Comparison of CD4+/CD8+ Lymphocytic Subpopulations Pre- and Post-Antituberculosis Treatment in Patients with Diabetes and Tuberculosis.

Is there a CD4+ and CD8+ immunity alteration in patients with pulmonary tuberculosis (TB) and diabetes (DM) that does not recover after antituberculosis treatment? This prospective comparative study evaluated CD4+ and CD8+ lymphocytic subpopulations and antituberculosis antibodies in patients with diabetes and tuberculosis (TB-DM), before and after antituberculosis treatment. CD4+ T cell counts were lower in patients with TB-DM compared to those with only TB or only DM, and these levels remained low even after two months of anti-TB treatment. Regarding the CD8+ T cell analysis, we identified higher blood values in the DM-only group, which may be explained by the high prevalence of latent tuberculosis (LTBI) in patients with DM. IgM antituberculosis antibodies levels were elevated in patients with only TB at baseline, and 2 months post-anti-TB treatment, IgG did not express any relevant alterations. Our results suggest an alteration in CD4+ immunity in patients with TB-DM that did not normalize after antituberculosis treatment.

Metabolism of NK cells during viral infections.

Cellular metabolism is essential for the correct function of immune system cells, including Natural Killer cells (NK). These cells depend on energy to carry out their effector functions, especially in the early stages of viral infection. NK cells participate in the innate immune response against viruses and tumors. Their main functions are cytotoxicity and cytokine production. Metabolic changes can impact intracellular signals, molecule production, secretion, and cell activation which is essential as the first line of immune defense. Metabolic variations in different immune cells in response to a tumor or pathogen infection have been described; however, little is known about NK cell metabolism in the context of viral infection. This review summarizes the activation-specific metabolic changes in NK cells, the immunometabolism of NK cells during early, late, and chronic antiviral responses, and the metabolic alterations in NK cells in SARS-CoV2 infection. The modulation points of these metabolic routes are also discussed to explore potential new immunotherapies against viral infections.

Early production of proinflammatory cytokines in response to Scedosporium apiospermum during murine pulmonary infection.

Scedosporium apiospermum is an opportunistic pathogen that can cause pulmonary infections in both immunosuppressive and immunocompetent patients. Cytokines are molecules that mediate the immune response to promote or eliminate fungal infections. In this work, we evaluated the cytokines profile in the lung and serum of mice infected with Scedosporium apiospermum. We found early production of IL-6, IL-1ß and TNF-α cytokines in the lung of infected mice during the first 5 days of infection. We suggest that release of pro-inflammatory cytokines could play a role in the control of fungal invasion.

Glucose and leukocyte esterase levels are possible biomarkers for bacterial septic arthritis.

OBJECTIVE: The objective of the study was to determine the added value of synovial fluid (SF) glucose levels and other biochemical parameters as possible biomarkers of bacterial septic arthritis (SA). MATERIALS AND METHODS: We prospectively examined adult patients with SA. As a control group, adults with uninfected joints were enrolled. SF samples were obtained, and microbiological analyses were made. SF glucose levels, pH, and leukocyte esterase were measured using a glucometer and colorimetric test strips. Blood samples were collected from both groups to determine glucose levels. RESULTS: We included eight subjects with knee ligaments lesions, six with meniscus lesions, and five with osteoarthritis as the control group, as well as 20 patients with SA. SF culture was positive in 60%. SF glucose levels from patients were lower than the controls (p = 0.0018) with the lowest concentration in patients with a positive culture (p = 0.0004). Blood and SF glucose concentration from the positive culture patients were compared (p < 0.0001). Leukocyte esterase presented the highest values in patients with a positive culture (p < 0.0001) and a more acidic pH was found compared to the control group (p < 0.0001). CONCLUSION: These biochemical parameters might be a quick and inexpensive added value for distinguishing between infective and non-infective joint disease.

OBJETIVO: Evaluar el valor añadido de los niveles de glucosa en el líquido sinovial (LS) y otros parámetros bioquímicos en el diagnostico de artritis séptica (AS). MATERIAL Y MÉTODOS: Análisis prospectivo de pacientes adultos con AS. Pacientes con articulaciones no infectadas fueron incluidos como grupo control. Se tomaron muestras de LS y sangre para la realización de análisis microbiológicos y bioquímicos en los pacientes y controles. RESULTADOS: Incluimos 8 sujetos con lesión ligamentosa de rodilla, 6 con lesiones meniscales y 5 con osteoartritis como grupo control, así como 20 pacientes con AS. El cultivo de LS fue positivo en 60%. Los niveles de glucosa en LS de pacientes con AS fueron más bajos que los controles (P = 0.0018) con la concentración más baja en pacientes con cultivo positivo (p = 0.0004). La relación de glucosa en sangre y LS de pacientes con cultivo positivo se vio afectada (p < 0.0001). La esterasa leucocitaria presentó valores más altos en pacientes con cultivo positivo (p < 0.0001); se encontró un pH más ácido en comparación con el grupo control (p < 0.0001). CONCLUSIÓN: Estos parámetros bioquímicos podrían ser un valor agregado útil, rápido y económico para distinguir entre enfermedad articular infecciosa y no infecciosa.

