ABSTRACT
Invasive Staphylococcus aureus infections are a leading cause of morbidity and mortality in both hospital and community settings, especially with the widespread emergence of virulent and ...multi-drug resistant methicillin-resistant S. aureus strains. There is an urgent and unmet clinical need for non-antibiotic immune-based approaches to treat these infections as the increasing antibiotic resistance is creating a serious threat to public health. However, all vaccination attempts aimed at preventing S. aureus invasive infections have failed in human trials, especially all vaccines aimed at generating high titers of opsonic antibodies against S. aureus surface antigens to facilitate antibody-mediated bacterial clearance. In this review, we summarize the data from humans regarding the immune responses that protect against invasive S. aureus infections as well as host genetic factors and bacterial evasion mechanisms, which are important to consider for the future development of effective and successful vaccines and immunotherapies against invasive S. aureus infections in humans. The evidence presented form the basis for a hypothesis that staphylococcal toxins (including superantigens and pore-forming toxins) are important virulence factors, and targeting the neutralization of these toxins are more likely to provide a therapeutic benefit in contrast to prior vaccine attempts to generate antibodies to facilitate opsonophagocytosis.
This review summarizes the data from humans regarding the immune responses that protect against invasive Staphylococcus aureus infections as well as host genetic factors and bacterial evasion mechanisms, which form the basis for a hypothesis that future vaccines and immune-based therapies that target the neutralization of staphylococcal toxins superantigens and pore-forming toxins are more likely to provide a therapeutic benefit.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by intense and debilitating fatigue not due to physical activity that has persisted for at least 6 months, ...post-exertional malaise, unrefreshing sleep, and accompanied by a number of secondary symptoms, including sore throat, memory and concentration impairment, headache, and muscle/joint pain. In patients with post-exertional malaise, significant worsening of symptoms occurs following physical exertion and exercise challenge serves as a useful method for identifying biomarkers for exertion intolerance. Evidence suggests that intestinal dysbiosis and systemic responses to gut microorganisms may play a role in the symptomology of ME/CFS. As such, we hypothesized that post-exertion worsening of ME/CFS symptoms could be due to increased bacterial translocation from the intestine into the systemic circulation. To test this hypothesis, we collected symptom reports and blood and stool samples from ten clinically characterized ME/CFS patients and ten matched healthy controls before and 15 minutes, 48 hours, and 72 hours after a maximal exercise challenge. Microbiomes of blood and stool samples were examined. Stool sample microbiomes differed between ME/CFS patients and healthy controls in the abundance of several major bacterial phyla. Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls (p = 0.005). There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls. These results provide evidence for a systemic effect of an altered gut microbiome in ME/CFS patients compared to controls. Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise. These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.
Phenome-Wide Association study (PheWAS) is a powerful tool designed to systematically screen clinical observations derived from medical records (phenotypes) for association with a variable of ...interest. Despite their usefulness, no systematic screening of phenotypes associated with Staphylococcus aureus infections (SAIs) has been done leaving potential novel risk factors or complications undiscovered. We tailored the PheWAS approach into a two-stage screening procedure to identify novel phenotypes correlating with SAIs. The first stage screened for co-occurrence of SAIs with other phenotypes within medical records. In the second stage, significant findings were examined for the correlations between their age of onset with that of SAIs. The PheWAS was implemented using the medical records of 754,401 patients from the Marshfield Clinic Health System. Any novel associations discovered were subsequently validated using datasets from TriNetX and All of Us, encompassing 109,884,571 and 118,538 patients respectively. Forty-one phenotypes met the significance criteria of a p-value 5. Out of these, we classified 23 associations either as risk factors or as complications of SAIs. Three novel associations were discovered and classified either as a risk (long-term use of aspirin) or complications (iron deficiency anemia and anemia of chronic disease). All novel associations were replicated in the TriNetX cohort. In the All of Us cohort, anemia of chronic disease was replicated according to our significance criteria. The PheWAS of SAIs expands our understanding of SAIs interacting phenotypes. Additionally, the novel two-stage PheWAS approach developed in this study can be applied to examine other disease-disease interactions of interest. Due to the possibility of bias inherent in observational data, the findings of this study require further investigation.
