Streptococcus pneumoniae is a clinically important pathogen responsible for significant morbidity and mortality worldwide. Disruption of the host gut microbiota by antibiotics reduces the pulmonary resistance to S. pneumoniae. The aim of our study was to determine the potential role of TLR4 in the reduced pulmonary resistance to S. pneumoniae following gut microbiota disruption. Wild-type and TLR4-deficient mice were given broad-spectrum antibiotics for 3 weeks by oral gavage to disrupt the gut microbiota, and subsequently inoculated intra-nasally with S. pneumoniae. The extent of the decline in pulmonary resistance in both animal groups was evaluated in terms of the overall survival and pulmonary bacterial clearance. Both survival and pulmonary clearance of S. pneumoniae were lower in the TLR4-deficient mice with disrupted gut microbiota, compared to their intestinally healthy counterparts after pneumococcal infection. However, the degree of decline was much lower in the TLR4-deficient mice compared to the wild-type mice. Our findings indicate that impaired TLR4 function might be the basis of the reduced pulmonary resistance to S. pneumoniae caused by gut microbiota disruption.

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Background The H9N2 virus can infect not only birds but also humans. The pathogenicity of H9N2 virus infection is determined by an excessive immune response in the lung. All-trans retinoic acid (ATRA), the active metabolite of vitamin A, plays an important regulatory role and has been widely used in the clinical practice. This study was aimed to investigate whether ATRA could regulate the immune response to H9N2 virus infection in the lungs of mice, thereby reducing the pathogenicity of the H9N2 virus in mice. Methods Mice were infected intranasally with H9N2 virus, and injected intraperitoneally with 0.2 mL of ATRA at low (1 mg/kg), medium (5 or 10 mg/kg), or high therapeutic dose (20 mg/kg), and toxic dose (40, 60, or 80 mg/kg), once per day for 10 days. Clinical signs, survival rates, and lung gross pathology were compared between the ATRA-treated H9N2-infected group, the ATRA group, and the H9N2-infected group, to investigate the effect of different doses of ATRA on the pathogenicity of H9N2 virus. Additionally, the viral load and cytokine concentration of lungs were measured at 3, 5, 7, and 9 days after infection, to investigate the potential mechanism of ATRA in affecting the pathogenicity of the H9N2 virus. Expression levels of cellular retinoic acid-binding protein 1 (CRABP1), cellular retinoic acid-binding protein 2 (CRABP2), and Retinoic acid-inducible gene-I (RIG-I) were detected using Western blotting. Results The ATRA-treated H9N2-infected mice showed more severe clinical signs compared with the H9N2-infected group. The medium and high therapeutic doses of ATRA reduced the survival rates, aggravated lung tissue damage, decreased the expression of interferon beta (IFN-β), and increased the concentrations of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and C-C motif chemokine ligand 2 (CCL2) in the lungs of the H9N2-infected mice. At the same time, the expression patterns of CRABP1, CRABP2, and RIG-I were changed in mice infected by H9N2 and treated with different concentrations of ATRA. Conclusions Our findings suggest that the therapeutic dose of ATRA can increase the pathogenicity of the H9N2 virus. Therefore, the consequences of those infected by influenza virus would be more severe after ATRA treatment.

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