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1.
Cell ; 187(9): 2079-2094, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38670066

ABSTRACT

Several conceptual pillars form the foundation of modern immunology, including the clonal selection theory, antigen receptor diversity, immune memory, and innate control of adaptive immunity. However, some immunological phenomena cannot be explained by the current framework. Thus, we still do not know how to design vaccines that would provide long-lasting protective immunity against certain pathogens, why autoimmune responses target some antigens and not others, or why the immune response to infection sometimes does more harm than good. Understanding some of these mysteries may require that we question existing assumptions to develop and test alternative explanations. Immunology is increasingly at a point when, once again, exploring new perspectives becomes a necessity.


Subject(s)
Allergy and Immunology , Humans , Animals , Allergy and Immunology/trends , Adaptive Immunity , Immunity, Innate , Immunologic Memory
2.
Annu Rev Immunol ; 34: 575-608, 2016 05 20.
Article in English | MEDLINE | ID: mdl-27168245

ABSTRACT

Mucosal surfaces provide a remarkably effective barrier against potentially dangerous pathogens. Therefore, enhancing mucosal immunity through vaccines-strengthening that first line of defense-holds significant promise for reducing the burden of viral diseases. The large and varied class of viral pathogens, however, continues to present thorny challenges to vaccine development. Two primary difficulties exist: Viruses exhibit a stunning diversity of strategies for evading the host immune response, and even when we understand the nature of effective immune protection against a given virus, eliciting that protection is technically challenging. Only a few mucosal vaccines have surmounted these obstacles thus far. Recent developments, however, could greatly improve vaccine design. In this review, we first sketch out our understanding of mucosal immunity and then compare the herpes simplex virus, human immunodeficiency virus, and influenza virus to illustrate the distinct challenges of developing successful vaccines and to outline potential solutions.


Subject(s)
HIV/immunology , Immune Evasion , Immunity, Mucosal , Orthomyxoviridae/immunology , Simplexvirus/immunology , Viral Vaccines/immunology , Virus Diseases/immunology , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Humans , Immunologic Memory , Virus Diseases/prevention & control
3.
Cell ; 185(14): 2452-2468.e16, 2022 07 07.
Article in English | MEDLINE | ID: mdl-35768006

ABSTRACT

COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.


Subject(s)
COVID-19 , Influenza, Human , Neoplasms , Animals , Humans , Influenza, Human/pathology , Mice , Microglia/pathology , Myelin Sheath , Neoplasms/pathology , SARS-CoV-2
4.
Cell ; 184(20): 5077-5081, 2021 09 30.
Article in English | MEDLINE | ID: mdl-34534444

ABSTRACT

As the SARS-CoV-2 pandemic evolves, new variants continue to emerge. Some highly transmissible variants, such as Delta, also raised concerns about the effectiveness provided by current vaccines. Understanding immunological correlates of protection and how laboratory findings correspond to clinical effectiveness is imperative to shape future vaccination strategies.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/epidemiology , COVID-19/prevention & control , Pandemics/prevention & control , SARS-CoV-2/immunology , Vaccination/methods , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/classification , Humans , Immunity, Cellular , Immunogenicity, Vaccine , Mutation , SARS-CoV-2/genetics
5.
Nat Immunol ; 24(10): 1616-1627, 2023 10.
Article in English | MEDLINE | ID: mdl-37667052

ABSTRACT

Millions of people are suffering from Long COVID or post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as potential drivers of PASC pathology. Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA-potentially capable of being translated to produce viral proteins-persist in tissue as a 'reservoir'. This reservoir could modulate host immune responses or release viral proteins into the circulation. Here we review studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology, including coagulation, microbiome and neuroimmune abnormalities, are delineated. We identify research priorities to guide the further study of a SARS-CoV-2 reservoir in PASC, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated.


