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Early-life immune exposures can profoundly impact lifelong health. However, functional mechanisms underlying fetal immune development remain incomplete. Erythrocytes are not typically considered active immune mediators, primarily because erythroid precursors discard their organelles as they mature, thus losing the ability to alter gene expression in response to stimuli. Erythroid progenitors and precursors circulate in human fetuses and neonates. Although there is limited evidence that erythroid precursors are immunomodulatory, our understanding of the underlying mechanisms remains inadequate. To define the immunobiological role of fetal and perinatal erythroid progenitors and precursors, we analyzed single cell RNA-sequencing data and found that transcriptomics support erythroid progenitors as putative immune mediators. Unexpectedly, we discovered that human erythroid progenitors constitutively express Major Histocompatibility Complex (MHC) class II antigen processing and presentation machinery, which are hallmarks of specialized antigen presenting immune cells. Furthermore, we demonstrate that erythroid progenitors internalize and cleave foreign proteins into peptide antigens. Unlike conventional antigen presenting cells, erythroid progenitors express atypical costimulatory molecules and immunoregulatory cytokines that direct the development of regulatory T cells, which are critical for establishing maternal-fetal tolerance. Expression of MHC II in definitive erythroid progenitors begins during the second trimester, coinciding with the appearance of mature T cells in the fetus, and is absent in primitive progenitors. Lastly, we demonstrate physical and molecular interaction potential of erythroid progenitors and T cells in the fetal liver. Our findings shed light on a unique orchestrator of fetal immunity and provide insight into the mechanisms by which erythroid cells contribute to host defense.
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The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.
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Adenosina Monofosfato , Adenosina , Alanina , Antivirales , COVID-19 , SARS-CoV-2 , Antivirales/farmacología , Antivirales/química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina/química , Humanos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Alanina/análogos & derivados , Alanina/farmacología , Alanina/química , COVID-19/inmunología , COVID-19/virología , Animales , Agentes Inmunomoduladores/farmacología , Agentes Inmunomoduladores/química , Antagonistas del Receptor de Adenosina A2/farmacología , Antagonistas del Receptor de Adenosina A2/química , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Pandemias , Tratamiento Farmacológico de COVID-19 , Chlorocebus aethiops , Replicación Viral/efectos de los fármacos , Células Vero , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Receptor de Adenosina A2A/metabolismo , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virologíaRESUMEN
Due to its frequent association with urinary tract infections (UTIs), Escherichia coli is the best characterized constituent of the urinary microbiota (urobiome). However, uropathogenic E. coli is just one member of the urobiome. In addition to bacterial constituents, the urobiome of both healthy and symptomatic individuals is home to a diverse population of bacterial viruses (bacteriophages). A prior investigation found that most bacterial species in the urobiome are lysogens, harboring one or more phages integrated into their genome (prophages). Many of these prophages are temperate phages, capable of entering the lytic cycle and thus lysing their bacterial host. This transition from the lysogenic to lytic life cycle can impact the bacterial diversity of the urobiome. While many phages that infect E. coli (coliphages) have been studied for decades in the laboratory setting, the coliphages within the urobiome have yet to be cataloged. Here, we investigated the diversity of urinary coliphages by first identifying prophages in all publicly available urinary E. coli genomes. We detected 3,038 intact prophage sequences, representative of 1,542 unique phages. These phages include both novel species as well as species also found within the gut microbiota. Ten temperate phages were isolated from urinary E. coli strains included in our analysis, and we assessed their ability to infect and lyse urinary E. coli strains. We also included in these host range assays other urinary coliphages and laboratory coliphages. The temperate phages and other urinary coliphages were successful in lysing urinary E. coli strains. We also observed that coliphages from non-urinary sources were most efficient in killing urinary E. coli strains. The two phages, T2 and N4, were capable of lysing 83.5% (n = 86) of strains isolated from females with UTI symptoms. In conclusion, our study finds a diverse community of coliphages in the urobiome, many of which are predicted to be temperate phages, ten of which were confirmed here. Their ability to infect and lyse urinary E. coli strains suggests that urinary coliphages may play a role in modulating the E. coli strain diversity of the urobiome.
