MicroRNAs (miRNAs) are single-stranded RNAs of 17-24 nt. These molecules regulate gene expression at the posttranscriptional level and are differentially expressed in viral acute respiratory infections (ARIs), which are responsible for high morbidity and mortality around the world. In recent years, miRNAs have been studied in order to discover anti-viral ARI drug targets as well as biomarkers for diagnosis, severity, and prognosis. This review presents an analysis of the regulatory response to viral ARIs of miRNAs, including their participation in the innate immune response, their utility as biomarkers, and their potential for future therapies and vaccine development.
Eosinophils have been mainly associated with parasitic infection and pathologies such as asthma. Some patients with asthma present a high number of eosinophils in their airways. Since respiratory viruses are associated with asthma exacerbations, several studies have evaluated the role of eosinophils against respiratory viruses. Eosinophils contain and produce molecules with antiviral activity, including RNases and reactive nitrogen species. They can also participate in adaptive immunity, serving as antigen-presenting cells. Eosinophil antiviral response has been demonstrated against some respiratory viruses in vitro and in vivo, including respiratory syncytial virus and influenza. Given the implication of respiratory viruses in asthma, the eosinophil antiviral role might be an important factor to consider in this pathology.
No association between TLR4 Asp299Gly and pulmonary TB was found. CD14 -159TT is a risk factor for development of pulmonary TB, whereas mCD14/sCD14 and mTLR4 are possible biomarkers for the prognosis for TB disease. CLINICAL TRIAL PROTOCOL ID: SA1168-05.
Mice infected for 60 days with Mycobacterium tuberculosis were treated with aerosolized XCL1-targeting small interfering RNA (siRNA) to induce local and transient suppression of XCL1/lymphotactin (an important chemokine in tuberculoid granuloma formation). The local pulmonary siRNA therapy resulted in a 50% decrease in the total amount of xcl1 gene transcripts at 3 days, and 40 to 50% protein suppression 3 and 5 days after treatment. Reduced XCL1 expression in the lungs was associated with decreased numbers of T lymphocytes, reduction in the IFN-g response, disorganized granulomatous lesions, and higher fibrosis when compared with control mice treated with either PBS or nontargeting siRNA. This indicates that a transient but strong modulation of the production of XCL1 in the lungs has a significant effect on the influx of IFN-g-secreting T cells, as well as local pathology, but without significantly altering containment of the infection.Keywords: tuberculosis; small interfering RNA; lymphotactin; XCL1; aerosol deliveryUp to now, in vivo studies addressing the role of specific components of the immune response during chronic infection with Mycobacterium tuberculosis were limited to the use of genetargeted knockout mice or systemic antibody and drug delivery. Although these methods provided important information in regards to tuberculosis infection, they do not allow for targeted examination of the lung-unique environment. Furthermore, gene knockout mice have the deficiency from the onset, thus not allowing more temporal manipulation of the immune response. For that reason, here, we tried an innovative approach in which newly developed immunotherapeutic molecules were applied directly to the lungs. Specifically, we transiently changed the lung immune environment by delivery of small interfering RNA (siRNA) transcripts.siRNA is a technology being used to evaluate the function of a variety of genes by transient silencing of mRNA expression. This new technology has been used as a therapeutic procedure to treat a variety of genetic, viral, and cancer-related diseases (1). It has demonstrated therapeutic benefits after both local and systemic administration into subcutaneous tissue, muscle, eye, and the central nervous system (2, 3). The major challenge of using siRNA as an immunotherapy is to deliver it into tissues and then into the cytoplasm of cells. Exceptions to this are the mucosal tissues and the lung. In these tissues, it has been demonstrated that siRNA uptake is extremely efficient and occurs even in the absence of transfection reagents (4-7). We took advantage of this, and developed a procedure to transiently block expression of proteins by using a noninvasive procedure for intrapulmonary delivery of aerosolized siRNA. Using this approach we studied changes in the immunopathology in mice chronically infected with M. tuberculosis.Tuberculosis is a global problem caused by infection with the M. tuberculosis bacilli. At the present time, one third of the world population has been exposed to this bacillus, and ...
