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1.
Cell ; 184(20): 5163-5178.e24, 2021 09 30.
Article in English | MEDLINE | ID: mdl-34559985

ABSTRACT

Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain poorly defined. Our genome-wide CRISPR screen identified low-density lipoprotein receptor-related protein 1 (mouse Lrp1/human LRP1), heat shock protein (Grp94), and receptor-associated protein (RAP) as critical host factors for RVFV infection. RVFV Gn directly binds to specific Lrp1 clusters and is glycosylation independent. Exogenous addition of murine RAP domain 3 (mRAPD3) and anti-Lrp1 antibodies neutralizes RVFV infection in taxonomically diverse cell lines. Mice treated with mRAPD3 and infected with pathogenic RVFV are protected from disease and death. A mutant mRAPD3 that binds Lrp1 weakly failed to protect from RVFV infection. Together, these data support Lrp1 as a host entry factor for RVFV infection and define a new target to limit RVFV infections.


Subject(s)
Host-Pathogen Interactions , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Rift Valley fever virus/physiology , Virus Internalization , Animals , Antibody Specificity/immunology , Base Sequence , Brain/pathology , Brain/virology , CRISPR-Cas Systems/genetics , Cell Membrane/metabolism , Cells, Cultured , Glycoproteins/metabolism , Glycosaminoglycans/metabolism , Glycosylation , Humans , LDL-Receptor Related Protein-Associated Protein/metabolism , Ligands , Low Density Lipoprotein Receptor-Related Protein-1/deficiency , Membrane Glycoproteins/metabolism , Mice , Protein Binding , Protein Denaturation , Rift Valley Fever/pathology , Rift Valley Fever/prevention & control , Rift Valley Fever/virology , Rift Valley fever virus/immunology
2.
Cell ; 184(9): 2332-2347.e16, 2021 04 29.
Article in English | MEDLINE | ID: mdl-33761326

ABSTRACT

The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARS-CoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.


Subject(s)
Antigens, Viral/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/virology , Cricetinae , Epitope Mapping , Genetic Variation , Models, Molecular , Mutation/genetics , Neutralization Tests , Protein Domains , RNA, Viral/genetics , SARS-CoV-2/isolation & purification , SARS-CoV-2/ultrastructure
3.
Cell ; 183(4): 1024-1042.e21, 2020 11 12.
Article in English | MEDLINE | ID: mdl-32991844

ABSTRACT

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.


Subject(s)
Antibodies, Neutralizing/immunology , Epitope Mapping/methods , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2 , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/chemistry , Antibodies, Viral/blood , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antigen-Antibody Reactions , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Epitopes/chemistry , Epitopes/immunology , Humans , Immunoglobulin A/blood , Immunoglobulin A/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Kinetics , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Binding , Protein Domains/immunology , Protein Structure, Quaternary , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
4.
Cell ; 177(5): 1084-1085, 2019 05 16.
Article in English | MEDLINE | ID: mdl-31100262

ABSTRACT

The virome is increasingly recognized as a key part of individual cells (as endogenous retroviruses or persistent infection) and multicellular organisms (as either pathogens or commensals) and, as shown by Gregory et al. (2019), as diverse components of ocean ecosystems.


Subject(s)
Drowning , Microbiota , Viruses/genetics , DNA , Humans
5.
Cell ; 170(4): 649-663.e13, 2017 Aug 10.
Article in English | MEDLINE | ID: mdl-28802038

ABSTRACT

Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-ß pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.


Subject(s)
Alzheimer Disease/pathology , Energy Metabolism , Membrane Glycoproteins/metabolism , Microglia/metabolism , Receptors, Immunologic/metabolism , AMP-Activated Protein Kinases/metabolism , Alzheimer Disease/metabolism , Animals , Autophagy , Creatinine/analogs & derivatives , Creatinine/metabolism , Disease Models, Animal , Humans , Lectins, C-Type/metabolism , Macrophages/metabolism , Membrane Glycoproteins/genetics , Mice , Microglia/pathology , Neurites/metabolism , Plaque, Amyloid/metabolism , Receptors, Immunologic/genetics , TOR Serine-Threonine Kinases/metabolism
6.
Cell ; 160(1-2): 20-35, 2015 Jan 15.
Article in English | MEDLINE | ID: mdl-25533784

ABSTRACT

Zoonotic viruses, such as HIV, Ebola virus, coronaviruses, influenza A viruses, hantaviruses, or henipaviruses, can result in profound pathology in humans. In contrast, populations of the reservoir hosts of zoonotic pathogens often appear to tolerate these infections with little evidence of disease. Why are viruses more dangerous in one species than another? Immunological studies investigating quantitative and qualitative differences in the host-virus equilibrium in animal reservoirs will be key to answering this question, informing new approaches for treating and preventing zoonotic diseases. Integrating an understanding of host immune responses with epidemiological, ecological, and evolutionary insights into viral emergence will shed light on mechanisms that minimize fitness costs associated with viral infection, facilitate transmission to other hosts, and underlie the association of specific reservoir hosts with multiple emerging viruses. Reservoir host studies provide a rich opportunity for elucidating fundamental immunological processes and their underlying genetic basis, in the context of distinct physiological and metabolic constraints that contribute to host resistance and disease tolerance.