Systemic and Local Cytokines Profile Determine Severity and Prognosis in Human Septic Arthritis.

BACKGROUND: Septic arthritis (SA) is a medical emergency. The most common etiological agents are bacteria, which activate the local immune response coordinated by cytokines; however, little is known about the cytokine profile in human SA. AIM: To determine the association of local and systemic cytokine profiles with the severity and prognosis of patients with SA. METHODS: Patients with clinical and laboratory diagnosed SA were enrolled as well as a control group. Serum and synovial fluid (SF) samples were obtained for determining cytokines and glucose levels; SF samples were used for histological analysis. Osteochondral damage and general health status and quality of life (SF-36) were evaluated during recruitment day. WOMAC osteoarthritis index score and SF-36 questionnaire were used a year after recruitment day as a follow up. RESULTS: A systemic and local proinflammatory cytokine profile was found in patients compared to the control group (p <0.05). IL-6 was 28 and 525 times higher than controls in sera and SF, respectively (p <0.0001). Systemic IL-6 correlated negatively with general mental health score (p = 0.0184) and was associated with a higher osteoarthritis index after one year follow-up in the patients (p = 0.0352). HMGB1 in SF was found higher in patients with SA (p <0.0001), and it was associated with osteochondral damage (p = 0.0042). TNF-α in SF correlated negatively with SF-36 questionnaire one year after patients' recruitment in role limitation score (p = 0.0318), body pain score (p = 0.0315), and general mental health score (p = 0.0197). CONCLUSION: Serum and SF cytokine signatures are associated with disease severity and prognosis in patients with SA.

Human Eosinophils Reduce Viral Titer, Secrete IL-8, and Increase RIG-I Expression in Response to Influenza A H1N1 pdm09.

Eosinophils participate in the immune response against many pathogens, including viruses. Since mouse eosinophils are susceptible to influenza A virus infection and possess antiviral activity, we evaluated the expression of sialic acid residues in human eosinophils and their response against influenza virus in vitro. We demonstrated that human eosinophils express α2,6- and α2,3-linked sialic acid, and drastically reduced influenza virus titer. After influenza virus exposure, eosinophils upregulated retinoic acid-inducible gene I (RIG-I) mRNA expression, but no other pattern recognition receptors. Finally, high concentrations of interleukin-8 (IL-8) were found in influenza virus-exposed eosinophil cultures. These data suggest that human eosinophils possess antiviral activity and may play a role in the innate immune response to influenza virus.

Cortisol and perceived stress are associated with cytokines levels in patients infected with influenza B virus.

Influenza B virus (IBV) causes respiratory infectious disease. Cytokines are important immune mediators during infectious diseases. Cortisol and stress have been related to respiratory infection susceptibility and cytokine regulation. Little is known about systemic cytokines, cortisol, and perceived stress in the early stages of IBV infection. We researched the systemic cytokines and cortisol, as well as the perceived stress and blood cell count in patients infected with IBV. The diagnosis was established using the Luminex xTAG RVP kit and confirmed with qRT-PCR for IBV viral load. The perceived stress was evaluated using the perceived stress scale (PSS-10). Twenty-five plasma cytokines were determined using multiplex immunoassay and cortisol by ELISA. The leukocyte differential count was measured with a standard laboratory protocol. Th1, Th17, and IL-10 cytokines were higher in IBV infected patients (P < 0.05). Leukocytes and neutrophil count negatively correlated with viral load (P < 0.05). Perceived stress had a negative effect on monocyte and systemic cytokines in IBV infected patients (P < 0.05). Cortisol was higher in patients infected with IBV and correlated positively with CCL20 (P < 0.05). Cortisol showed a positive effect on most of the systemic cytokines (P < 0.05). In conclusion, a cytokine pattern was found in IBV infected patients, as well as the possible role of leukocyte counts in the control of IBV. Our results suggest the importance of cortisol and perceived stress on systemic cytokines in patients infected with IBV, but more studies are needed to understand their role in cytokine production in respiratory infectious disease.