Tuberculosis is the most frequent coinfection in humans infected with HIV-1, but little is known about mechanisms that favors coinfection. The aim of this work is to understand tuberculosis and HIV infections. We determined the pattern of expression of CD11c, CD14, CD40, CCR5, and CXCR4 and quantified IL-1beta, IL-6, IL-8, TNF-alpha, and RANTES in tuberculosis patients and HIV patients. Monocytes from healthy PPD+ volunteers (HP(+)V) stimulated with intracellular proteins (IP), lipids, and polysaccharides (PLS) from Mycobacterium tuberculosis down regulate CD11c expression (p < 0.05). On the contrary, CD14 expression was elevated in tuberculosis patients (p < 0.05) and HIV-infected patients (p > 0.05). CD14 expression was elevated on monocytes from HP(+)V stimulated with PLS and lipids (p < 0.05). CD40 low expression was found in tuberculosis patients and on monocytes from HP(+)V stimulated with lipids, but it was elevated in HIV-infected patients (p < 0.05). CXCR4 and CCR5 expression was high in pulmonary tuberculosis patients and low in HIV-infected patients (p < 0.05). Finally, CCR5+ monocytes from HP(+)V after stimulation with PLS and CXCR4+ lymphocytes were elevated after stimulation with IP (p < 0.05). In general, high levels of IL-1beta, IL-6, and TNF-alpha were found in all groups, but low levels of RANTES were found in pulmonary tuberculosis patients. In conclusion, the pulmonary tuberculosis patients have a microenvironment that facilitates the HIV infection through three possible mechanisms: (1) increasing the coreceptor for HIV entrance, (2) increasing proinflammatory cytokines, and (3) down-regulating RANTES. At the same time, HIV patients have a microenvironment that facilitates entry of M. tuberculosis into macrophages through CD14.
Members of the CSF cytokine family play important roles in macrophage recruitment and activation. However, the role of M-CSF in pulmonary infection with Mycobacterium tuberculosis is not clear. In this study, we show the lungs of mice infected with M. tuberculosis displayed a progressive decrease in M-CSF in contrast to increasing levels of GM-CSF. Restoring pulmonary M-CSF levels during infection resulted in a significant decrease in the presence of foamy macrophages and increased expression of CCR7 and MHC class II, specifically on alveolar macrophages. In response to M-CSF, alveolar macrophages also increased their T cell-stimulating capacity and expression of DEC-205. These studies show that the levels of expression of M-CSF and GM-CSF participate in the progression of macrophages into foamy cells and that these cytokines are important factors in the differentiation and regulation of expression of dendritic cell-associated markers on alveolar macrophages. In addition, these studies demonstrate that M-CSF may have a role in the adaptive immune response to infection with M. tuberculosis.
BackgroundCommunity-acquired pneumonia (CAP) is considered the most important cause of death from infectious disease in developed countries. Severity assessment scores partially address the difficulties in identifying high-risk patients. A lack of specific and valid pathophysiologic severity markers affect early and effective sepsis therapy. HMGB-1, sRAGE and RAGE have been involved in sepsis and their potential as severity markers has been proposed. The aim of this study was to evaluate HMGB-1, RAGE and sRAGE levels in patients with CAP-associated sepsis and determine their possible association with clinical outcome.MethodWe evaluated 33 patients with CAP-associated sepsis admitted to the emergency room and followed in the medical wards. Severity assessment scores (CURB-65, PSI, APACHE II, SOFA) and serologic markers (HMGB-1, RAGE, sRAGE) were evaluated on admission.ResultsThirty patients with a diagnosis of CAP-associated sepsis were enrolled in the study within 24 hours after admission. Fourteen (46.6%) had pandemic (H1N1) influenza A virus, 2 (6.6%) had seasonal influenza A and 14 other diagnoses. Of the patients in the study group, 16 (53.3%) had a fatal outcome. ARDS was observed in 17 (56.6%) and a total of 22 patients had severe sepsis on admission (73%). The SOFA score showed the greatest difference between surviving and non-surviving groups (P = .003) with similar results in ARDS patients (P = .005). sRAGE levels tended to be higher in non-surviving (P = .058) and ARDS patients (P = .058). Logistic regression modeling demonstrated that SOFA (P = .013) and sRAGE (P = .05) were the only variables that modified the probability of a fatal outcome.ConclusionThe association of elevated sRAGE with a fatal outcome suggests that it may have an independent causal effect in CAP. SOFA scores were the only clinical factor with the ability to identify surviving and ARDS patients.
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