Biology subjects

Sperk, M.

Publications and source records attributed to Sperk, M..

5 recordsLinked to original sources

bioRxiv2025

Systemic Multi-Omics Analysis Reveals Interferon Response Heterogeneity and Links Lipid Metabolism to Immune Alterations in Severe COVID-19

The immune response to SARS-CoV-2 infection is highly heterogeneous, and interferon (IFN)-stimulated genes (ISGs) play a central but context-dependent role in antiviral defense and immune dysregulation. To investigate how ISG heterogeneity relates to immune and metabolic states, we performed an integrated analysis of whole-blood transcriptomics, plasma proteomics, metabolomics, and immune activation markers in hospitalized COVID-19 patients and COVID-negative healthy controls and covalescent individuals. Patients segregated into low (LIS), moderate (MIS), and high (HIS) ISG expression endotypes, largely independent of clinical severity. While high ISG expression was associated with systemic inflammation and innate immune activation, severe disease within the HIS endotype was characterized by marked metabolic perturbations, including depletion of tricarboxylic acid cycle intermediates and multiple lipid classes involved in membrane integrity and immunometabolic signaling. Plasma-transfer assays demonstrated that plasma from severe HIS patients impaired neutrophil and monocyte activation ex vivo, indicating functional attenuation of innate immune responses despite elevated ISG expression. These metabolic alterations correlated with reduced immune activation, supporting the existence of an interferon-associated immune-metabolic axis that constrains immune functionality in severe disease. Although type I IFN neutralization was detected in a subset of patients with IFN antigen reactivity, these samples did not account for ISG heterogeneity or disease severity. Together, these findings show that high ISG expression defines a transcriptional endotype permissive for inflammation but insufficient for effective immune function, highlighting the importance of immune-metabolic context in shaping COVID-19 disease outcomes.

immunology↗

bioRxiv2021

Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

Viruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data and in vitro infection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

microbiology↗

bioRxiv2020

Distinct lipid profile, low-level inflammation and increased antioxidant defense as a signature in HIV-1 elite control status

HIV-1 elite controllers (EC) are a rare but heterogeneous group of HIV-1-infected individuals who are able to suppress viral replication in the absence of antiretroviral therapy. The mechanisms of how EC achieve undetectable viral loads remain unclear. This study aimed to investigate host plasma metabolomics and targeted plasma proteomics in a Swedish HIV-1 cohort including EC and treatment-naive viremic progressors (VP) as well as HIV-negative individuals (HC) to get insights into mechanisms governing EC status. Metabolites belonging to antioxidant defense had higher levels in EC relative to VP while inflammation markers were increased in VP compared to EC. Only four plasma proteins (CCL4, CCL7, CCL20, and NOS3) were increased in EC compared to HC and CCL20/CCR6 axis can play important role. Our study suggests that low-level inflammation and oxidative stress at physiological levels could be important factors contributing to control of viral replication. One Sentence SummaryHIV-1 elite controllers had a distinct lipid profile, reduced inflammation, and increased antioxidant defense that might contribute to elite control status.

microbiology↗

bioRxiv2020

Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

How Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remain largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected HuH7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a significant reduction in activated S6K1 and 4E-BP1 at 72 hours post infection. Unlike other human respiratory viruses, we found a significant inhibition of HIF-1 through the entire time course of the infection, suggesting a crosstalk between the SARS-CoV-2 and the mTOR/HIF-1 signaling. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe COVID-19 patients.

microbiology↗

bioRxiv2018

Systemic inflammation following long-term successful antiretroviral therapy in people living with HIV (PLHIV)

The ART program in low- and middle-income countries (LMIC) like India, has a public health approach with the standardized regimen for all people living with HIV (PLHIV). Based on the evidence from high-income countries (HIC), the successful implication and scale-up of ART in India, the risk of an enhanced and accentuated onset of premature-aging or age-related diseases could be observed in PLHIV. However, very limited data is available on residual inflammation and immune activation in the populations who are on first-generation anti-HIV drugs like zidovudine and lamivudine that had more toxic side effects. Therefore, the aim of the present study was to evaluate the levels of systemic inflammation and understand the risk of age-associated diseases in PLHIV on long-term suppressive ART using a large number of biomarkers of the inflammation and immune activation. Blood samples were obtained from therapy naive PLHIV (Pre-ART, n=43), PLHIV on ART for >5 years (ART, n=53), and HIV-negative healthy controls (HIVNC, n=41). Samples were analyzed for 92 markers of inflammation, sCD14, sCD163, and telomere length. Several statistical tests were performed to compare the groups under study. Multivariate linear regression was used to investigate the associations. Despite a median duration of eight years of successful ART, sCD14 (p<0.001) and sCD163 (p=0.04) levels continued to be significantly elevated in ART group as compared to HIVNC. Eleven inflammatory markers, including 4E-BP1, ADA, CCL23, CD5, CD8A, CST5, MMP1, NT3, SLAMF1, TRAIL and TRANCE, were found to be significantly different (p<0.05) between the groups. Many of these markers are associated with age-related co-morbidities including cardiovascular disease, neurocognitive decline and some of these markers are being reported for the first time in the context of HIV-induced inflammation. Linear regression analysis showed a significant negative association between HIV-1-positivity and telomere length (p<0.0001). In ART-group CXCL1 (p=0.048) and TGF- (p=0.026) have a significant association with increased telomere length and IL-10RA was significantly associated with decreased telomere length (p=0.042). This observation warrants further mechanistic studies to generate evidence to highlight the need for enhanced treatment monitoring and special interventions in HIV-infected individuals.

immunology↗