Corrigendum to "CD206+ Cell Number Differentiates Influenza A (H1N1)pdm09 from Seasonal Influenza A Virus in Fatal Cases".

[This corrects the article DOI: 10.1155/2014/921054.].

Eosinophils and Respiratory Viruses.

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.

microRNAs in viral acute respiratory infections: immune regulation, biomarkers, therapy, and vaccines.

MicroRNAs (miRNAs) are single-stranded RNAs of 17-24 nt. These molecules regulate gene expression at the post-transcriptional 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.

Inflammatory and Anti-inflammatory Responses Co-exist Inside Lung Granuloma of Fatal Cases of Coccidioidomycosis: A Pilot Report.

Coccidioidomycosis is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. These fungi are endemic in the southern USA and northern Mexico. Immunocompromised patients are susceptible to develop severe forms of this fungal infection. Cytokines play an important role in controlling the fungal infection, but little is known about the predominant immunological environment in human lung tissue from fatal cases. Our aim was to analyze the pro-inflammatory and anti-inflammatory cytokines and monocyte/macrophages markers (CD14 and CD206) in the granulomas of six fatal cases of coccidioidomycosis. Cytokines and surface markers were higher in coccidioidomycosis cases when compared to control (P < 0.05). CD14 positive cells were increased inside the coccidioidal granuloma when compared to the outside (P < 0.05). No differences were found in the number of CD206+ cells inside the granuloma when compared to the outer population (P > 0.05). Interestingly, an analysis of stain intensity signals showed an increased signaling of CD14, CD206, IL-10 and TNFα inside the granuloma when compared to the outside (P < 0.05). iNOS and IL-12 gene expression were not detected in coccidioidomycosis cases, while IL-10, IL-6 and TGFß gene expression were detected, but the differences when compared to healthy lungs were not significant (P > 0.05). TNFα gene expression was lower in coccidioidomycosis cases when compared to healthy lung (P = 0.05). In conclusion, pro- and anti-inflammatory responses co-exist inside of the granulomas of fatal cases of coccidioidomycosis and the absent of iNOS and IL-12 gene expression may be related with patient's outcome.

Cytokines profile in immunocompetent mice during Trichosporon asahii infection.

Trichosporon asahii is an opportunistic yeastlike fungus commonly associated with systemic infections in immunocompromised patients. Neutropenia is recognized as the main risk factor in infections by T. asahii; however, little is known about the cytokine response during trichosporonosis. Here, we evaluated systemic and local cytokine production and histological damage in immunocompetent mice during systemic infection with T. asahii. We found a significant increased presence of G-CSF, TNF-α, IFN-γ, and IL-6 in sera samples. High levels of G-CSF were found in organs (kidney, liver and spleen); meanwhile IL-10, IL-17A, IL-2, IL-4 and TNF-α were found in low levels. Neutrophils and fungal structures were found in early stage in analyzed organs. Our results demonstrated that T. asahii induces a systemic inflammatory response and G-CSF environment in infected organs in immunocompetent mice and neutrophil recruitment in analyzed tissue suggests the importance of these cells for fungal control.

Relevant Cytokines in the Management of Community-Acquired Pneumonia.

Community-acquired pneumonia (CAP) is the leading cause of infectious death in the world. Immune dysregulation during acute lung infection plays a role in lung injury and the systemic inflammatory response. Cytokines seem to be major players in severe lung infection cases. Here, we present a review of published papers in the last 3 years regarding this topic. The cytokine response during pneumonia is different in bacterial vs viral infections; some of these cytokines correlate with clinical severity scales such as CURB65 or SOFA. Treatment focused in the cytokine environment is an interesting area that could impact the prognosis of CAP. Some of the agents that have been studied as co-adjuvant therapy are corticosteroids, macrolides, and linezolid, but anyone of those have shown a clear or proven efficacy or have been recommended as a part of the standard of care for CAP. More studies designed to define the role of immunomodulatory agents, such as co-adjuvant therapy in pneumonia, are needed.

Possible association of rare polymorphism in the ABCB1 gene with rifampin and ethambutol drug-resistant tuberculosis.