Subject(s)
Virus Physiological Phenomena , Zoonoses/virology , Animals , Communicable Diseases, Emerging/immunology , Communicable Diseases, Emerging/transmission , Communicable Diseases, Emerging/virology , Disease Reservoirs , Host-Pathogen Interactions , Humans , Virus Diseases , Zoonoses/immunology , Zoonoses/transmission
7.
Cell ; 160(3): 447-60, 2015 Jan 29.
Article in English | MEDLINE | ID: mdl-25619688

ABSTRACT

Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn's disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.


Subject(s)
Caudovirales/isolation & purification , Colitis, Ulcerative/virology , Crohn Disease/virology , Dysbiosis/virology , Microviridae/isolation & purification , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , Case-Control Studies , Caudovirales/genetics , Cohort Studies , Colitis, Ulcerative/microbiology , Colitis, Ulcerative/pathology , Colitis, Ulcerative/therapy , Crohn Disease/microbiology , Crohn Disease/pathology , Crohn Disease/therapy , Dysbiosis/microbiology , Dysbiosis/pathology , Dysbiosis/therapy , Feces/microbiology , Feces/virology , Humans , Metagenome , Microviridae/genetics
8.
Cell ; 157(1): 142-50, 2014 Mar 27.
Article in English | MEDLINE | ID: mdl-24679532

ABSTRACT

The virome contains the most abundant and fastest mutating genetic elements on Earth. The mammalian virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. Virome interactions with the host cannot be encompassed by a monotheistic view of viruses as pathogens. Instead, the genetic and transcriptional identity of mammals is defined in part by our coevolved virome, a concept with profound implications for understanding health and disease.


Subject(s)
Bacteriophages/physiology , Mammals/virology , Microbiota , Viruses/genetics , Animals , Bacteria/virology , Bacteriophages/classification , Bacteriophages/genetics , Host-Pathogen Interactions , Humans , Mammals/genetics , Mammals/immunology , Viruses/classification , Viruses/metabolism
9.
Nature ; 618(7965): 590-597, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37258672

ABSTRACT

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.


Subject(s)
Antibodies, Viral , Antibody Specificity , Influenza A virus , Influenza B virus , Influenza Vaccines , Influenza, Human , Molecular Mimicry , Neuraminidase , Animals , Humans , Mice , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , Antibody Specificity/immunology , Arginine/chemistry , Catalytic Domain , Hemagglutinins, Viral/immunology , Influenza A virus/classification , Influenza A virus/enzymology , Influenza A virus/immunology , Influenza A Virus, H3N2 Subtype/enzymology , Influenza A Virus, H3N2 Subtype/immunology , Influenza B virus/classification , Influenza B virus/enzymology , Influenza B virus/immunology , Influenza Vaccines/chemistry , Influenza Vaccines/immunology , Influenza Vaccines/therapeutic use , Influenza, Human/immunology , Influenza, Human/prevention & control , Neuraminidase/antagonists & inhibitors , Neuraminidase/chemistry , Neuraminidase/immunology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , Seasons , Sialic Acids/chemistry
10.
Cell ; 151(2): 253-66, 2012 Oct 12.
Article in English | MEDLINE | ID: mdl-23063120

ABSTRACT

Pathogenic simian immunodeficiency virus (SIV) infection is associated with enteropathy, which likely contributes to AIDS progression. To identify candidate etiologies for AIDS enteropathy, we used next-generation sequencing to define the enteric virome during SIV infection in nonhuman primates. Pathogenic, but not nonpathogenic, SIV infection was associated with significant expansion of the enteric virome. We identified at least 32 previously undescribed enteric viruses during pathogenic SIV infection and confirmed their presence by using viral culture and PCR testing. We detected unsuspected mucosal adenovirus infection associated with enteritis as well as parvovirus viremia in animals with advanced AIDS, indicating the pathogenic potential of SIV-associated expansion of the enteric virome. No association between pathogenic SIV infection and the family-level taxonomy of enteric bacteria was detected. Thus, enteric viral infections may contribute to AIDS enteropathy and disease progression. These findings underline the importance of metagenomic analysis of the virome for understanding AIDS pathogenesis.


