RESUMEN
In this issue of JEM, Davidson et al. (https://doi.org/10.1084/jem.20222171) and Takeda et al. (https://doi.org/10.1084/jem.20231941) independently report on a dominant negative form of OTULIN deficiency in three unrelated patients.
RESUMEN
Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.
Asunto(s)
Infecciones Asintomáticas , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/genética , COVID-19/inmunología , SARS-CoV-2/inmunología , Masculino , Femenino , Alelos , Antígenos HLA/genética , Persona de Mediana Edad , Adulto , Estudios Prospectivos , Anciano , Predisposición Genética a la EnfermedadRESUMEN
Here, we describe an adult female with severe fasciitis and skin necrosis who carried a private, predicted deleterious missense mutation in OTULIN in heterozygosity. OTULIN is a cellular regulator of deubiquitination that has been shown to play a key role in intrinsic immunity against staphylococcal α-toxin. The patient was treated with broad-spectrum antibiotics, and multiple surgical explorations were conducted without clinical response. Since autoinflammation was the predominant clinical feature, TNF inhibition was started with a good clinical response. We show that excessive inflammation in OTULIN haploinsufficiency can be effectively treated by TNF inhibition.
Asunto(s)
Fascitis , Haploinsuficiencia , Femenino , Humanos , Inflamación/genética , Necrosis , UbiquitinaciónRESUMEN
Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B*15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B*15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the US (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B*15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified. These findings suggest that memory T-cell immunity to seasonal coronaviruses does not strongly influence the outcome of SARS-CoV-2 infection in unvaccinated individuals.
RESUMEN
The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.
Asunto(s)
Toxinas Bacterianas , Síndrome del Maullido del Gato , Endopeptidasas , Haploinsuficiencia , Proteínas Hemolisinas , Infecciones Estafilocócicas , Staphylococcus aureus , Toxinas Bacterianas/inmunología , Síndrome del Maullido del Gato/genética , Síndrome del Maullido del Gato/inmunología , Endopeptidasas/genética , Haploinsuficiencia/genética , Haploinsuficiencia/inmunología , Proteínas Hemolisinas/inmunología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Celular/genética , Necrosis , Infecciones Estafilocócicas/genética , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/patologíaRESUMEN
SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection.
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COVID-19/genética , Resistencia a la Enfermedad/genética , Predisposición Genética a la Enfermedad , SARS-CoV-2/patogenicidad , Animales , COVID-19/inmunología , COVID-19/virología , Heterogeneidad Genética , Interacciones Huésped-Patógeno , Humanos , Fenotipo , Factores Protectores , Medición de Riesgo , Factores de Riesgo , SARS-CoV-2/inmunologíaRESUMEN
Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, and there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer-dependent and p65:p65 homodimer-independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10-15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.
Asunto(s)
Inmunodeficiencia Variable Común/genética , Subunidad p50 de NF-kappa B/genética , Animales , Células COS , Línea Celular , Chlorocebus aethiops , Células HEK293 , Haploinsuficiencia/genética , Humanos , FN-kappa B/genética , Fenotipo , Activación Transcripcional/genéticaRESUMEN
The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4-CD8- double-negative αß T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.
Asunto(s)
Autoinmunidad/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Receptor de Muerte Celular Programada 1/genética , Factor de Transcripción STAT3/genética , Tuberculosis/inmunología , Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Antígeno CD56/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Niño , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/efectos adversos , Interleucina-23/genética , Interleucina-6/genética , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/patología , Masculino , Mycobacterium tuberculosis/patogenicidad , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Receptor de Muerte Celular Programada 1/deficiencia , Tuberculosis/genética , Tuberculosis/mortalidadRESUMEN
Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.
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Genes Dominantes , Síndrome de Job/genética , Mutación/genética , Factor de Transcripción STAT3/genética , Adolescente , Adulto , Alelos , Empalme Alternativo/genética , Niño , Preescolar , Codón sin Sentido/genética , Evolución Molecular , Familia , Femenino , Mutación del Sistema de Lectura/genética , Genética de Población , Células HEK293 , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Linaje , Biosíntesis de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
High-dimensional cytometry is a powerful technique for deciphering the immunopathological factors common to multiple individuals. However, rational comparisons of multiple batches of experiments performed on different occasions or at different sites are challenging because of batch effects. In this study, we describe the integration of multibatch cytometry datasets (iMUBAC), a flexible, scalable, and robust computational framework for unsupervised cell-type identification across multiple batches of high-dimensional cytometry datasets, even without technical replicates. After overlaying cells from multiple healthy controls across batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples from multiple batches in a unified manner. We illustrate unbiased and streamlined immunophenotyping using both public and in-house mass cytometry and spectral flow cytometry datasets. The method is available as the R package iMUBAC (https://github.com/casanova-lab/iMUBAC).