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Bacteriófagos , Microbiota , Femenino , Humanos , Escherichia coli/genética , Colifagos/genética , Bacteriófagos/genética , Lisogenia , Profagos/genética , BacteriasRESUMEN
High-throughput sequencing of microbial communities has uncovered a large, diverse population of phages. Frequently, phages found are integrated into their bacterial host genome. Distinguishing between phages in their integrated (lysogenic) and unintegrated (lytic) stage can provide insight into how phages shape bacterial communities. Here we present the Prophage Induction Estimator (PIE) to identify induced phages in genomic and metagenomic sequences. PIE takes raw sequencing reads and phage sequence predictions, performs read quality control, read assembly, and calculation of phage and non-phage sequence abundance and completeness. The distribution of abundances for non-phage sequences is used to predict induced phages with statistical confidence. In silico tests were conducted to benchmark this tool finding that PIE can detect induction events as well as phages with a relatively small burst size (10×). We then examined isolate genome sequencing data as well as a mock community and urinary metagenome data sets and found instances of induced phages in all three data sets. The flexibility of this software enables users to easily include phage predictions from their preferred tool of choice or phage sequences of interest. Thus, genomic and metagenomic sequencing now not only provides a means for discovering and identifying phage sequences but also the detection of induced prophages.
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Bacteriófagos , Bacteriófagos/genética , Lisogenia , Profagos/genética , Mapeo Cromosómico , Genoma BacterianoRESUMEN
Staphylococcus aureus infections are of growing concern given the increased incidence of antibiotic resistant strains. Egypt, like several other countries, has seen alarming increases in methicillin-resistant S. aureus (MRSA) infections. This species can rapidly acquire genes associated with resistance, as well as virulence factors, through mobile genetic elements, including phages. Recently, we sequenced 56 S. aureus genomes from Alexandria Main University Hospital in Alexandria, Egypt, complementing 17 S. aureus genomes publicly available from other sites in Egypt. In the current study, we found that the majority (73.6%) of these strains contain intact prophages, including Biseptimaviruses, Phietaviruses, and Triaviruses. Further investigation of these prophages revealed evidence of horizontal exchange of the integrase for two of the prophages. These Egyptian S. aureus prophages are predicted to encode numerous virulence factors, including genes associated with immune evasion and toxins, including the Panton-Valentine leukocidin (PVL)-associated genes lukF-PV/lukS-PV. Thus, prophages are likely to be a major contributor to the virulence of S. aureus strains in circulation in Egypt.
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Profagos/aislamiento & purificación , Fagos de Staphylococcus/aislamiento & purificación , Staphylococcus aureus/virología , Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Egipto , Humanos , Profagos/clasificación , Profagos/genética , Infecciones Estafilocócicas/microbiología , Fagos de Staphylococcus/clasificación , Fagos de Staphylococcus/genética , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , VirulenciaRESUMEN
Urinary tract infections (UTIs) are one of the most common human bacterial infections. While UTIs are commonly associated with colonization by Escherichia coli, members of this species also have been found within the bladder of individuals with no lower urinary tract symptoms (no LUTS), also known as asymptomatic bacteriuria. Prior studies have found that both uropathogenic E. coli (UPEC) strains and E. coli isolates that are not associated with UTIs encode for virulence factors. Thus, the reason(s) why E. coli sometimes causes UTI-like symptoms remain(s) elusive. In this study, the genomes of 66 E. coli isolates from adult female bladders were sequenced. These isolates were collected from four cohorts, including women: (1) without lower urinary tract symptoms, (2) overactive bladder symptoms, (3) urgency urinary incontinence, and (4) a clinical diagnosis of UTI. Comparative genomic analyses were conducted, including core and accessory genome analyses, virulence and motility gene analyses, and antibiotic resistance prediction and testing. We found that the genomic content of these 66 E. coli isolates does not correspond with the participant's symptom status. We thus looked beyond the E. coli genomes to the composition of the entire urobiome and found that the presence of E. coli alone was not sufficient to distinguish between the urobiomes of individuals with UTI and those with no LUTS. Because E. coli presence, abundance, and genomic content appear to be weak predictors of UTI status, we hypothesize that UTI symptoms associated with detection of E. coli are more likely the result of urobiome composition.
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The majority of bacteria within the human body are lysogens, often harboring multiple bacteriophage sequences (prophages) within their genomes. While several different types of environmental stresses can trigger or induce prophages to enter into the lytic cycle, they have yet to be fully explored and understood in the human microbiota. In the laboratory, the most common induction method is the DNA damaging chemical Mitomycin C. Although pH has been listed in the literature as an induction method, it is not widely used. Here, we detail a protocol for prophage induction by culture under different pH conditions. We explored the effects of pH on prophage induction in bacterial isolates from the bladder, where the pH is well documented to vary significantly between individuals as well as between healthy individuals and individuals with urinary tract symptoms or disease. Using this protocol, we successfully induced phages from seven bladder E. coli strains. Testing conditions and stressors appropriate to the environment from which a lysogen is isolated may provide insight into community dynamics of the human microbiota.