Human P-glycoprotein (P-gp) is a membrane transporter encoded by ABCB1 (also known as MDR1) that plays a critical role in pharmacokinetics of many unrelated drugs. Rifampin (RMP) and ethambutol (ETB), two anti-tubercular agents, are substrates of P-gp. Single nucleotide polymorphisms (SNPs) in ABCB1 have been associated with resistance to several drugs; however, their association with RMP and ETB resistance in tuberculosis patients has not yet been studied. Genotype/allele frequencies in C1236T, G2677T/A and C3435T SNPs of ABCB1 were obtained from 99 tuberculosis patients susceptible or resistant to RMP and ETB (NoRER or RER). 2677G>A allele prevalence was found to be significantly higher in the RER group compared to NoRER (5 resistant vs 2 non-resistant patients, P < 0.01; OR, 11.0; 95% CI, 2.00-56.00). No differences were found in genotype/allele frequencies in C1236T and C3435T SNPs of ABCB1 and resistance to RMP and ETB in tuberculosis patients (P > 0.05). The present study suggests the 2677G>A allele of ABCB1 could be associated with simultaneous resistance to RMP and ETB in pulmonary tuberculosis patients. Further studies with larger sample sizes are needed to confirm this association and explore its nature.

Candida parapsilosis complex induces local inflammatory cytokines in immunocompetent mice.

Despite the increasing incidence of the Candida parapsilosis complex in the clinical setting and high mortality rates associated with disseminated infection, the host-fungus interactions regarding Candida parapsilosis sensu stricto and the closely related species C. orthopsilosis and C. metapsilosis remains blurred. In this study, we analyzed inflammatory cytokines levels and histopathology as well as fungal burden in spleen, kidney and lung of mice infected with six strains of the "psilosis" group with different enzymatic profiles. Strong interleukin 22 (IL-22) and tumor necrosis factor α (TNF-α) responses were observed in analyzed organs from infected mice (P < .0001) regardless of the species and enzymatic profile. TNF-α and IL-22 levels were related with spleen inflammation and fungal load. Fungal cells were detected only in spleen and kidney of infected mice, especially by day 2 post-challenge. The kidney showed glomerular retraction and partial destruction of renal tubules. Our data suggest that a strong inflammatory response, mainly of IL-22 and TNF-α, could be involved in Candida parapsilosis complex infection control.

TGF-ß Blood Levels Distinguish Between Influenza A (H1N1)pdm09 Virus Sepsis and Sepsis due to Other Forms of Community-Acquired Pneumonia.

There is a strong interest in finding adequate biomarkers to aid in the diagnosis and prognosis of influenza A (H1N1)pdm09 virus infection. In this study, serum levels of inflammatory cytokines and laboratory markers were evaluated to assess their usefulness as biomarkers of influenza A (H1N1)pdm09 and their association with fatal cases. Serum samples of consecutive patients with a clinical presentation suggestive of influenza A (H1N1)pdm09 and progression to sepsis were evaluated. Serum inflammatory cytokines and routine laboratory tests were performed and correlated with positivity for influenza A (H1N1)pdm09 influenza by real time reverse transcription polymerase chain reaction and the results of three clinical severity scores (Sequential Organ Failure Assessment [SOFA], CURB-65, and Acute Physiology and Chronic Health Evaluation II [APACHE II]). High SOFA scores and some of its individual components, but not CURB-65 or APACHE II scores, correlate with fatal cases regardless of etiology. Total and unconjugated bilirubin, Ca(++), Cl(-), prothrombin times, and partial thromboplastin times discriminate influenza A (H1N1)pdm09 from other causes of community-acquired pneumonia. High levels of IL-8, IL-10, and IL-17 were increased in influenza A (H1N1)pdm09 patients when compared with controls (p<0.05). IL-6 levels were significantly elevated in influenza A (H1N1)pdm09 patients and non-(H1N1)pdm09 patients when compared with controls (p<0.05). TGF-ß serum levels discern between healthy controls, influenza A (H1N1)pdm09 patients, and patients with other causes of community-acquired pneumonia. TGF-ß levels were negatively correlated with SOFA on admission in influenza A (H1N1)pdm09 patients. TGF-ß levels are a useful tool for differentiating influenza A (H1N1)pdm09 from other causes of pneumonia progressing to sepsis.

Biofilm formation and genetic variability of BCR1 gene in the Candida parapsilosis complex.

