Viral immunology最新文献

The constant emergence of variants of concern (VOCs) challenges the effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines over time. This is most concerning in clinically vulnerable groups, such as older adults. This study aimed to determine whether the novel adjuvant MF59-like adjuvant can improve cross-immunity against VOCs in aged animals. We compared the humoral and cellular immune responses of Alum and MF59-like adjuvant-formulated inactivated coronavirus disease 2019 (COVID-19) vaccines against prototype and SARS-CoV-2 variants in 18-month-old mice. Our results showed that two doses of the MF59-like adjuvant inactivated vaccines induced more robust binding and pseudo-neutralizing antibodies (Nabs) against the SARS-CoV-2 prototype and VOCs compared to the Alum-adjuvant and reduced Omicron variant escapes from Nabs in aged mice. The humoral immune responses of inactivated vaccines were much lower against VOCs than the prototype with or without adjuvants; however, T cell responses against VOCs were not affected. In addition, Alum and MF59-like adjuvanted vaccines induced Th1-biased immune responses with increased interferon-gamma and interleukin (IL)-2 secreting cells, and hardly detectable IL-4 and IL-5. Furthermore, the MF59-like adjuvant vaccine produced 1.9-2.0 times higher cross-reactive T cell responses against the SARS-CoV-2 prototype and VOCs than the Alum adjuvant. Therefore, our data have important implications for vaccine adjuvant strategies against SARS-CoV-2 VOCs in older adults.

Vitamin D exerts its antiviral effect through vitamin D receptor (VDR)/retinoid X receptor-mediated host immunomodulation. Besides the downregulation of VDR expression, its polymorphism was also observed among hepatitis B virus (HBV)-positive patients. To understand the possible link between VDR polymorphism and its altered expression during HBV infection and disease progression, VDR Apa-I [rs7975232 (C>A)] single nucleotide polymorphism (SNP) was analyzed in a case-control manner. VDR Apa-I (rs7975232, C>A) polymorphism was studied using 340 HBV patients and 102 healthy controls. Genotype analysis and gene expression study was performed using restriction fragment length polymorphism and quantitative polymerase chain reaction, respectively. Statistical analysis was performed using SPSS (IBM) considering p-value <0.05 as significant for comparing the differences between the groups. Significant mean difference in VDR expression was observed between HBV-positive patients (1.6 ± 0.94) and controls (0.69 ± 0.73). Furthermore, the mean fold change of Healthy control with CC genotype (1.92 ± 0.99) was found to be marginally significant compared with mutant genotype (CA/AA) (1.08 ± 0.43/0.59 ± 0.56, p = 0.045). In HBV+ patients, the mean fold change in the CC genotype was 0.88 ± 0.38, which exhibits a significant mean difference upon comparison with other genotypes (0.52 ± 0.49, 0.113 ± 0.34; p = 0.018, p = 0.048). However, the fold change value does not differ between CA and AA genotypes. Further comparative analysis of VDR expression between the control and case also exhibits significant differences (p = 0.001) among allelic variants. Observed genotype distribution frequency exhibits a significant association with disease type. The mutant genotype was found to be significantly associated with HBV infection and disease progression, (odds ratio = 0.730, 95% confidence interval = 0.462-1.152, p = 0.06). VDR SNP rs7975232 (C>A) may affect VDR expression by controlling several other variables and suggest that deviation from wild-type genotype (CC) is associated with downregulation of expression, which in turn involved in host immunomodulation in favor of HBV infection and disease progression.

Omicron variants have become the dominant SARS-CoV-2 variants due to their increased transmissibility and immune-escape ability. An outbreak of the Omicron variant BA.5.1.3 occurred in August 2022 in Sanya, China. Studying Omicron variants can promote the understanding of them and further contribute to managing the SARS-CoV-2 prevalence. This retrospective study analyzed the data of 258 patients with asymptomatic or mild SARS-CoV-2 admitted to the First Cabin Hospital of Sanya, China, between August 14 and September 4, 2022. The 258 patients comprised 128 males and 130 females with a mean age of 36.6 years and mean length of medical observation (LMO) of 10.1 days. Multiple linear regression analysis indicated that LMO was positively and negatively associated with age (p = 0.036) and vaccination status (p = 0.004), respectively. A Cox proportional-hazards model revealed that age (hazard ratio [HR] = 0.99, p = 0.029) and vaccination (HR = 1.23, p = 0.023) were risk and protective factors for LMO, respectively. Causal mediation analysis indicated that vaccination suppressed the effect of prolonging LMO caused by increasing age. Recovery times became longer with increasing age, which could be counterbalanced by vaccination. The present results indicate that vaccination interventions, even those developed through inactivated approaches, can still provide protection against Omicron variants.