Subject(s)
COVID-19 , Humans , Post-Acute COVID-19 Syndrome , RNA, Viral/genetics , SARS-CoV-2 , Antiviral Agents , Disease Progression
7.
Cell ; 183(5): 1312-1324.e10, 2020 11 25.
Article in English | MEDLINE | ID: mdl-33212011

ABSTRACT

Interferon (IFN)-Is are crucial mediators of antiviral immunity and homeostatic immune system regulation. However, the source of IFN-I signaling under homeostatic conditions is unclear. We discovered that commensal microbes regulate the IFN-I response through induction of IFN-ß by colonic DCs. Moreover, the mechanism by which a specific commensal microbe induces IFN-ß was identified. Outer membrane (OM)-associated glycolipids of gut commensal microbes belonging to the Bacteroidetes phylum induce expression of IFN-ß. Using Bacteroides fragilis and its OM-associated polysaccharide A, we determined that IFN-ß expression was induced via TLR4-TRIF signaling. Antiviral activity of this purified microbial molecule against infection with either vesicular stomatitis virus (VSV) or influenza was demonstrated to be dependent on the induction of IFN-ß. In a murine VSV infection model, commensal-induced IFN-ß regulated natural resistance to virus infection. Due to the physiological importance of IFN-Is, discovery of an IFN-ß-inducing microbial molecule represents a potential approach for the treatment of some human diseases.


Subject(s)
Immunity, Innate , Microbiota , Virus Diseases/microbiology , Animals , Bacteroides fragilis/physiology , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Cell Membrane/drug effects , Cell Membrane/metabolism , Colon/pathology , Colon/virology , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Female , Gene Expression Regulation/drug effects , Glycolipids/metabolism , Immunity, Innate/drug effects , Interferon-beta/blood , Interferon-beta/metabolism , Male , Mice, Inbred C57BL , Microbiota/drug effects , Polysaccharides, Bacterial/pharmacology , Toll-Like Receptor 4/metabolism , Vesiculovirus/physiology , Virus Diseases/genetics
8.
Cell ; 181(5): 990-996.e5, 2020 05 28.
Article in English | MEDLINE | ID: mdl-32386545

ABSTRACT

The novel coronavirus SARS-CoV-2 was first detected in the Pacific Northwest region of the United States in January 2020, with subsequent COVID-19 outbreaks detected in all 50 states by early March. To uncover the sources of SARS-CoV-2 introductions and patterns of spread within the United States, we sequenced nine viral genomes from early reported COVID-19 patients in Connecticut. Our phylogenetic analysis places the majority of these genomes with viruses sequenced from Washington state. By coupling our genomic data with domestic and international travel patterns, we show that early SARS-CoV-2 transmission in Connecticut was likely driven by domestic introductions. Moreover, the risk of domestic importation to Connecticut exceeded that of international importation by mid-March regardless of our estimated effects of federal travel restrictions. This study provides evidence of widespread sustained transmission of SARS-CoV-2 within the United States and highlights the critical need for local surveillance.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/transmission , Pneumonia, Viral/transmission , Travel , Betacoronavirus/isolation & purification , COVID-19 , Connecticut/epidemiology , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Epidemiological Monitoring , Humans , Likelihood Functions , Pandemics , Phylogeny , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2 , Travel/legislation & jurisprudence , United States/epidemiology , Washington/epidemiology
9.
Cell ; 178(5): 1176-1188.e15, 2019 08 22.
Article in English | MEDLINE | ID: mdl-31442406

ABSTRACT

Adaptive immunity provides life-long protection by generating central and effector memory T cells and the most recently described tissue resident memory T (TRM) cells. However, the cellular origin of CD4 TRM cells and their contribution to host defense remain elusive. Using IL-17A tracking-fate mouse models, we found that a significant fraction of lung CD4 TRM cells derive from IL-17A-producing effector (TH17) cells following immunization with heat-killed Klebsiella pneumonia (Kp). These exTH17 TRM cells are maintained in the lung by IL-7, produced by lymphatic endothelial cells. During a memory response, neither antibodies, γδ T cells, nor circulatory T cells are sufficient for the rapid host defense required to eliminate Kp. Conversely, using parabiosis and depletion studies, we demonstrated that exTH17 TRM cells play an important role in bacterial clearance. Thus, we delineate the origin and function of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design.