Himalayan rivers are the paramount source of water supply to millions of people in northern India for drinking, irrigation and hydropower generation. Several researches reported that the hydrological ...regime of these Himalayan rivers is vulnerable to climate change. In order to understand the hydrologic response of their headwaters and examine the climate change impacts on streamflow, a hydrological modelling study is carried out in the upper part of the Satluj river basin in western Himalaya by using a temperature index based SWAT (Soil Water Assessment Tool) model. The model performed well for both calibration (years 1986–2000) and validation (2001–2005) periods against the observed daily streamflow at Rampur (R2 ≈ 0.9 and NSE ≥ 0.85). The study reveals that having a larger snow covered area, the snowmelt runoff is the major contributor to the Satluj river discharge at Rampur that comes out to be about 68–71% of the average annual water yield of about 600 mm. The actual evapotranspiration comes out to be about 14% of precipitation. The water yield of the basin is about 50% of the precipitation, for which the major part is generated in early summer.
Further, to study the climate change impact on future streamflow, the downscaled data of CORDEX CCSM4 under two Representative Concentration Pathways (RCP4.5 and RCP8.5) scenarios are used. The bias correction is applied at point level to remove biases from future time series of downscaled data and subsequently loaded into the SWAT model to simulate the future streamflows at the end of the century. The future climate variability in terms of precipitation and temperature exhibited that the climate in the region would become wetter and warmer. A 14% to 21% of increase in annual precipitation is predicted towards the end of the century from the current average annual precipitation of about 420 mm under RCP4.5 and RCP8.5, respectively. Similar to precipitation, the temperature will also be increased by 2.18 °C to 5.71 °C (in both the RCPs) than the current temperature values. The changed climate conditions in future are transformed into the possible range of stream flows using the SWAT model and found that the future climate would increase the streamflow by over 11%–19% at the end of the century under RCP4.5 and RCP8.5 scenarios, respectively. The outcome of this study can be used to develop the suitable strategies for sustainable water management in the region.
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•Hydrological modelling of a highly snow/glacier-fed western Himalayan river basin, using SWAT model.•Changes evaluation in CORDEX future precipitation & temperature and streamflows assessment under RCP4.5 & RCP8.5 scenarios•Observed an overall increase in the future precipitation and temperature at the end of the century•Observed a significant increase in annual and seasonal streamflows at the end of the century•The impact of climate change was higher in RCP8.5 scenarios than in RCP4.5.
The etiological complexity of multiple sclerosis, an immune-mediated, neurodegenerative disease with multifactorial etiology is still elusive because of an incomplete understanding of the complex ...synergy between contributing factors such as genetic susceptibility and aberrant immune response. Recently, the disease phenotypes have also been shown to be associated with dysbiosis of the gut microbiome, a dynamic reservoir of billions of microbes, their proteins and metabolites capable of mimicring the autoantigens. Microbial factors could potentially trigger the neuroinflammation and symptoms of MS. In this perspective article, we discussed how microbial molecules resulting from a leaky gut might mimic a host’s autoantigen, potentially contributing to the disease disequilibrium. It further highlights the importance of targeting the gut microbiome for alternate therapeutic options for the treatment of MS.