Asunto(s)
Inmunofenotipificación/métodos , Leucocitos Mononucleares/fisiología , Programas Informáticos , Algoritmos , Biología Computacional , Citometría de Flujo , HumanosRESUMEN
Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
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Autoanticuerpos/sangre , Infecciones por Coronavirus/inmunología , Interferón Tipo I/inmunología , Interferón alfa-2/inmunología , Neumonía Viral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Infecciones Asintomáticas , Betacoronavirus , COVID-19 , Estudios de Casos y Controles , Enfermedad Crítica , Femenino , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Pandemias , SARS-CoV-2RESUMEN
Bacterial pathogens have evolved to secrete strong anti-inflammatory proteins that target the immune system. It was long speculated whether these virulence factors could serve as therapeutics in diseases in which abnormal immune activation plays a role. We adopted the secreted chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) as a model virulence factor-based therapeutic agent for diseases in which C5AR1 stimulation plays an important role. We show that the administration of CHIPS in human C5AR1 knock-in mice successfully dampens C5a-mediated neutrophil migration during immune complex-initiated inflammation. Subsequent CHIPS toxicology studies in animal models were promising. However, during a small phase I trial, healthy human volunteers showed adverse effects directly after CHIPS administration. Subjects showed clinical signs of anaphylaxis with mild leukocytopenia and increased C-reactive protein concentrations, which are possibly related to the presence of relatively high circulating anti-CHIPS antibodies and suggest an inflammatory response. Even though our data in mice show CHIPS as a potential anti-inflammatory agent, safety issues in human subjects temper the use of CHIPS in its current form as a therapeutic candidate. The use of staphylococcal proteins, or other bacterial proteins, as therapeutics or immune-modulators in humans is severely hampered by pre-existing circulating antibodies.
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Anticuerpos Antibacterianos/efectos adversos , Proteínas Bacterianas/metabolismo , Adolescente , Adulto , Animales , Complejo Antígeno-Anticuerpo/metabolismo , Biomarcadores/sangre , Movimiento Celular , Complemento C5a/metabolismo , Modelos Animales de Enfermedad , Voluntarios Sanos , Humanos , Masculino , Mastocitos/enzimología , Ratones Transgénicos , Persona de Mediana Edad , Neutrófilos/metabolismo , Receptor de Anafilatoxina C5a/metabolismo , Triptasas/sangre , Adulto JovenAsunto(s)
Síndrome Linfoproliferativo Autoinmune/diagnóstico , Linfocitos B/fisiología , Síndromes de Inmunodeficiencia/diagnóstico , Mutación/genética , Infecciones Neumocócicas/diagnóstico , Streptococcus pneumoniae/fisiología , Receptor fas/genética , Síndrome Linfoproliferativo Autoinmune/genética , Femenino , Humanos , Inmunoglobulina M/metabolismo , Síndromes de Inmunodeficiencia/genética , Memoria Inmunológica/genética , Lactante , Masculino , Linaje , Infecciones Neumocócicas/genéticaRESUMEN
Staphylococcal bi-component pore-forming toxins, also known as leukocidins, target and lyse human phagocytes in a receptor-dependent manner. S-components of the leukocidins Panton-Valentine leukocidin (PVL), γ-haemolysin AB (HlgAB) and CB (HlgCB), and leukocidin ED (LukED) specifically employ receptors that belong to the class of G-protein coupled receptors (GPCRs). Although these receptors share a common structural architecture, little is known about the conserved characteristics of the interaction between leukocidins and GPCRs. In this study, we investigated host cellular pathways contributing to susceptibility towards S. aureus leukocidin cytotoxicity. We performed a genome-wide CRISPR/Cas9 library screen for toxin-resistance in U937 cells sensitized to leukocidins by ectopic expression of different GPCRs. Our screen identifies post-translational modification (PTM) pathways involved in the sulfation and sialylation of the leukocidin-receptors. Subsequent validation experiments show differences in the impact of PTM moieties on leukocidin toxicity, highlighting an additional layer of refinement and divergence in the staphylococcal host-pathogen interface. Leukocidin receptors may serve as targets for anti-staphylococcal interventions and understanding toxin-receptor interactions will facilitate the development of innovative therapeutics. Variations in the genes encoding PTM pathways could provide insight into observed differences in susceptibility of humans to infections with S. aureus.
Asunto(s)
Interacciones Microbiota-Huesped/genética , Leucocidinas/toxicidad , Procesamiento Proteico-Postraduccional , Receptores Acoplados a Proteínas G/metabolismo , Infecciones Estafilocócicas/patología , Staphylococcus aureus/patogenicidad , Sistemas CRISPR-Cas , Técnicas de Cultivo de Célula , Supervivencia Celular/genética , Farmacorresistencia Bacteriana/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Células HEK293 , Humanos , Leucocidinas/genética , Leucocidinas/metabolismo , Fagocitos/microbiología , Fagocitos/patología , Unión Proteica , Receptores Acoplados a Proteínas G/genética , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , Células U937RESUMEN
In the version of this Article originally published, the name of author Robert Jan Lebbink was coded wrongly, resulting in it being incorrect when exported to citation databases. This has now been corrected, though no visible changes will be apparent.