BACKGROUND: Candida parapsilosis sensu stricto, Candida orthopsilosis, and Candida metapsilosis are cryptic species that belong to the C. parapsilosis complex, which has been increasingly associated to fungemia in various geographic regions, principally due to the capability of these yeasts to form biofilms on indwelling medical devices. BCR1 is one of the most studied genes related to Candida spp. biofilms. AIMS: To evaluate the biofilm forming capability of a subset of 65 clinical isolates of the C. parapsilosis complex using two conventional approaches, and to look for an association between the biofilm forming phenotype and genetic variants of a fragment of BCR1. METHODS: The biofilm determination was carried out by crystal violet staining and tetrazolium reduction assay. On the other hand, a segment of BCR1 gene was sequenced by Sanger methodology. RESULTS: C. parapsilosis sensu stricto was statistically associated with a low biofilm production phenotype, while C. orthopsilosis was significantly associated with both phenotypes (high and low biofilm producers). According to the BCR1 sequence analysis, genetic variability was detected in C. orthopsilosis and C. metapsilosis without a particular biofilm formation phenotype association. CONCLUSIONS: Under the adopted experimental design, C. parapsilosis sensu stricto was associated with the low biofilm phenotype and C. orthopsilosis with both phenotypes (high and low biofilm producers). On the other hand, an association between a biofilm forming phenotype and a particular genetic variant of the analyzed BCR1 fragment was not found.

CD206+ cell number differentiates influenza A (H1N1)pdm09 from seasonal influenza A virus in fatal cases.

In 2009, a new influenza A (H1N1) virus affected many persons around the world. There is an urgent need for finding biomarkers to distinguish between influenza A (H1N1)pdm09 and seasonal influenza virus. We investigated these possible biomarkers in the lung of fatal cases of confirmed influenza A (H1N1)pdm09. Cytokines (inflammatory and anti-inflammatory) and cellular markers (macrophages and lymphocytes subpopulation markers) were analyzed in lung tissue from both influenza A (H1N1)pdm09 and seasonal influenza virus. High levels of IL-17, IFN-γ, and TNF-α positive cells were identical in lung tissue from the influenza A (H1N1)pdm09 and seasonal cases when compared with healthy lung tissue (P < 0.05). Increased IL-4+ cells, and CD4+ and CD14+ cells were also found in high levels in both influenza A (H1N1)pdm09 and seasonal influenza virus (P < 0.05). Low levels of CD206+ cells (marker of alternatively activated macrophages marker in lung) were found in influenza A (H1N1)pdm09 when compared with seasonal influenza virus (P < 0.05), and the ratio of CD206/CD14+ cells was 2.5-fold higher in seasonal and noninfluenza group compared with influenza A (H1N1)pdm09 (P < 0.05). In conclusion, CD206+ cells differentiate between influenza A (H1N1)pdm09 and seasonal influenza virus in lung tissue of fatal cases.

Retnla down-regulation and IL-13-rich environment correlate with inflammation severity in experimental actinomycetoma by Nocardia brasiliensis.

Nocardia brasiliensis (Nb) is a facultative intracellular pathogen that may cause actinomycetoma when immune response is unable to control the pathogenic invasion. We used comparative real-time PCR to evaluate the expression level of molecules indicative of either classical or alternative activation of macrophages, as well as of cytokines involved in macrophage polarization, during the experimental infection in BALB/c mice. We found induction or increased expression of the pro-inflammatory markers csf2/GM-CSF, interferon-gamma, and nos2/iNOS. The expression of Ym1 and IL-13, which are usually related with alternative activation of macrophage, was also increased. However, retnla/FIZZ1 expression decreased sharply during the infection. We concluded that Nb infection induces both a pro-inflammatory and anti-inflammatory environment, in which there is a strong inverse correlation between IL-13 and retnla expression.

Expression of CCR5, CXCR4 and DC-SIGN in Cervix of HIV-1 Heterosexually Infected Mexican Women.

BACKGROUND: A number of studies have demonstrated that receptor and co-receptor expression levels which may affect viral entry, promoting cervical HIV infection. The aim was to evaluate the expression levels of CCR5, CXCR4and DC-SIGN mRNA in a sample of heterosexually HIV infected Mexican women. METHODS: We enrolled twenty-six HIV heterosexual infected women attending a local infectious diseases medical unit.RNA was isolated from the cervix and gene expression analysis was performed using real-time PCR. RESULTS: Expression rates for mRNA of CCR5 (median 1.82; range 0.003-2934) were higher than those observed for CXCR4 (0.79; 0.0061-3312) and DC-SIGN (0.33; 0.006-532) receptors (p < 0.05). A high correlation was found between the mRNA expression levels of these three receptors (rs = 0.52 to 0.85, p < 0.01). CONCLUSION: Levels of expression of the tested chemokine receptors in the cervix are different from each other and alsovary from woman to woman, and seem to support the suggestion that chemokine receptor expression in genital tissues may be playing a role in the HIV transmission.