Subject(s)
Caliciviridae/isolation & purification , Intestines/virology , Parvoviridae/isolation & purification , Picornaviridae/isolation & purification , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/physiology , Animals , Caliciviridae/classification , Caliciviridae/genetics , Chlorocebus aethiops , Feces/microbiology , Feces/virology , Intestines/microbiology , Molecular Sequence Data , Parvoviridae/classification , Parvoviridae/genetics , Phylogeny , Picornaviridae/classification , Picornaviridae/genetics , Polymerase Chain Reaction , Simian Acquired Immunodeficiency Syndrome/microbiology , Simian Immunodeficiency Virus/pathogenicity
11.
Nature ; 596(7873): 495-504, 2021 08.
Article in English | MEDLINE | ID: mdl-34237771

ABSTRACT

There is a realistic expectation that the global effort in vaccination will bring the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) under control. Nonetheless, uncertainties remain about the type of long-term association that the virus will establish with the human population and, in particular, whether coronavirus disease 2019 (COVID-19) will become an endemic disease. Although the trajectory is difficult to predict, the conditions, concepts and variables that influence this transition can be anticipated. Persistence of SARS-CoV-2 as an endemic virus, perhaps with seasonal epidemic peaks, may be fuelled by pockets of susceptible individuals and waning immunity after infection or vaccination, changes in the virus through antigenic drift that diminish protection and re-entries from zoonotic reservoirs. Here we review relevant observations from previous epidemics and discuss the potential evolution of SARS-CoV-2 as it adapts during persistent transmission in the presence of a level of population immunity. Lack of effective surveillance or adequate response could enable the emergence of new epidemic or pandemic patterns from an endemic infection of SARS-CoV-2. There are key pieces of data that are urgently needed in order to make good decisions; we outline these and propose a way forward.


Subject(s)
COVID-19/epidemiology , COVID-19/virology , Pandemics , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Animals , COVID-19/immunology , COVID-19/transmission , COVID-19 Vaccines/immunology , COVID-19 Vaccines/supply & distribution , Evolution, Molecular , Humans , Immune Evasion , Immunization Programs , Influenza, Human/immunology , Influenza, Human/prevention & control , Influenza, Human/virology , SARS-CoV-2/immunology , Time Factors
12.
Nature ; 598(7880): 342-347, 2021 10.
Article in English | MEDLINE | ID: mdl-34464958

ABSTRACT

SARS-CoV-2 infection-which involves both cell attachment and membrane fusion-relies on the angiotensin-converting enzyme 2 (ACE2) receptor, which is paradoxically found at low levels in the respiratory tract1-3, suggesting that there may be additional mechanisms facilitating infection. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) function as attachment receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the amino-terminal domain or to the conserved site at the base of the receptor-binding domain, while poorly neutralizing infection of ACE2-overexpressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the receptor binding motif, while potently neutralizing infection of ACE2-overexpressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN and trigger fusogenic rearrangement of the spike, promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.


Subject(s)
Antibodies, Neutralizing/immunology , Lectins/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/metabolism , Animals , Cell Adhesion Molecules/metabolism , Cell Fusion , Cell Line , Cricetinae , Female , Humans , Lectins/immunology , Lectins, C-Type/metabolism , Membrane Fusion , Receptors, Cell Surface/metabolism , SARS-CoV-2/immunology , Sialic Acid Binding Ig-like Lectin 1/metabolism , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
13.
Nature ; 593(7857): 136-141, 2021 05.
Article in English | MEDLINE | ID: mdl-33706364

ABSTRACT

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/isolation & purification , COVID-19/metabolism , COVID-19/virology , Female , HEK293 Cells , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Immunization, Passive , Male , Middle Aged , Models, Molecular , Mutation , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Synthetic/administration & dosage , COVID-19 Serotherapy , mRNA Vaccines
14.
Nature ; 597(7874): 103-108, 2021 09.
Article in English | MEDLINE | ID: mdl-34280951

ABSTRACT

The recent emergence of SARS-CoV-2 variants of concern1-10 and the recurrent spillovers of coronaviruses11,12 into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , Broadly Neutralizing Antibodies/therapeutic use , COVID-19/prevention & control , SARS-CoV-2/classification , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Viral/chemistry , Antibodies, Viral/therapeutic use , Broadly Neutralizing Antibodies/chemistry , COVID-19/immunology , COVID-19/virology , Cross Reactions/immunology , Disease Models, Animal , Female , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Mesocricetus/immunology , Mesocricetus/virology , Mutation , Neutralization Tests , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Viral Zoonoses/immunology , Viral Zoonoses/prevention & control , Viral Zoonoses/virology
15.
Nat Immunol ; 15(12): 1152-61, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25362489