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Bacteriophages (phages) play a key role in shaping microbial communities, including those of the human body. Phages are abundant members of the urogenital tract, most often persisting through the lysogenic life cycle as prophages integrated within the genomes of their bacterial hosts. While numerous studies of the urogenital microbiota have focused on the most abundant bacterial member of this niche-Lactobacillus species-very little is known about Lactobacillus phages. Focusing on Lactobacillus jensenii strains from the urinary tract, we identified numerous prophages related to the previously characterized Lv-1 phage from a vaginal L. jensenii strain. Furthermore, we identified a new L. jensenii phage, Lu-1. Evidence suggests that both phages are abundant within the urogenital tract. CRISPR spacer sequences matching to Lv-1 and Lu-1 prophages were identified. While first detected in urinary isolates, the Lu-1 phage was also discovered in L. jensenii isolates from vaginal and perineal swabs, and both phages were found in metagenomic data sets. The prevalence of these phages in the isolates suggests that both phages are active members of the urogenital microbiota.
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Bacteriófagos/aislamiento & purificación , Lactobacillus/virología , Perineo/microbiología , Vagina/microbiología , Bacteriófagos/genética , Biología Computacional , Femenino , Humanos , MicrobiotaRESUMEN
Actinomyces neuii is an opportunistic pathogen. Within the urogenital tract, it has been associated with bacterial vaginosis and overactive bladder symptoms. Here, we investigate a draft genome sequence of A. neuii UMB1295, which was isolated from a catheterized urine sample from a woman with a urinary tract infection.
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Lactobacillus crispatus is a Gram-positive bacterium shown to protect against urinary and vaginal infections. Here, we report the draft genome sequence of L. crispatus UMB1163, isolated from the female urinary tract.
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Here, we present the draft genome sequence of Streptococcus anginosus UMB0839, isolated from the female urinary tract. The total size of the genome is 2,104,786 bp assembled into 42 contigs with a GC content of 38.8% and 284× genome coverage.
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Here, we present the draft genome sequence of Escherichia coli UMB1353, isolated from a patient with a urinary tract infection. The sequence of this antibiotic-resistant E. coli strain contains one intact P2-like phage.
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Staphylococcus epidermidis is a native member of the human microbiota. Here, we report the draft genome sequence of S. epidermidis UMB8493, an isolate from a catheterized urine sample from a female with overactive bladder symptoms. The 2.54-Mbp draft genome encodes genes associated with beta-lactam and fosfomycin resistance.
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Escherichia coli is a Gram-negative, motile, rod-shaped bacterium that causes the majority of uncomplicated urinary tract infections (UTIs). Here, we report the draft genome of E. coli strain UMB9246, an isolate from a woman with recurrent UTI.
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Proteus mirabilis is a Gram-negative motile and rod-shaped bacterium that is a common pathogen of the urinary tract. Here, we report the draft genome sequence of P. mirabilis UMB0038, which was isolated from a woman without lower urinary tract symptoms.
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We sequenced the genome of Lactobacillus mulieris UMB7784, isolated from the urinary tract. With a genome size of 1,695,489 bp and a GC content of 34.2%, the draft genome sequence presented here expands our understanding of lactobacilli in the female bladder.
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Lactobacillus jensenii is a frequent member of both the vaginal and urinary microbiota. Here, we present the draft genome sequence for L. jensenii UMB0836, isolated from catheterized urine obtained from a pregnant female. The genome is 1,648,234 bp long, assembled in 40 contigs.
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Streptococcus anginosus recently was implicated as a pathogen involved in urinary tract infections. A strain of S. anginosus was isolated from the female urogenital tract. Here, we present the draft genome sequence of S. anginosus strain UMB7768.
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Proteus mirabilis is a Gram-negative bacterium that is linked to common complications within the urinary tract. Here, we present the draft genome for P. mirabilis UMB1310, which was isolated from the urine of a woman with a urinary tract infection.
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Lactobacillus jensenii is a beneficial and prominent community member within both the vaginal and female urinary microbiota. As more genomes for L. jensenii strains are made publicly available, we gain more knowledge about this beneficial community member. Here, we present the draft genome sequence of L. jensenii UMB7766, which was isolated from a urine specimen from a catheterized female patient with recurrent urinary tract infections.