Subject(s)
Klebsiella Infections/immunology , Th17 Cells/immunology , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Diphtheria Toxin/pharmacology , Disease Models, Animal , Female , Immunologic Memory , Interleukin-17/genetics , Interleukin-17/metabolism , Klebsiella Infections/pathology , Klebsiella pneumoniae/immunology , Klebsiella pneumoniae/pathogenicity , Lung/drug effects , Lung/metabolism , Lung/microbiology , Mice , Mice, Inbred C57BL , Th17 Cells/cytology , Th17 Cells/metabolism
10.
Annu Rev Cell Dev Biol ; 36: 441-468, 2020 10 06.
Article in English | MEDLINE | ID: mdl-32722920

ABSTRACT

Fetal neurodevelopment in utero is profoundly shaped by both systemic maternal immunity and local processes at the maternal-fetal interface. Immune pathways are a critical participant in the normal physiology of pregnancy and perturbations of maternal immunity due to infections during this period have been increasingly linked to a diverse array of poor neurological outcomes, including diseases that manifest much later in postnatal life. While experimental models of maternal immune activation (MIA) have provided groundbreaking characterizations of the maternal pathways underlying pathogenesis, less commonly examined are the immune factors that serve pathogen-independent developmental functions in the embryo and fetus. In this review, we explore what is known about the in vivo role of immune factors in fetal neurodevelopment during normal pregnancy and provide an overview of how MIA perturbs the proper orchestration of this sequence of events. Finally, we discuss how the dysregulation of immune factors may contribute to the manifestation of a variety of neurological disorders.


Subject(s)
Fetus/embryology , Fetus/immunology , Immunologic Factors/metabolism , Nervous System/embryology , Nervous System/immunology , Animals , Cytokines/metabolism , Female , Humans , Maternal-Fetal Exchange/immunology , Models, Biological , Pregnancy
11.
Immunity ; 55(9): 1609-1626.e7, 2022 09 13.
Article in English | MEDLINE | ID: mdl-35963236

ABSTRACT

The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7. Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-ß, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.


Subject(s)
Aging , Interferons , Macrophages , Osteonectin , Humans , Inflammation/metabolism , Interferons/metabolism , Macrophages/metabolism , Osteonectin/genetics , Osteonectin/metabolism
12.
Cell ; 166(5): 1247-1256.e4, 2016 Aug 25.
Article in English | MEDLINE | ID: mdl-27565347

ABSTRACT

Zika virus (ZIKV) can be transmitted sexually between humans. However, it is unknown whether ZIKV replicates in the vagina and impacts the unborn fetus. Here, we establish a mouse model of vaginal ZIKV infection and demonstrate that, unlike other routes, ZIKV replicates within the genital mucosa even in wild-type (WT) mice. Mice lacking RNA sensors or transcription factors IRF3 and IRF7 resulted in higher levels of local viral replication. Furthermore, mice lacking the type I interferon (IFN) receptor (IFNAR) became viremic and died of infection after a high-dose vaginal ZIKV challenge. Notably, vaginal infection of pregnant dams during early pregnancy led to fetal growth restriction and infection of the fetal brain in WT mice. This was exacerbated in mice deficient in IFN pathways, leading to abortion. Our study highlights the vaginal tract as a highly susceptible site of ZIKV replication and illustrates the dire disease consequences during pregnancy.


Subject(s)
Brain Diseases/virology , Brain/virology , Fetal Growth Retardation/virology , Pregnancy Complications, Infectious/virology , Vagina/virology , Virus Replication , Zika Virus Infection/transmission , Zika Virus/physiology , Abortion, Habitual/virology , Animals , Brain Diseases/immunology , Disease Models, Animal , Female , Fetal Growth Retardation/immunology , Interferon Regulatory Factor-3/genetics , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Pregnancy , Pregnancy Complications, Infectious/immunology , Receptor, Interferon alpha-beta/genetics
14.
Nature ; 628(8006): 204-211, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38418880

ABSTRACT

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.


