Blood is the predominant source for molecular analyses in humans, both in clinical and research settings. It is the target for many therapeutic strategies, emphasizing the need for comprehensive ...molecular maps of the cells constituting human blood. In this study, we performed a genome-wide transcriptomic analysis of protein-coding genes in sorted blood immune cell populations to characterize the expression levels of each individual gene across the blood cell types. All data are presented in an interactive, open-access Blood Atlas as part of the Human Protein Atlas and are integrated with expression profiles across all major tissues to provide spatial classification of all protein-coding genes. This allows for a genome-wide exploration of the expression profiles across human immune cell populations and all major human tissues and organs.
Immune-microbe interactions early in life influence the risk of allergies, asthma, and other inflammatory diseases. Breastfeeding guides healthier immune-microbe relationships by providing nutrients ...to specialized microbes that in turn benefit the host’s immune system. Such bacteria have co-evolved with humans but are now increasingly rare in modern societies. Here we show that a lack of bifidobacteria, and in particular depletion of genes required for human milk oligosaccharide (HMO) utilization from the metagenome, is associated with systemic inflammation and immune dysregulation early in life. In breastfed infants given Bifidobacterium infantis EVC001, which expresses all HMO-utilization genes, intestinal T helper 2 (Th2) and Th17 cytokines were silenced and interferon β (IFNβ) was induced. Fecal water from EVC001-supplemented infants contains abundant indolelactate and B. infantis-derived indole-3-lactic acid (ILA) upregulated immunoregulatory galectin-1 in Th2 and Th17 cells during polarization, providing a functional link between beneficial microbes and immunoregulation during the first months of life.
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•An ordered sequence of immune changes after birth driven by microbial interactions•Lack of gut bifidobacteria and HMO-utilization genes correlates with systemic inflammation•Feeding B. infantis EVC001 upregulates IFNβ and silences intestinal Th2 and Th17•EVC001-associated indole-3-lactic acid upregulates inhibitory galectin-1 in T cells
A lack of bifidobacteria and/or their genes required for the utilization of human milk oligosaccharides from breast milk is associated with systemic inflammation and immune imbalance early in life. Infant supplementation of Bifidobacterium infantis EVC001 shows promise in mitigating this by reducing Th2 and Th17 cytokines in the intestine through upregulation of the immunoregulatory factor galectin-1.
Severe disease of SARS-CoV-2 is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5–7 days of stable disease. Efforts to modulate this hyperinflammation ...and the associated acute respiratory distress syndrome rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Given that every patient is captured at different stages of infection, longitudinal monitoring of the immune response is critical and systems-level analyses are required to capture cellular interactions. Here, we report on a systems-level blood immunomonitoring study of 37 adult patients diagnosed with COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ-eosinophil axis activated before lung hyperinflammation and changes in cell-cell co-regulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.
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Immunomonitoring from acute to recovery phase COVID-19An IFNγ-eosinophil axis precedes lung hyperinflammationBasophils modulate SARS-CoV-2 IgG responsesA shared trajectory of immunological recovery in COVID-19
Immune dysregulation plays a pivotal role during severe COVID-19. Rodriguez et al. present a systems-level, longitudinal study of 37 COVID-19 patients monitored from acute to recovery phases of disease. This study reveals cell-protein dependencies and co-regulated features, as well as a shared immunological trajectory during recovery.
Preterm newborns are more likely to suffer from infectious diseases at birth compared to children delivered at term. Whether this is due to compromised cellular, humoral, or organ-specific ...development remains unclear. To begin to define whether maternal-fetal antibody transfer profiles differ across preterm (PT) and fullterm (FT) infants, the overall quantity and functional quality of an array of 24 vaccine-, endemic pathogen-, and common antigen-specific antibodies were assessed across a cohort of 11 PT and 12 term-delivered maternal:infant pairs from birth through week 12. While total IgG levels to influenza, pneumo, measles, rubella, EBV, and RSV were higher in FT newborns, selective Fc-receptor binding antibodies was noted in PT newborns. In fact, near equivalent antibody-effector functions were observed across PT and FT infants, despite significant quantitative differences in transferred antibody levels. Moreover, temporal transfer analysis revealed the selective early transfer of FcRn, FcγR2, and FcγR3 binding antibodies, pointing to differential placental sieving mechanisms across gestation. These data point to selectivity in placental transfer at distinct gestational ages, to ensure that children are endowed with the most robust humoral immunity even if born preterm.
Prostate cancer is a heterogeneous disease with a need for new prognostic biomarkers. Human leukocyte antigen (HLA) genes are highly polymorphic genes central to antigen presentation to T‐cells. Two ...alleles, HLA‐A*02:01 and HLA‐A*24:02, have been associated with prognosis in patients diagnosed with de novo metastatic prostate cancer. We leveraged the next‐generation sequenced cohorts CPC‐GENE and TCGA‐PRAD to examine HLA alleles, antiviral T‐cell receptors and prostate cancer disease recurrence after prostatectomy. Carrying HLA‐A*02:01 (111/229; 48% of patients) was independently associated with disease recurrence in patients with low‐intermediate risk prostate cancer. HLA‐A*11 (carried by 42/441; 10% of patients) was independently associated with rapid disease recurrence in patients with high‐risk prostate cancer. Moreover, HLA‐A*02:01 carriers in which anti‐cytomegalovirus T‐cell receptors (CMV‐TCR) were identified in tumors (13/144; 10% of all patients in the cohort) had a higher risk of disease recurrence than CMV‐TCR‐negative patients. These findings suggest that HLA‐type and CMV immunity may be valuable biomarkers for prostate cancer progression.