Allergic and autoimmune diseases had been attributed to lack of exposure to biodiversity, an important factor in regulating immune homeostasis in a healthy host. We posit that the microbiome of ...healthy dairy farmers (DF) will be richer than non-farmers (NF) living in urban settings due to exposure to a greater biodiversity in the dairy environment. However, no studies have investigated the relationships between microbiota of dairy farmers (DF) compared with urban non-farmers (NF). We compared the nasal and oral microbiota of dairy farmers (N_DF, O_DF, respectively) with nasal and oral microbiota of NF in the same geographical area. The N_DF showed high microbial diversity with hundreds of unique genera that reflected environmental/occupational exposures. The nasal and oral microbiomes clustered separately from each other using Principal Coordinate Analysis, and with DF harboring two-fold and 1.5-fold greater exclusive genera in their nose and mouth respectively, than did non-farmers. Additionally, the N_DF group had a lower burden of Staphylococcus spp. suggesting a correlation between higher microbial diversity and competition for colonization by staphylococci. The N_DF samples were negative for the mecA gene, a marker of methicillin-resistance in staphylococci. The lower burden of staphylococci was found to be independent of the abundance of Corynebacterium spp. Exposure to greater biodiversity could enhance microbial competition, thereby reducing colonization with opportunistic pathogens. Future studies will analyze whether exposure to livestock microbiomes offers protection from acute and chronic diseases.
Staphylococcus aureus is a major human pathogen and emergence of antibiotic resistance in clinical staphylococcal isolates raises concerns about our ability to control these infections. Cell ...wall-active antibiotics cause elevated synthesis of methionine sulfoxide reductases (Msrs: MsrA1 and MsrB) in S. aureus. MsrA and MsrB enzymes reduce S-epimers and R-epimers of methionine sulfoxide, respectively, that are generated under oxidative stress. In the S. aureus chromosome, there are three msrA genes (msrA1, msrA2 and msrA3) and one msrB gene. To understand the precise physiological roles of Msr proteins in S. aureus, mutations in msrA1, msrA2 and msrA3 and msrB genes were created by site-directed mutagenesis. These mutants were combined to create a triple msrA (msrA1, msrA2 and msrA3) and a quadruple msrAB (msrA1, msrA2, msrA3, msrB) mutant. These mutants were used to determine the roles of Msr proteins in staphylococcal growth, antibiotic resistance, adherence to human lung epithelial cells, pigment production, and survival in mice relative to the wild-type strains. MsrA1-deficient strains were sensitive to oxidative stress conditions, less pigmented and less adherent to human lung epithelial cells, and showed reduced survival in mouse tissues. In contrast, MsrB-deficient strains were resistant to oxidants and were highly pigmented. Lack of MsrA2 and MsrA3 caused no apparent growth defect in S. aureus. In complementation experiments with the triple and quadruple mutants, it was MsrA1 and not MsrB that was determined to be critical for adherence and phagocytic resistance of S. aureus. Overall, the data suggests that MsrA1 may be an important virulence factor and MsrB probably plays a balancing act to counter the effect of MsrA1 in S. aureus.
Bladder urothelial carcinoma (BLC) is one of the most common cancers in men, and its heterogeneity challenges the treatment to cure this disease. Recently, microRNAs (miRNAs) gained promising ...attention as biomarkers due to their potential roles in cancer biology. Identifying survival-associated miRNAs may help identify targets for therapeutic interventions in BLC. This work aims to identify a miRNA signature that could estimate the survival in patients with BLC. We developed a survival estimation method called BLC-SVR based on support vector regression incorporated with an optimal feature selection algorithm to select a robust set of miRNAs as a signature to estimate the survival in patients with BLC. BLC-SVR identified a miRNA signature consisting of 29 miRNAs and obtained a mean squared correlation coefficient and mean absolute error of 0.79 ± 0.02 and 0.52 ± 0.32 year between actual and estimated survival times, respectively. The prediction performance of BLC-SVR had a better estimation capability than other standard regression methods. In the identified miRNA signature, 14 miRNAs, hsa-miR-432-5p, hsa-let-7e-3p, hsa-miR-652-3p, hsa-miR-629-5p, and hsa-miR-203a-3p, hsa-miR-129-5p, hsa-miR-769-3p, hsa-miR-570-3p, hsa-miR-320c, hsa-miR-642a-5p, hsa-miR-496, hsa-miR-5480-3p, hsa-miR-221-5p, and hsa-miR-7-1-3p, were found to be good biomarkers for BLC diagnosis; and the six miRNAs, hsa-miR-652-5p, hsa-miR-193b-5p, hsa-miR-129-5p, hsa-miR-143-5p, hsa-miR-496, and hsa-miR-7-1-3p, were found to be good biomarkers of prognosis. Further bioinformatics analysis of this miRNA signature demonstrated its importance in various biological pathways and gene ontology annotation. The identified miRNA signature would further help in understanding of BLC diagnosis and prognosis in the development of novel miRNA-target based therapeutics in BLC.
