IL-17A is a pleiotropic cytokine and intimately associated with asthma, but its role in respiratory syncytial virus (RSV) infection is conflicting in the literature.
Children hospitalized in the ...respiratory department with RSV infection during RSV pandemic season of 2018-2020 were included. Nasopharyngeal aspirates were collected for pathogen and cytokines determination. In the murine model, RSV intranasal administrations were performed in wild-type and IL-17A-/- mice. Leukocytes and cytokines in bronchoalveolar lavage fluid (BALF), lung histopathology, and airway hyperresponsiveness (AHR) were measured. RORγt mRNA and IL-23R mRNA were semi-quantified by qPCR.
IL-17A increased significantly in RSV-infected children and was positively associated with pneumonia severity. In the murine model, IL-17A significantly increased in BALF of mice with RSV infection. Airway inflammation, lung tissue damage and AHR were significantly alleviated in wild-type mice following IL-17A neutralization and in the IL-17A-/- mice. IL-17A decreased by removing CD4
T cells but increased by depleting CD8
T cells. IL-6, IL-21, RORγt mRNA and IL-23R mRNA dramatically increased in parallel with the rise of IL-17A.
IL-17A contributes to the airway dysfunctions induced by RSV in children and murine. CD3
CD4
T cells are its major cellular sources and the IL-6/IL-21-IL-23R-RORγt signaling pathway might participate in its regulation.
Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB) causing high mortality and disability. TBM arises due to immune dysregulation, but the underlying immune mechanisms are ...unclear.
We performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells isolated from children (n=6) with TBM using 10 xGenomics platform. We used unsupervised clustering of cells and cluster visualization based on the gene expression profiles, and validated the protein and cytokines by ELISA analysis.
We revealed for the first time 33 monocyte populations across the CSF cells and PBMCs of children with TBM. Within these populations, we saw that CD4_C04 cells with Th17 and Th1 phenotypes and Macro_C01 cells with a microglia phenotype, were enriched in the CSF. Lineage tracking analysis of monocyte populations revealed myeloid cell populations, as well as subsets of CD4 and CD8 T-cell populations with distinct effector functions. Importantly, we discovered that complement-activated microglial Macro_C01 cells are associated with a neuroinflammatory response that leads to persistent meningitis. Consistently, we saw an increase in complement protein (C1Q), inflammatory markers (CRP) and inflammatory factor (TNF-α and IL-6) in CSF cells but not blood. Finally, we inferred that Macro_C01 cells recruit CD4_C04 cells through CXCL16/CXCR6.
We proposed that the microglial Macro_C01 subset activates complement and interacts with the CD4_C04 cell subset to amplify inflammatory signals, which could potentially contribute to augment inflammatory signals, resulting in hyperinflammation and an immune response elicited by
-infected tissues.
Tuberculosis (TB), which is caused by the single pathogenic bacterium, Mycobacterium tuberculosis, is among the top 10 lethal diseases worldwide. This situation has been exacerbated by the increasing ...number of cases of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Histamine is an organic nitrogenous compound that mediates a plethora of cell processes via different receptors. The expression of histamine receptor H1 (HRH1), one of the four histamine receptors identified to date was previously reported to be augmented by M. tuberculosis infection, although the underlying mechanism is unclear. In the present study, we applied confocal microscopy, flow cytometry, and Western blotting to show that HRH1 expression was enhanced in macrophages following mycobacterial infection. Furthermore, by combining techniques of gene knockdown, immunoprecipitation, intracellular bacterial burden analysis, fluorescence labeling, and imaging, we found that M. tuberculosis targeted the host HRH1 to suppress NOX2-mediated cROS production and inhibit phagosome maturation and acidification via the GRK2-p38MAPK signaling pathway. Our findings clarified the underlying mechanism of the M. tuberculosis and host HRH1 interaction and may provide useful information for the development of novel antituberculosis treatments. IMPORTANCE Once engulfed in macrophage phagosomes, M. tuberculosis adopts various strategies to take advantage of the host environment for its intracellular survival. Histamine is an organic nitrogen-containing compound that mediates a plethora of cellular processes via different receptors, but the crosstalk mechanism between M. tuberculosis and HRH1 in macrophages is not clear. Our results revealed that M. tuberculosis infection enhanced HRH1 expression, which in turn restrained macrophage bactericidal activity by modulating the GRK2-p38MAPK signaling pathway, inhibiting NOX2-mediated cROS production and phagosome maturation. Clarification of the underlying mechanism by which M. tuberculosis utilizes host HRH1 to favor its intracellular survival may provide useful information for the development of novel antituberculosis treatments.
Abstract
Background
RSV can lead to persistent airway inflammation and airway hyperresponsiveness (AHR), and is intimately associated with childhood recurrent wheezing and asthma, but the underlying ...mechanisms remain unclear. Lipopolysaccharide (LPS) is also implicated in the onset and exacerbation of asthma. However, whether inhalation of LPS can boost airway inflammation induced by RSV is not clear. In this study, we utilized an LPS- and RSV-superinfected mouse model to explore underlying pathogenesis.
Methods
Mice were infected with RSV on day 0 and inoculated with LPS from day 35 to day 41, samples were collected on day 42. Inflammatory cells, lung histopathology and AHR were measured. Cytokines were detected by ELISA and ERK, JNK, p38 was determined by western blot. MMP408, PD98059, SP600125 and SB203580 were used to inhibit MMP-12, ERK, JNK and p38 respectively.