Subject(s)
Brain , Eye , Lymphatic System , Animals , Female , Humans , Male , Mice , Rabbits , Bacteria/immunology , Brain/anatomy & histology , Brain/immunology , Dependovirus/immunology , Eye/anatomy & histology , Eye/immunology , Glioblastoma/immunology , Herpesvirus 2, Human/immunology , Intravitreal Injections , Lymphatic System/anatomy & histology , Lymphatic System/immunology , Lymphatic Vessels/anatomy & histology , Lymphatic Vessels/immunology , Macaca mulatta , Meninges/immunology , Optic Nerve/immunology , Swine , Zebrafish , Vascular Endothelial Growth Factor C/immunology , Vascular Endothelial Growth Factor C/metabolism , Vascular Endothelial Growth Factor C/pharmacology
15.
Nat Immunol ; 23(7): 987, 2022 07.
Article in English | MEDLINE | ID: mdl-35726062

Subject(s)
Social Media , Humans
16.
Nat Immunol ; 18(8): 899-910, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28604719

ABSTRACT

Mammalian autophagy-related 8 (Atg8) homologs consist of LC3 proteins and GABARAPs, all of which are known to be involved in canonical autophagy. In contrast, the roles of Atg8 homologs in noncanonical autophagic processes are not fully understood. Here we show a unique role of GABARAPs, in particular gamma-aminobutyric acid (GABA)-A-receptor-associated protein-like 2 (Gabarapl2; also known as Gate-16), in interferon-γ (IFN-γ)-mediated antimicrobial responses. Cells that lacked GABARAPs but not LC3 proteins and mice that lacked Gate-16 alone were defective in the IFN-γ-induced clearance of vacuolar pathogens such as Toxoplasma. Gate-16 but not LC3b specifically associated with the small GTPase ADP-ribosylation factor 1 (Arf1) to mediate uniform distribution of interferon-inducible GTPases. The lack of GABARAPs reduced Arf1 activation, which led to formation of interferon-inducible GTPase-containing aggregates and hampered recruitment of interferon-inducible GTPases to vacuolar pathogens. Thus, GABARAPs are uniquely required for antimicrobial host defense through cytosolic distribution of interferon-inducible GTPases.


Subject(s)
ADP-Ribosylation Factor 1/immunology , Autophagy/immunology , Carrier Proteins/immunology , Interferon-gamma/immunology , Microtubule-Associated Proteins/immunology , Toxoplasma/immunology , Toxoplasmosis/immunology , ADP-Ribosylation Factor 1/metabolism , Animals , Apoptosis Regulatory Proteins , Autophagy-Related Protein 8 Family , CRISPR-Cas Systems , Carrier Proteins/metabolism , Computer Simulation , Cytoskeletal Proteins/immunology , Cytoskeletal Proteins/metabolism , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Fluorescent Antibody Technique , GTP Phosphohydrolases/immunology , GTP Phosphohydrolases/metabolism , Gene Editing , Immunoblotting , Immunoprecipitation , Interferon-gamma/metabolism , Intracellular Signaling Peptides and Proteins , Membrane Proteins/immunology , Membrane Proteins/metabolism , Mice , Microtubule-Associated Proteins/metabolism
17.
Immunity ; 52(6): 1007-1021.e8, 2020 06 16.
Article in English | MEDLINE | ID: mdl-32497523

ABSTRACT

N6-methyladenosine (m6A) is the most abundant RNA modification, but little is known about its role in mammalian hematopoietic development. Here, we show that conditional deletion of the m6A writer METTL3 in murine fetal liver resulted in hematopoietic failure and perinatal lethality. Loss of METTL3 and m6A activated an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs were long, highly m6A modified in their native state, characterized by low folding energies, and predominantly protein coding. We identified coinciding activation of pattern recognition receptor pathways normally tasked with the detection of foreign dsRNAs. Disruption of the aberrant immune response via abrogation of downstream Mavs or Rnasel signaling partially rescued the observed hematopoietic defects in METTL3-deficient cells in vitro and in vivo. Our results suggest that m6A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development.


