Biology subjects

Bahadoran, A.

Publications and source records attributed to Bahadoran, A..

3 recordsLinked to original sources

bioRxiv2023

Establishing thresholds for cytokine storm and defining their relationship to disease severity in respiratory viral infections

Previous studies have identified cytokines associated with respiratory virus infection illness outcome. However, few studies have included comprehensive cytokine panels, longitudinal analyses, and/or simultaneous assessment across the severity spectrum. This, coupled with subjective definitions of cytokine storm syndrome (CSS), have contributed to inconsistent findings of cytokine signatures, particularly with COVID severity. Here, we measured 38 plasma cytokines and compared profiles in healthy, SARS-CoV-2 infected, and multisystem inflammatory syndrome in children (MIS-C) patients (n = 169). Infected patients spanned the severity spectrum and were classified as Asymptomatic, Mild, Moderate or Severe. Our results showed acute cytokine profiles and longitudinal dynamics of IL1Ra, IL10, MIP1b, and IP10 can differentiate COVID severity groups. Only 4% of acutely infected patients exhibited hypercytokinemia. Of these subjects, 3 were Mild, 3 Moderate, and 1 Severe, highlighting the lack of association between CSS and COVID severity. Additionally, we identified IL1Ra and TNFa as potential biomarkers for patients at high risk for long COVID. Lastly, we compare hypercytokinemia profiles across COVID and influenza patients and show distinct elevated cytokine signatures, wherein influenza induces the most elevated cytokine profile. Together, these results identify key analytes that, if obtained at early time points, can predict COVID illness outcome and/or risk of complications, and provide novel insight for improving the conceptual framework of hypercytokinemia, wherein CSS is a subgroup that requires concomitant severe clinical manifestations, and including a list of cytokines that can distinguish between subtypes of hypercytokinemia.

immunology↗

bioRxiv2020

Respiratory Syncytial Virus Infections Induce Hypermetabolism in Pediatric Upper Airways

To determine whether respiratory syncytial virus (RSV) regulates human metabolism, we used positron emission tomography (PET) of patient lungs along with bioenergetics and metabolomics of patient upper airway cells and fluids. We previously found a significant negative monotonic relationship between glucose uptake and respiratory viral infection in 20 pediatric patients (e.g., 70% of infected patients had glucose uptake within 0-3 days). In our recent study, 3 out of 4 patients positive for glucose uptake at later times (>5 days) were positive for RSV infection. At present, the bioenergetics of upper respiratory cells (URCs) from nasal pharyngeal aspirates have not been investigated, and in vitro studies indicate RSV reduces metabolism in cell lines. To define metabolic changes in RSV-infected pediatric patients, we acquired fresh aspirates from 6 pediatric patients. Immediately following aspiration of URCs, we measured the two major energy pathways using an XFe flux analyzer. Glycolysis and mitochondrial respiration were significantly increased in URCs from RSV-infected patients, and mitochondrial respiration was operating at near maximal levels, resulting in loss of cellular capacity to increase respiration with impaired coupling efficiency. Metabolomics analysis of metabolites flushed from the upper airways confirmed a significant increase in TCA cycle intermediates. Taken together, these studies demonstrate RSV induces significant hypermetabolism in pediatric patients lungs and respiratory tract. Thus, hypermetabolism is a potential anti-viral drug target and reveals RSV can regulate human metabolism. Contributions to the fieldMetabolic changes in humans in response to viral infection are largely unknown. In this brief clinical report, we find metabolism is markedly increased in live upper respiratory cells from infants infected with respiratory syncytial virus (RSV) concomitant to changes in metabolites in their upper airway fluids. This sheds light on viral induced hypermetabolism in the airways and offers potential biomarkers for RSV. In addition, this identifies potential therapeutic targets for host directed therapies of aberrant metabolism in RSV. This work has clinical impact as biomarkers and therapeutics for RSV are needed for this pervasive virus that causes infections with long term consequence for some children. Further, advancements in molecular mechanisms underpinning RSV infection biology are constrained by the difficulties in translating model systems to humans as well as relating human studies in adults to infants (Mestas and Hughes, 2004; Papin et al., 2013).

systems biology↗

bioRxiv2020

Dynamic metabolic reprogramming in dendritic cells: an early response to influenza infection that is essential for effector function

Infection with the influenza virus triggers an innate immune response aimed at initiating the adaptive response to halt viral replication and spread. However, the metabolic response fueling the molecular mechanisms underlying changes in innate immune cell homeostasis remain undefined. Thus, we compared the metabolic response of dendritic cells to that of those infected with active and inactive influenza A virus or treated with toll like receptor agonists. While influenza infects dendritic cells, it does not productively replicate in these cells, and therefore metabolic changes upon infection may represent an adaptive response on the part of the host cells. Using quantitative mass spectrometry along with pulse chase substrate utilization assays and metabolic flux measurements, we found global metabolic changes 17 hours post infection, including significant changes in carbon commitment via glycolysis and glutaminolysis, as well as ATP production via TCA cycle and oxidative phosphorylation. Influenza infection of dendritic cells led to a metabolic phenotype, distinct from that induced by TLR agonists, with significant resilience in terms of metabolic plasticity. We identified Myc as one transcription factor modulating this response. Restriction of either Myc activity or mitochondrial substrates resulted in significant changes in the innate immune functions of dendritic cells, including reduced motility and T cell activation. Transcriptome analysis of inflammatory dendritic cells isolated following influenza infection showed similar metabolic reprogramming occurs in vivo. Thus, early in the infection process dendritic cells respond with global metabolic restructuring that is present in lung DC 9 days following infection and impacts their effector function, suggesting that metabolic switching in dendritic cells plays a vital role in initiating the immune response to influenza infection. Author SummaryIn response to influenza infection we found that dendritic cells, cells that are critical in mounting an effective immune response, undergo a profound metabolic shift. They alter the concentration and location of hundreds of proteins, including c-MYC, mediating a shift to a highly glycolytic phenotype that is also flexible in terms of fueling respiration. Dendritic cells initiate the immune response to influenza and activate the adaptive response allowing viral clearance and manifesting immune memory for protection against subsequent infections. We found that limiting access to specific metabolic pathways or substrates diminished key immune functions. Previously we described an immediate, fixed, hypermetabolic state in infected respiratory epithelial cells. We now show the metabolic responses of epithelial and dendritic cells are distinct. Here, we also demonstrate that dendritic cells tailor their metabolic response to the pathogen or TLR stimulus. This metabolic reprogramming occurs rapidly in vitro and it is sustained in inflammatory dendritic cells in vivo for at least 9 days following influenza infection. Thus, drugs targeting metabolism are likely to have cell- and pathogen-specific activities in the context of infection. These studies open the possibility of modulating the immune response to viral infection via customizing metabolic therapy to enhance or diminish the function of specific cells.

immunology↗