Results
LPS exposure superimposed on RSV-infected lungs could lead to more vigorous cellular influx, lung structures damage, augmented AHR and higher MMP-12 levels. Inhibition of MMP-12 or ERK signaling pathway in vivo both diminished LPS-driven airway inflammation and AHR.
Conclusions
Exposure to LPS in RSV-infected mice is associated with enhanced increases in ERK-MMP-12 expression that translates into increased lung inflammation and AHR. These findings contribute novel information to the field investigating the onset of post-RSV bronchiolitis recurrent wheezing as a result of LPS exposure.
Human respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in infants and children under 5years of age. The novel genotype ON1 has a 72-nucleotide ...duplication, which is the largest duplicated genome portion of RSV. Whether the ON1 genotype will follow the pattern of the BA genotype, which has a 60-nucleotide duplication, and become the predominant RSV-A strain is a global concern. To obtain information regarding the prevalence of the ON1 genotype in Chongqing in Southwestern China, we examined the circulation pattern of RSV-A identified over four consecutive years (June 2009 to August 2013). In this study, 312 (12%) RSV-A strains were isolated from 2601 nasopharyngeal aspirates, and partial G gene was sequenced successfully in 250 isolates. Of the sequenced Chongqing RSV-A isolates, 237 (94.8%) strains were the NA1 genotype, 4 (1.6%) strains were the NA3 genotype, 4 (1.6%) strains were the NA4 genotype, 1 (0.4%) strain was the GA1 genotype, and 4 (1.6%) strains were identified as the ON1 genotype. Analysis of the distribution, phylogeny, and evolution of the ON1 strains that were collected globally until December 2013 revealed that the ON1 genotype has rapidly disseminated across the world under positive selection pressures. Future studies will determine whether this new genotype will continue to spread and become the dominant strain of RSV-A worldwide. These findings may contribute to the understanding of RSV evolution and to the potential development of a vaccine against RSV.
To assess and summarize current evidence on the effectiveness and safety of ertapenem for treatment of childhood infections, in consideration of high infection prevalence in children and wide use of ...ertapenem.
The following 8 databases were searched on 13th May 2021: Web of Science, Embase via Ovid SP, PubMed, The Cochrane Library (CENTRAL), Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), VIP and Wanfang. The primary outcome was treatment success rate. Risk ratios (RRs) and 95% confidence interval (CI) were estimated using random-effect models. Subgroup analysis was conducted where heterogeneity was found.
Fifteen studies (8 randomized controlled trials, 1 observational comparative study, and 6 before and after studies) involving 2,528 patients were included in the final review. Ertapenem had similar treatment success rates with β-lactam antibiotics relative risk (RR) = 1.08, 95% CI: 0.99-1.19. In a subgroup analysis, similar efficacy (RR = 1.08, 95% CI: 0.97-1.20) between ertapenem and other carbapenems. Compared with β-lactam antibiotics, ertapenem did not increase the risk of any adverse events (RR = 1.02, 95%CI: 0.71-1.48), drug-related diarrhea (all non-Asian children, RR = 0.62, 95%CI: 0.31-1.25), or injection site pain (all non-Asian children, RR = 1.66, 95%CI: 0.59-4.68). Subgroup analysis showed no obvious difference between ertapenem group and carbapenems or non-carbapenems group on risk of adverse events.
Our findings suggest that ertapenem is effective and safe in treatment for children with infection. Further comparative real-world data is needed to supplement clinical evidence on the overall benefits of ertapenem in this population.
In the current study, we report on 4 children with confirmed SARS-CoV-2 infection, of which 3 of them were asymptomatic. These patients had both pharyngeal swabs and anal swabs testing during ...hospital or after discharge. All the 4 children showed long-time positive viral RNA in the stool specimens after pharyngeal swabs turned negative during the follow-up stage, especially in the asymptomatic children. The positive RNA in stool specimens of asymptomatic children last for more than 54 days after admission or 30 days after discharge.
Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in young children and the leading cause of infant hospitalization worldwide. Uncontrolled response ...to RSV is mediated by a toll-like receptor (TLR)-mediated immune response. Resveratrol possesses anti-RSV activity and is an inhibitor of the TRIF/TBK1/IRF-3 complex. We hypothesize that resveratrol inhibits the TRIF-dependent pathway through upregulation of SARM post-RSV infection. BALB/c mice were infected with RSV and were injected with resveratrol 1 h postinoculation. SARM short interfering RNA was administered to RSV-infected and resveratrol-treated mice. Lung function was measured by whole-body plethysmography, lung histopathology was examined, and lymphocytes in bronchoalveolar lavage fluid were quantified. SARM and TRIF protein expression were detected in the lung by Western blot analyses. The expression of gamma interferon in bronchoalveolar lavage fluid (BALF) was evaluated by enzyme-linked immunosorbent assay (ELISA). SARM expression was reduced and TRIF expression was increased after infection with RSV. Resveratrol increased SARM expression and decreased TRIF expression after RSV infection. SARM knockdown in resveratrol-treated mice enhanced gamma interferon production, RSV-induced airway inflammation, and airway hyperresponsiveness (AHR). Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression. Resveratrol-mediated inhibition of the TRIF-dependent pathway may be dependent on SARM expression.
Our study provides insights into the regulation of innate immunity in response to RSV infection. The results suggest that resveratrol-mediated alterations in SARM have therapeutic potential against RSV immunopathology caused by deregulation of the TLR-mediated immune response. Ultimately, improved insight into the complex interplay between TLR adaptor proteins and the occurrence of severe RSV infection might lead to novel therapeutic treatment strategies, such as TLR adjuvants.
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