching according to the low-level HBsAg group. A comparative analysis was conducted with the HBV S gene sequences from ASCs with low HBsAg expression and the HBV reference S gene sequences from ASCs with high HBsAg expression. The population with low-level HBsAg expression displayed the following primary clinical characteristics: mostly chronic asymptomatic HBV carriers, older age (mean age 55.09 years), HBsAg/anti-HBe/anti-HBc (core) positivity as the main serological pattern (97.1%), low HBV DNA replication (1.32 ± 1.60 log10 IU/mL), a low HBV-DNA positive rate (45.65%) and primarily genotype B (82.54%) and serotype adw (84.13%). The comparative analysis of the HBV S gene sequences from ASCs with low-level HBsAg showed significant mutations (including co-mutations) on both sides of the main hydrophilic region (MHR). Significant mutations in multiple regions and at multiple sites (including co-mutations) on both sides of the MHR may be one cause of the low HBsAg expression level in this population.

Sequence analysis of the Pre-S gene in chronic asymptomatic HBV carriers with low-level HBsAg

In a hepatitis B virus (HBV)-infected population, persistently low expression levels of serum HBV serum antigen (HBsAg) are present, particularly in chronic asymptomatic HBV carriers (ASCs). The present study sequenced the HBV Pre-S gene, and aimed to elucidate its features in ASCs with low HBsAg expression compared with in the established HBV Pre-S reference gene sequences from ASCs with high HBsAg expression. A total of 1,308 ASCs were grouped according to HBsAg serum levels (cut-off value, 10 IU/ml), and clinical characteristics were analyzed in detail. The HBV Pre-S gene was sequenced in 276 ASCs with low-level HBsAg; in addition, 100 of the remaining 1,032 ASCs with high-level HBsAg were randomly selected for HBV Pre-S gene sequencing on the basis of age matching with the low-level HBsAg group. Comparative analysis of the gene sequences from these groups was subsequently conducted. The major clinical features of the population with low-level HBsAg were as follows: Most were ASCs with chronic HBV infection; 97.1% were HBsAg/anti-HBe/anti-HBc-positive; 82.54% carried the B genotype; and 84.13% displayed the adw serotype. The results indicated that there were novel and meaningful mutations, including co-mutations, at numerous loci and sites in the Pre-S gene, as well as deletion mutations in the Pre-S2 gene. These mutations in the Pre-S1 and Pre-S2 gene frag ments accounted for 65.38% (68/104) of the 104 B genotype cases in the low-level HBsAg group and 90.91% (20/22) of the 22 C genotype cases in the low-level HBsAg group, respectively. In conclusion, Pre-S gene mutations may be associated with HBV replication defects, which may be the cause of the observed low expression levels of HBsAg.

Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10−4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10−12; rs1110446: OR = 1.79, P = 1.66 × 10−13; and rs3094137: OR = 1.73, P = 7.09 × 10−9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A*33:03 (OR = 1.97, P = 4.58 × 10−4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

IRF4 haploinsufficiency in a family with Whipple's disease.

Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.

Serum levels of miRNA in patients with hepatitis B virus-associated acute-on-chronic liver failure

BackgroundHepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum miRNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF. MethodsSerum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to 30 chronic asymptomatic HBV carriers as controls. The miRNAs expressions were measured by real-time quantitative PCR (q-PCR). Statistical analyses were conducted to assess the ability of differentially expressed miRNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model. ResultsReal-time q-PCR indicated that serum miR-146a-5p, miR-122-3p and miR-328-3p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na+, INR, gastrointestinal bleeding and miR-122-3p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 × Na+ − 1.72 × INR − 4.963 × gastrointestinal bleeding (Yes = 0; No = 1)−0.278 × (miR-122-3p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve (AUROC) was 0.847. ConclusionsExpression levels of these miRNAs (miR-146a-5p, miR-122-3p and miR-328-3p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity.

Decreased CD122 on CD56dim NK associated with its impairment in asymptomatic chronic HBV carriers with high levels of HBV DNA, HBsAg and HBeAg

AimsNK cells play important roles in inhibiting HBV replication and preventing HBV infection. However, NK-cell dysfunction has not been fully studied in asymptomatic chronic HBV carriers (ASC). This study aims to assess decreased expression of CD122 associated with impaired NK cells and the restoration of NK cells with IL-2 and IL-15 stimulation. Main methodsThe experiments were performed by flow cytometer, cytotoxicity assay, ELISA and western blotting. Key findingsThe reduced CD122 on CD56+ NK cells and CD56dim NK cells is associated with high levels of HBV DNA, HBsAg or HBeAg in ASCs, in which CD56dim NK-cell impairment is observed. Moreover, decreased IFN-γ and degranulation and low cytotoxicity by CD56dim NK cells after CD122 blockade were revealed. IL-2 and/or IL-15 can restore impaired CD56dim NK cells, together with increased p-STAT5, which can be reversed by CD122 blockade. Additionally, IL-2 or IL-15 can enhance IFN-α2-activated CD56dim NK-cell immune responses via up-regulating interferon alpha and beta receptor subunit 2 (IFNAR2). SignificanceDown-regulated CD122 on CD56dim NK cell in ASCs with massive viral antigens and high viremia is associated with its impairment, which can be restored by IL-2 and/or IL-15, or combined with IFN-α2.