Zika virus infections lead to neurological complications such as congenital Zika syndrome and Guillain-Barré syndrome. Rising Zika infections in newborns and adults have triggered the need for vaccine development. In the current study, the precursor membrane (prM) protein of the Zika virus is explored for its functional importance and design of epitopes enriched conserved peptides with the usage of different immunoinformatics approach. Phylogenetic and mutational analyses inferred that the prM protein is highly conserved. Three conserved peptides containing multiple T and B cell epitopes were designed by employing different epitope prediction algorithms. IEDB population coverage analysis of selected peptides in six different continents has shown the population coverage of 60-99.8% (class I HLA) and 80-100% (class II HLA). Molecular docking of selected peptides/epitopes was carried out with each of class I and II HLA alleles using HADDOCK. A majority of peptide-HLA complex (pHLA) have HADDOCK scores found to be comparable and more than native-HLA complex representing the good binding interaction of peptides to HLA. Molecular dynamics simulation with best docked pHLA complexes revealed that pHLA complexes are stable with RMSD <5.5Å. Current work highlights the importance of prM as a strong antigenic protein and selected peptides have the potential to elicit humoral and cell-mediated immune responses.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulates the plasma B cells to secrete specific antibodies against the viral antigen. However, not all antibodies can prevent the virus from entering the cells. The subpopulation of antibodies which blocks the entry of the virus into host cells is termed neutralizing antibodies (NAbs). The gold standard test for the detection of NAbs is the viral plaque reduction and neutralization test; however, various other methods can also be utilized to detect NAbs. In this study, we have developed an Enzyme Linked Immunosobent Assay (ELISA)-based protocol for rapid detection of SARS CoV-2 NAb by inhibiting the binding of the spike protein receptor-binding domain to angiotensin converting enzyme 2 and compared it with cPASS neutralizing antibody kit, which was approved by the Food and Drug Administration (FDA). The results obtained suggest that the in-house ELISA developed for the detection of NAbs against SARS-CoV-2 is rapid and reliable. Compared to FDA-approved GenScript's cPass assay, the specificity and the sensitivity of the in-house-developed ELISA kit were 100% (95% confidence intervals of 69.15-100.00) and 96% (95% confidence intervals of 86.29-99.51), respectively. Thus, the ELISA protocol developed to test the neutralizing activities of antibodies is rapid, which requires a BSL-2 infrastructure facility and can be easily performed. It has very high potential applications in the rapid screening of NAb against SARS-CoV-2.

Although cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are considered latent viruses, their reactivation occurs in immunosuppressed conditions. We previously reported that CMV and EBV are reactivated in patients receiving immunosuppressive therapy and/or chemotherapy. This retrospective, single-center study aimed to determine the frequency of viral reactivation and clinical characteristics of patients with B cell lymphoma (B-ML) receiving chemotherapy. Twenty-four patients (mean age 73 years, range 40-87 years; male-to-female ratio, 15:9) with diffuse large B cell lymphoma (n = 15), follicular lymphoma (n = 8), or mantle cell lymphoma (n = 1) were enrolled. Serum CMV and EBV DNA levels were analyzed using quantitative real-time polymerase chain reaction in patients with B-ML receiving chemotherapy. We determined the cumulative reactivation of each virus and analyzed the relationship between viral reactivation and clinical characteristics. Three patients experienced relapse or refractory (R/R) disease and the others had de novo lymphomas. The frequencies of CMV and EBV reactivations were 54.2% and 37.5%, respectively. CMV reactivation occurred significantly earlier during chemotherapy courses in R/R patients than in de novo patients (p = 0.0038), while EBV reactivation was frequently found before treatment. Baseline serum levels of soluble interleukin-2 receptor were higher (4318.0 vs. 981.1 U/mL, p = 0.010) and hemoglobin levels were lower (11.1 vs. 13.0 g/dL, p = 0.0038) in patients with EBV reactivation than in those without reactivation. These findings were not observed in patients with CMV reactivation. CMV reactivation was associated with iatrogenic immunosuppression, whereas EBV reactivation was related to immunosuppression by lymphoma, indicating that the mechanisms of these viral reactivations differed.