Abstract
Multiple sclerosis (MS) is a complex autoimmune disease in which both the roles of genetic susceptibility and environmental/microbial factors have been investigated. More than 200 genetic ...susceptibility variants have been identified along with the dysbiosis of gut microbiota, both independently have been shown to be associated with MS. We hypothesize that MS patients harboring genetic susceptibility variants along with gut microbiome dysbiosis are at a greater risk of exhibiting the disease. We investigated the genetic risk score for MS in conjunction with gut microbiota in the same cohort of 117 relapsing remitting MS (RRMS) and 26 healthy controls. DNA samples were genotyped using Illumina’s Infinium Immuno array-24 v2 chip followed by calculating genetic risk score and the microbiota was determined by sequencing the V4 hypervariable region of the 16S rRNA gene. We identified two clusters of MS patients, Cluster A and B, both having a higher genetic risk score than the control group. However, the MS cases in cluster B not only had a higher genetic risk score but also showed a distinct gut microbiome than that of cluster A. Interestingly, cluster A which included both healthy control and MS cases had similar gut microbiome composition. This could be due to (i) the non-active state of the disease in that group of MS patients at the time of fecal sample collection and/or (ii) the restoration of the gut microbiome post disease modifying therapy to treat the MS. Our study showed that there seems to be an association between genetic risk score and gut microbiome dysbiosis in triggering the disease in a small cohort of MS patients. The MS Cluster A who have a higher genetic risk score but microbiome profile similar to that of healthy controls could be due to the remitting phase of the disease or due to the effect of disease modifying therapies.
Due to the lack of fossil evidence, the timescales of bacterial evolution are largely unknown. The speed with which genetic change accumulates in populations of pathogenic bacteria, however, is a key ...parameter that is crucial for understanding the emergence of traits such as increased virulence or antibiotic resistance, together with the forces driving pathogen spread. Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of hospital-acquired infections. We have investigated an MRSA strain (ST225) that is highly prevalent in hospitals in Central Europe. By using mutation discovery at 269 genetic loci (118,804 basepairs) within an international isolate collection, we ascertained extremely low diversity among European ST225 isolates, indicating that a recent population bottleneck had preceded the expansion of this clone. In contrast, US isolates were more divergent, suggesting they represent the ancestral population. While diversity was low, however, our results demonstrate that the short-term evolutionary rate in this natural population of MRSA resulted in the accumulation of measurable DNA sequence variation within two decades, which we could exploit to reconstruct its recent demographic history and the spatiotemporal dynamics of spread. By applying Bayesian coalescent methods on DNA sequences serially sampled through time, we estimated that ST225 had diverged since approximately 1990 (1987 to 1994), and that expansion of the European clade began in 1995 (1991 to 1999), several years before the new clone was recognized. Demographic analysis based on DNA sequence variation indicated a sharp increase of bacterial population size from 2001 to 2004, which is concordant with the reported prevalence of this strain in several European countries. A detailed ancestry-based reconstruction of the spatiotemporal dispersal dynamics suggested a pattern of frequent transmission of the ST225 clone among hospitals within Central Europe. In addition, comparative genomics indicated complex bacteriophage dynamics.
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