ABSTRACT

The importance of autophagy in the generation of memory CD8(+) T cells in vivo is not well defined. We report here that autophagy was dynamically regulated in virus-specific CD8(+) T cells during acute infection of mice with lymphocytic choriomeningitis virus. In contrast to the current paradigm, autophagy decreased in activated proliferating effector CD8(+) T cells and was then upregulated when the cells stopped dividing just before the contraction phase. Consistent with those findings, deletion of the gene encoding either of the autophagy-related molecules Atg5 or Atg7 had little to no effect on the proliferation and function of effector cells, but these autophagy-deficient effector cells had survival defects that resulted in compromised formation of memory T cells. Our studies define when autophagy is needed during effector and memory differentiation and warrant reexamination of the relationship between T cell activation and autophagy.


Subject(s)
Autophagy/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Immunologic Memory/immunology , Animals , Cell Separation , Cell Survival/immunology , Chromatography, Liquid , Flow Cytometry , Immunoblotting , Lymphocyte Activation/immunology , Lymphocytic Choriomeningitis/immunology , Mass Spectrometry , Mice , Mice, Mutant Strains , Oligonucleotide Array Sequence Analysis , Real-Time Polymerase Chain Reaction , Transduction, Genetic
16.
Immunity ; 47(4): 723-738.e5, 2017 10 17.
Article in English | MEDLINE | ID: mdl-29031786

ABSTRACT

Noroviruses can establish chronic infections with active viral shedding in healthy humans but whether persistence is associated with adaptive immune dysfunction is unknown. We used genetically engineered strains of mouse norovirus (MNV) to investigate CD8+ T cell differentiation during chronic infection. We found that chronic infection drove MNV-specific tissue-resident memory (Trm) CD8+ T cells to a differentiation state resembling inflationary effector responses against latent cytomegalovirus with only limited evidence of exhaustion. These MNV-specific Trm cells remained highly functional yet appeared ignorant of ongoing viral replication. Pre-existing MNV-specific Trm cells provided partial protection against chronic infection but largely ceased to detect virus within 72 hours of challenge, demonstrating rapid sequestration of viral replication away from T cells. Our studies revealed a strategy of immune evasion by MNV via the induction of a CD8+ T cell program normally reserved for latent pathogens and persistence in an immune-privileged enteric niche.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Caliciviridae Infections/immunology , Cell Differentiation/immunology , Gastroenteritis/immunology , Norovirus/immunology , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , Caliciviridae Infections/genetics , Caliciviridae Infections/virology , Cell Differentiation/genetics , Cell Line , Cellular Microenvironment/genetics , Cellular Microenvironment/immunology , Gastroenteritis/genetics , Gastroenteritis/virology , Gene Expression Profiling/methods , Gene Ontology , HEK293 Cells , Host-Pathogen Interactions/immunology , Humans , Immunologic Memory/genetics , Immunologic Memory/immunology , Mice, Inbred C57BL , Norovirus/physiology , Oligonucleotide Array Sequence Analysis/methods
17.
Immunity ; 46(1): 29-37, 2017 01 17.
Article in English | MEDLINE | ID: mdl-28087240

ABSTRACT

Elevated inflammation in the female genital tract is associated with increased HIV risk. Cervicovaginal bacteria modulate genital inflammation; however, their role in HIV susceptibility has not been elucidated. In a prospective cohort of young, healthy South African women, we found that individuals with diverse genital bacterial communities dominated by anaerobes other than Gardnerella were at over 4-fold higher risk of acquiring HIV and had increased numbers of activated mucosal CD4+ T cells compared to those with Lactobacillus crispatus-dominant communities. We identified specific bacterial taxa linked with reduced (L. crispatus) or elevated (Prevotella, Sneathia, and other anaerobes) inflammation and HIV infection and found that high-risk bacteria increased numbers of activated genital CD4+ T cells in a murine model. Our results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells. These findings might be leveraged to reduce HIV acquisition in women living in sub-Saharan Africa.


