Biology subjects

Smolen, K. K.

Publications and source records attributed to Smolen, K. K..

4 recordsLinked to original sources

bioRxiv2023

Integrated longitudinal multi-omics study identifies immune programs associated with COVID-19 severity and mortality in 1152 hospitalized participants

Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study, we carried out deep immunophenotyping and conducted longitudinal multi-omics modeling integrating ten distinct assays on a total of 1,152 IMPACC participants and identified several immune cascades that were significant drivers of differential clinical outcomes. Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, NETosis, and T-cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma immunoglobulins and B cells, as well as dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to the failure of viral clearance in patients with fatal illness. Our longitudinal multi-omics profiling study revealed novel temporal coordination across diverse omics that potentially explain disease progression, providing insights that inform the targeted development of therapies for hospitalized COVID-19 patients, especially those critically ill.

immunology↗

bioRxiv2023

Early cellular and molecular signatures correlate with severity of West Nile Virus infection

Infection with West Nile Virus (WNV) can drive a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To identify cellular and molecular signatures distinguishing WNV severity, we employed systems profiling of peripheral blood from asymptomatic and severely ill individuals infected with WNV. We interrogated immune responses longitudinally from acute infection through convalescence at 3 months and 1 year employing multiplexed single cell protein and transcriptional profiling (CyTOF and Seq-Well) complemented with matched serum proteomics and metabolomics. At the acute time point, we detected both an elevated proportion of pro-inflammatory markers in innate immune cell types and reduced frequency of regulatory T cell activity in participants with severe infection compared to those with asymptomatic infection. Single-cell transcriptomics of paired samples revealed that asymptomatic donors had higher expression of genes associated with innate immune pathways, in particular anti-inflammatory CD16+ monocytes at the acute time point. A multi-omics analysis identified factors--beyond those from individual analyses--that distinguished immune state trajectory between severity groups. Here we highlighted the potential of systems immunology using multiple cell-type and cell-state-specific analyses to identify correlates of infection severity and host cellular activity contributing to an effective anti-viral response.

immunology↗

bioRxiv2021

Determinants of precocious B-cell aging in European adolescences living with perinatally acquired HIV-1 after over 10 years of suppressive therapy

HIV infection results in a state of chronic immune activation leading to premature immune aging, B-cells dysfunction, that persists despite prolonged virological suppression. In this scenario, adolescence living with perinatally acquired HIV (PHIV), deserve a peculiar attention since potentially exposed for their entire life to chronic immune activation. Here we identified determinants of precocious aging B cells in 40 PHIV undergoing suppressive antiretroviral therapy (ART) for median 13.5 years. All individuals started ART by 2nd year of life and achieved virus suppression within the 1st year of ART, with majority of patient maintaining suppression until analysis and 5/40 experiencing viral Spike (transient elevation of HIV-1 VL, 50-999 copies/ml). We employed a multiomics approach including deep immunological B and T cell phenotype in PBMC, with aging B cells defined by the expression of T-bet and CD11c; plasma proteomics analysis by mass spectrometry and serum level of anti-measles antibodies as correlates of humoral response. We found that individuals with expansion of aging B cell, defined by the expression of T-bet+CD11c+, were those starting treatment later, presenting detectable levels of cell-associated HIV-1 RNA, history of Spikes, and a higher frequency of exhausted T-cells, including those expressing PD-1, LAG3, TIGIT. Accordingly, the proteomic analysis revealed that subjects with expansion of aging B cells and exhausted T cells had enrichment of proteins involved in immune inflammation and complement activation pathways, such as CLU and APCS which are also involved in tumor progression. Signs of precocious aging were associated with a reduced capacity to maintain virological memory against measles vaccination. To our knowledge, this is the first study focusing on precocious B-cell aging and dysfunctionality in PHIV with long-term virological suppression. Our experimental strategy enabled identification of clinical, viral, cellular and plasma soluble markers associated with B-cells aging. Our results pave the way to further define risk of disease progression or lymphoproliferative disorders in PHIV. Author summaryDespite a successful antiretroviral therapy (ART), adolescence living with perinatally acquired HIV (PHIV) experience B-cells dysfunction, including loss of vaccine-induced immunological memory and higher risk of developing B-cells associated tumors. It is thus paramount to define novel and precise correlates of precious aging B cell for the definition of novel therapeutic strategies. Here, we studied 40 PHIV who started treatment by 2nd year of life and maintain virological suppression for 13.5 years, with 5/40 patients experiencing transient elevation of the HIV-1 load in the plasma (Spike). We applied a multi-omics approach including immunological B and T cell phenotype, plasma proteomics analysis and serum level of anti-measles antibodies as functional correlates of vaccine-induced immunity. We found that levels of aging B cells were positively associated with age at ART start, cell associated HIV-1 RNA (caHIV-1 RNA) and the presence of Spikes. Individuals with increased proportions of aging B cells had concomitant expansion of exhausted T cells and were unable to maintain vaccine-induced immunity over time. B-cell aging, and T-cell exhaustion were also associated with proteins involved in immune inflammation. The factors found here to be associated with aging B-cell could inform further therapeutic studies.

immunology↗

bioRxiv2020

Proteomics on longitudinal serum samples differentiates localized and disseminated Lyme disease

Lyme disease (LD) is the most prevalent vector-borne disease in North America, with ~300,000 new cases annually in the USA alone. LD is most often recognized by the appearance of the skin lesion erythema migrans (EM) at the tick bite site but also can present with signs of disseminated infection manifesting as multiple EM lesions and/or involvement of the heart, nervous system or joints. In this study, we examined the serum proteome of study participants presenting with either a single EM (localized LD) or early disseminated infection (disseminated LD). Samples collected at the time of diagnosis and at convalescent time points were assessed using our in-house developed MStern blotting-based serum proteomics platform. After technical validation of our platform, the temporal analysis from diagnosis to clinical resolution of the infection demonstrates LD stage-associated pathways activation such as a temporary upregulation of acute phase response specific to the participants with disseminated LD. In addition, we identified the members of the serum amyloid A protein family as potentially promising candidate biomarkers to identify those with disseminated LD. The results of this pilot study demonstrate the feasibility of using our time- and cost-effective sample sparing MStern blotting-based serum proteomics platform to efficiently interrogate proteome changes over time in those suffering infections such as LD. These observations establish a new approach to human serum proteomics, provide fresh insight into the host immune responses associated with disease severity (localized versus disseminated infection) and suggest novel biomarker candidate panels for LD stages. ImportanceWe investigated the proteome changes of Borrelia burgdorferi-infected participants with either a single erythema migrans or early disseminated Lyme disease infection. Using our in-house time-and cost-effective proteomics platform, the temporal analysis from diagnosis to clinical resolution of the infection shows a temporary upregulation of the acute phase response specific to the participants with disseminated infection. Finally, specific protein panels were identified as possible biomarker candidates to categorize those having an initial diagnosis of disseminated manifestation using a reference cohort of acute localized infection and a clinically resolved convalescent phase disease samples from the same Lyme disease participants.

immunology↗