In this study, we find that variants of genes that are essential for the immune system (HLA‐A*02:01 and HLA‐A*11) are associated with prostate cancer progression after radical prostatectomy. Local detection of immunity to cytomegalovirus, but not EBV or Influenza A, was associated with particularly low disease recurrence‐free survival, suggesting that HLA‐type and viral immunity could predict cancer progression.
The objective of this study was to inform public health actions to limit first-line ART failure and HIV drug resistance in Mozambique.
This was a cross-sectional study. HIV-1-infected adults on ...first-line ART for at least 1 year attending routine visits in the Manhiça District Hospital, in a semi-rural area in southern Mozambique with no HIV-1 RNA monitoring available, were evaluated for clinical, socio-demographic, therapeutic, immunological and virological characteristics. Factors associated with HIV-1 RNA ≥1000 copies/mL and HIV drug resistance were determined using multivariate logistic regression.
The study included 334 adults on first-line ART for a median of 3 years, of which 65% (214/332) had suppressed viraemia, 11% (37/332) had low-level viraemia (HIV-1 RNA 150-999 copies/mL) and 24% (81/332) had overt virological failure (HIV-1 RNA ≥1000 copies/mL). HIV drug resistance was detected in 89% of subjects with virological failure, but in none with low-level viraemia. Younger age OR = 0.97 per additional year (95% CI = 0.94-1.00), P = 0.039, ART initiation at WHO stage III/IV OR = 2.10 (95% CI = 1.23-3.57), P = 0.003 and low ART adherence OR = 2.69 (95% CI = 1.39-5.19), P = 0.003 were associated with virological failure. Longer time on ART OR = 1.55 per additional year (95% CI = 1.00-2.43), P = 0.052 and illiteracy OR = 0.24 (95% CI = 0.07-0.89), P = 0.033 were associated with HIV drug resistance. Compared with HIV-1 RNA, clinician's judgement of ART failure, based on clinical and immunological outcomes, only achieved 29% sensitivity and misdiagnosed 1 out of every 4.5 subjects.
Public health programmes in Mozambique should focus on early HIV diagnosis, early ART initiation and adherence support. Virological monitoring drastically improves the diagnosis of ART failure, enabling a better use of resources.
To explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects.
In a ...proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%.
7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir.
In this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment-experienced subjects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In order to design strategies for eradication of HIV-1 from infected individuals, detailed insight into the HIV-1 reservoirs that persist in patients on suppressive antiretroviral therapy (ART) is ...required. In this regard, most studies have focused on integrated (proviral) HIV-1 DNA forms in cells circulating in blood. However, the majority of proviral DNA is replication-defective and archival, and as such, has limited ability to reveal the dynamics of the viral population that persists in patients on suppressive ART. In contrast, extrachromosomal (episomal) viral DNA is labile and as a consequence is a better surrogate for recent infection events and is able to inform on the extent to which residual replication contributes to viral reservoir maintenance. To gain insight into the diversity and compartmentalization of HIV-1 under suppressive ART, we extensively analyzed longitudinal peripheral blood mononuclear cells (PBMC) samples by deep sequencing of episomal and integrated HIV-1 DNA from patients undergoing raltegravir intensification. Reverse-transcriptase genes selectively amplified from episomal and proviral HIV-1 DNA were analyzed by deep sequencing 0, 2, 4, 12, 24 and 48 weeks after raltegravir intensification. We used maximum likelihood phylogenies and statistical tests (AMOVA and Slatkin-Maddison (SM)) in order to determine molecular compartmentalization. We observed low molecular variance (mean variability ≤0.042). Although phylogenies showed that both DNA forms were intermingled within the phylogenetic tree, we found a statistically significant compartmentalization between episomal and proviral DNA samples (P<10(-6) AMOVA test; P = 0.001 SM test), suggesting that they belong to different viral populations. In addition, longitudinal analysis of episomal and proviral DNA by phylogeny and AMOVA showed signs of non-chronological temporal compartmentalization (all comparisons P<10(-6)) suggesting that episomal and proviral DNA forms originated from different anatomical compartments. Collectively, this suggests the presence of a chronic viral reservoir in which there is stochastic release of infectious virus and in which there are limited rounds of de novo infection. This could be explained by the existence of different reservoirs with unique pharmacological accessibility properties, which will require strategies that improve drug penetration/retention within these reservoirs in order to minimise maintenance of the viral reservoir by de novo infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more ...analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 μL of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis.
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•Cord blood is not representative of postnatal immunity•Preterm and term children differ at birth but rapidly converge thereafter•Immune system development follows a stereotypic pattern early in life•Dynamic parameters imply microbial interactions during early immune development
Longitudinal profiling of blood immune cells from 100 newborns provides a systemic view on the ontogeny of the human neonatal immune system.
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