Subject(s)
Cervix Uteri/microbiology , HIV Infections/microbiology , Vagina/microbiology , Animals , Bacteria, Anaerobic , CD4-Positive T-Lymphocytes/immunology , Cohort Studies , Female , Flow Cytometry , Humans , Lactobacillus , Mice , Microbiota/immunology , Prevotella , South Africa
18.
Cell ; 147(1): 44-56, 2011 Sep 30.
Article in English | MEDLINE | ID: mdl-21962506

ABSTRACT

The microbiome is a complex community of Bacteria, Archaea, Eukarya, and viruses that infect humans and live in our tissues. It contributes the majority of genetic information to our metagenome and, consequently, influences our resistance and susceptibility to diseases, especially common inflammatory diseases, such as type 1 diabetes, ulcerative colitis, and Crohn's disease. Here we discuss how host-gene-microbial interactions are major determinants for the development of these multifactorial chronic disorders and, thus, for the relationship between genotype and phenotype. We also explore how genome-wide association studies (GWAS) on autoimmune and inflammatory diseases are uncovering mechanism-based subtypes for these disorders. Applying these emerging concepts will permit a more complete understanding of the etiologies of complex diseases and underpin the development of both next-generation animal models and new therapeutic strategies for targeting personalized disease phenotypes.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/microbiology , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/microbiology , Metagenomics , Precision Medicine , Animals , Genetic Predisposition to Disease , Humans , Metagenome
19.
Nature ; 588(7838): 485-490, 2020 12.
Article in English | MEDLINE | ID: mdl-33032297

ABSTRACT

Antibodies against viral pathogens represent promising therapeutic agents for the control of infection, and their antiviral efficacy has been shown to require the coordinated function of both the Fab and Fc domains1. The Fc domain engages a wide spectrum of receptors on discrete cells of the immune system to trigger the clearance of viruses and subsequent killing of infected cells1-4. Here we report that Fc engineering of anti-influenza IgG monoclonal antibodies for selective binding to the activating Fcγ receptor FcγRIIa results in enhanced ability to prevent or treat lethal viral respiratory infection in mice, with increased maturation of dendritic cells and the induction of protective CD8+ T cell responses. These findings highlight the capacity for IgG antibodies to induce protective adaptive immunity to viral infection when they selectively activate a dendritic cell and T cell pathway, with important implications for the development of therapeutic antibodies with improved antiviral efficacy against viral respiratory pathogens.


Subject(s)
Antibodies, Viral/chemistry , Antibodies, Viral/immunology , CD8-Positive T-Lymphocytes/immunology , Immunoglobulin Fc Fragments/chemistry , Influenza, Human/immunology , Orthomyxoviridae/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation , Dendritic Cells/cytology , Dendritic Cells/immunology , Female , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Humans , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/chemistry , Immunoglobulin G/immunology , Influenza, Human/drug therapy , Influenza, Human/mortality , Influenza, Human/prevention & control , Lymphocyte Activation , Mice , Neuraminidase/immunology , Receptors, IgG/chemistry , Receptors, IgG/immunology
20.
Nature ; 584(7821): 353-363, 2020 08.
Article in English | MEDLINE | ID: mdl-32659783

ABSTRACT

Antibody-dependent enhancement (ADE) of disease is a general concern for the development of vaccines and antibody therapies because the mechanisms that underlie antibody protection against any virus have a theoretical potential to amplify the infection or trigger harmful immunopathology. This possibility requires careful consideration at this critical point in the pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we review observations relevant to the risks of ADE of disease, and their potential implications for SARS-CoV-2 infection. At present, there are no known clinical findings, immunological assays or biomarkers that can differentiate any severe viral infection from immune-enhanced disease, whether by measuring antibodies, T cells or intrinsic host responses. In vitro systems and animal models do not predict the risk of ADE of disease, in part because protective and potentially detrimental antibody-mediated mechanisms are the same and designing animal models depends on understanding how antiviral host responses may become harmful in humans. The implications of our lack of knowledge are twofold. First, comprehensive studies are urgently needed to define clinical correlates of protective immunity against SARS-CoV-2. Second, because ADE of disease cannot be reliably predicted after either vaccination or treatment with antibodies-regardless of what virus is the causative agent-it will be essential to depend on careful analysis of safety in humans as immune interventions for COVID-19 move forward.


Subject(s)
Antibodies, Viral/adverse effects , Antibodies, Viral/immunology , Antibody-Dependent Enhancement/immunology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Coronavirus Infections/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Animals , Antibodies, Neutralizing/adverse effects , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/prevention & control , Dengue Virus/immunology , Disease Models, Animal , HEK293 Cells , Humans , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/immunology , Macaca mulatta , Mice , Middle East Respiratory Syndrome Coronavirus/immunology , Orthomyxoviridae/immunology , Pandemics , Rats , Severe acute respiratory syndrome-related coronavirus/immunology , SARS-CoV-2 , Viral Vaccines/adverse effects , Viral Vaccines/immunology
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