This study aimed to investigate the changes of toll-like receptor 4 (TLR4), proinflammatory cytokine expression, hepatitis B virus surface antigen (HBsAg), and hepatitis B virus envelope antigen (HBeAg) expression as well as innate immune cell percentages in a mouse model of persistent hepatitis B virus (HBV) infection to better understand the innate immune response. Mouse models of persistent HBV infection, HBsAg expression, and HBeAg expression were developed using high-pressure tail-vein injection of recombinant adeno-associated viruses. Enzyme-linked immunosorbent assays (ELISAs) were used to determine the serum proinflammatory cytokine levels. Immunohistochemistry and western blot assays were used to detect TLR4 expression. Flow cytometric analysis was used to assess the percentage of innate immune cells in the whole blood. Persistent HBV infection, HBsAg expression, and HBeAg expression each significantly decreased the expression of TLR4. Persistent HBV infection significantly increased the percentages of T cells and monocytes, whereas it decreased the percentage of natural killer (NK) cells. Persistent HBeAg expression also decreased the percentage of NK cells, whereas persistent HBsAg expression increased the percentage of NK cells. Both persistent HBsAg and HBeAg expression increased the percentage of monocytes. However, both persistent HBsAg and HBeAg expression decreased the percentage of T cells. HBV as well as HBsAg and HBeAg showed similar effects on the expression of TLR4 and proinflammatory cytokines as well as the percentage of monocytes. Persistent HBV infection increased the percentage of T cells and decreased the percentage of NK cells, whereas only persistent HBeAg expression contributed to a decreased percentage of NK cells.

Respiratory virus infections are the main causes of pediatric diseases. Human metapneumovirus (hMPV) is an enveloped RNA virus similar to severe acute respiratory syndrome coronavirus type 2, both of which have emerged as important new respiratory viruses. Recent studies have found that interleukin-4 (IL-4) is involved in the replication of a variety of viruses, and its role differs in different viruses. The purpose of this study was to investigate the effect of IL-4 on hMPV and to elucidate its mechanism of action. We found that hMPV infection promoted the expression of IL-4 in human bronchial epithelial cells. The replication of the virus was reduced using small interfering RNA knockdown of IL-4 expression, while the addition of exogenous recombinant human IL-4 to IL-4 knockdown cells restored viral replication ability. These results demonstrate that the expression of IL-4 is closely related to the replication of hMPV; moreover, further experiments revealed that IL-4 promotes the replication of hMPV through a mechanism dependent on the Janus kinase/signal transductor and transcription activator 6 signaling pathway. Therefore, anti-IL-4 strategies may be a promising avenue for the treatment of hMPV infection, representing an important breakthrough for children at risk from hMPV infection.

Respiratory syncytial virus (RSV) causes annual epidemics of infections affecting the whole population. In vitro, it has been shown to infect and persist in human dendritic cells (DCs) for prolonged periods. Initially persistence is associated with low levels of replication before the virus becomes dormant. Reactivation of viral replication can be triggered many months later. Infection of DCs is likely to influence the host's ability to generate effective long-term memory responses. A well-established animal was utilized to confirm that RSV both infects and persists in pulmonary DCs in vivo. Mice were infected with a modified strain of RSV expressing red fluorescent protein (RSV-RFP) when replicating. Clinical symptoms of infection were monitored using weight change and inflammatory cell counts from bronchoalveolar lavage, which correlated with the RSV viral titer (quantitative polymerase chain reaction). Lung tissues were collected at 3, 5, 7, and 21 days postinfection (dpi) to assess leukocyte populations by flow cytometry. Clinical symptoms and RSV viral load peaked at 5 dpi. RSV-RFP was most prevalent in macrophages at 3 dpi and also observed in B cells and DCs. At 21 dpi, RSV-RFP remained evident in a subset of conventional DCs (CD103⁺CD11b⁺) even though both clinical symptoms and pulmonary inflammation had resolved. These results confirm that in this well-established mouse model, RSV persists in lung conventional DCs following resolution of the acute infection. Further work is required to explore whether the virus continues with low-level replication before becoming dormant in vivo, as has been described in vitro.

Monocytes in hepatitis C virus (HCV) infection play a critical role in chronic liver inflammation and fibrosis. We studied circulating monocytes and monocyte receptors in patients with HCV infection who were naive to treatment and those who received direct acting antiviral therapy and achieved sustained virological response. CD64⁺ CCR2⁺ (M1-like) and CD206⁺ CD163⁺ CX3CR1⁺ (M2-like) monocyte numbers and receptor expression were evaluated by flow cytometry. Higher expression of the monocyte chemokine receptor CCR2 predicted the severity of liver fibrosis, independent of successful treatment and viral clearance (R² = 0.235, p = 0.002), whereas monocyte CX3CR1 expression was lower in both treated and untreated patients compared with controls (p = 0.011). The expression of the scavenger receptor CD163 was lower in patients with successful treatment (p = 0.005), supporting its role as a marker of treatment response. CD64⁺ CCR2⁺ (M1-like) and CD206⁺ CD163⁺ CX3CR1⁺ (M2-like) monocyte numbers were not altered with fibrosis progression or treatment response. Our findings reflect the diverse functions of monocytes in liver inflammation, fibrosis, and therapy. However, HCV clearance did not lead to complete monocyte reconstitution. Targeting monocytes and their chemokine receptors bears therapeutic potential to reduce liver fibrosis and improve disease outcome.