Subject(s)
Adenosine/chemistry , Hematopoiesis/genetics , Hematopoiesis/immunology , Immunity, Innate/genetics , RNA, Double-Stranded/metabolism , Animals , Biomarkers , Bone Marrow Failure Disorders/etiology , Bone Marrow Failure Disorders/metabolism , Bone Marrow Failure Disorders/pathology , Cell Differentiation/genetics , Disease Models, Animal , Epigenesis, Genetic , Gene Expression , Hematopoietic Stem Cells , Immunophenotyping , Methylation , Methyltransferases/genetics , Methyltransferases/metabolism , Mice , Mice, Knockout , RNA, Double-Stranded/chemistry
18.
Cell ; 156(4): 705-16, 2014 Feb 13.
Article in English | MEDLINE | ID: mdl-24529375

ABSTRACT

The Toll-like receptors (TLRs) of the innate immune system are unusual in that individual family members are located on different organelles, yet most activate a common signaling pathway important for host defense. It remains unclear how this common signaling pathway can be activated from multiple subcellular locations. Here, we report that, in response to natural activators of innate immunity, the sorting adaptor TIRAP regulates TLR signaling from the plasma membrane and endosomes. TLR signaling from both locations triggers the TIRAP-dependent assembly of the myddosome, a protein complex that controls proinflammatory cytokine expression. The actions of TIRAP depend on the promiscuity of its phosphoinositide-binding domain. Different lipid targets of this domain direct TIRAP to different organelles, allowing it to survey multiple compartments for the presence of activated TLRs. These data establish how promiscuity, rather than specificity, can be a beneficial means of diversifying the subcellular sites of innate immune signal transduction.


Subject(s)
Immunity, Innate , Membrane Glycoproteins/metabolism , Receptors, Interleukin-1/metabolism , Signal Transduction , Toll-Like Receptors/metabolism , Animals , Cell Membrane/metabolism , Endosomes/metabolism , Herpes Simplex/immunology , Macrophages/immunology , Macrophages/metabolism , Mice, Inbred C57BL , Myeloid Differentiation Factor 88/metabolism , Toll-Like Receptors/immunology
19.
Cell ; 159(7): 1563-77, 2014 Dec 18.
Article in English | MEDLINE | ID: mdl-25525875

ABSTRACT

The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death.


Subject(s)
Apoptosis , Caspases/metabolism , Interferon Type I/metabolism , Signal Transduction , Animals , DNA, Mitochondrial/metabolism , Inflammation/immunology , Inflammation/metabolism , Interferon Type I/immunology , Mice , Mice, Knockout , Virus Diseases/immunology
20.
Nature ; 623(7985): 139-148, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37748514

ABSTRACT

Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2-4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.


Subject(s)
Antibodies, Viral , Herpesvirus 4, Human , Hydrocortisone , Lymphocytes , Myeloid Cells , Post-Acute COVID-19 Syndrome , SARS-CoV-2 , Humans , Antibodies, Viral/blood , Antibodies, Viral/immunology , Biomarkers/blood , Cross-Sectional Studies , Herpesvirus 4, Human/immunology , Hydrocortisone/blood , Immunophenotyping , Lymphocytes/immunology , Machine Learning , Myeloid Cells/immunology , Post-Acute COVID-19 Syndrome/diagnosis , Post-Acute COVID-19 Syndrome/immunology , Post-Acute COVID-19 Syndrome/physiopathology , Post-Acute COVID-19 Syndrome/virology , SARS-CoV-2/immunology
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