RESUMEN
The staphylococcal bi-component leukocidins Panton-Valentine leukocidin (PVL) and γ-haemolysin CB (HlgCB) target human phagocytes. Binding of the toxins' S-components to human complement C5a receptor 1 (C5aR1) contributes to cellular tropism and human specificity of PVL and HlgCB. To investigate the role of both leukocidins during infection, we developed a human C5aR1 knock-in (hC5aR1KI) mouse model. HlgCB, but unexpectedly not PVL, contributed to increased bacterial loads in tissues of hC5aR1KI mice. Compared to humans, murine hC5aR1KI neutrophils showed a reduced sensitivity to PVL, which was mediated by the toxin's F-component LukF-PV. By performing a genome-wide CRISPR-Cas9 screen, we identified CD45 as a receptor for LukF-PV. The human-specific interaction between LukF-PV and CD45 provides a molecular explanation for resistance of hC5aR1KI mouse neutrophils to PVL and probably contributes to the lack of a PVL-mediated phenotype during infection in these mice. This study demonstrates an unsuspected role of the F-component in driving the sensitivity of human phagocytes to PVL.
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Toxinas Bacterianas/metabolismo , Exotoxinas/metabolismo , Leucocidinas/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Receptor de Anafilatoxina C5a/genética , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/patogenicidad , Animales , Carga Bacteriana , Proteínas Bacterianas/metabolismo , Sistemas CRISPR-Cas , Línea Celular , Modelos Animales de Enfermedad , Proteínas Hemolisinas/metabolismo , Humanos , Ratones , Ratones Noqueados , Neutrófilos/metabolismo , Infecciones Estafilocócicas/genética , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismoRESUMEN
Staphylococcus aureus is a major bacterial pathogen that causes disease worldwide. The emergence of strains that are resistant to commonly used antibiotics and the failure of vaccine development have resulted in a renewed interest in the pathophysiology of this bacterium. Staphylococcal leukocidins are a family of bi-component pore-forming toxins that are important virulence factors. During the past five years, cellular receptors have been identified for all of the bi-component leukocidins. The identification of the leukocidin receptors explains the cellular tropism and species specificity that is exhibited by these toxins, which has important biological consequences. In this Review, we summarize the recent discoveries that have reignited interest in these toxins and provide an outlook for future research.
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Citotoxinas , Leucocidinas , Receptores de Superficie Celular , Staphylococcus aureus/patogenicidad , Humanos , Leucocidinas/química , Leucocidinas/fisiología , Receptores de Superficie Celular/metabolismo , Staphylococcus aureus/genética , Tropismo , Factores de VirulenciaRESUMEN
In order for Staphylococcus aureus to thrive inside the mammalian host, the bacterium has to overcome iron scarcity. S. aureus is thought to produce toxins that lyse erythrocytes, releasing hemoglobin, the most abundant iron source in mammals. Here we identify the Duffy antigen receptor for chemokines (DARC) as the receptor for the S. aureus hemolytic leukocidins LukED and HlgAB. By assessing human erythrocytes with DARC polymorphisms, we determined that HlgAB- and LukED-mediated lysis directly relates to DARC expression. DARC is required for S. aureus-mediated lysis of human erythrocytes, and DARC overexpression is sufficient to render cells susceptible to toxin-mediated lysis. HlgA and LukE bind directly to DARC through different regions, and by targeting DARC, HlgAB and LukED support S. aureus growth in a hemoglobin-acquisition-dependent manner. These findings elucidate how S. aureus targets and lyses erythrocytes to release one of the scarcest nutrients within the mammalian host.
Asunto(s)
Sistema del Grupo Sanguíneo Duffy/metabolismo , Eritrocitos/efectos de los fármacos , Hemólisis , Interacciones Huésped-Patógeno , Leucocidinas/metabolismo , Receptores de Superficie Celular/metabolismo , Staphylococcus aureus/metabolismo , Humanos , Unión ProteicaRESUMEN
Staphylococcus aureus is well adapted to the human host. Evasion of the host phagocyte response is critical for successful infection. The staphylococcal bicomponent pore-forming toxins Panton-Valentine leukocidin LukSF-PV (PVL) and γ-hemolysin CB (HlgCB) target human phagocytes through interaction with the complement receptors C5aR1 and C5aR2. Currently, the apparent redundancy of both toxins cannot be adequately addressed in experimental models of infection because mice are resistant to PVL and HlgCB. The molecular basis for species specificity of the two toxins in animal models is not completely understood. We show that PVL and HlgCB feature distinct activity toward neutrophils of different mammalian species, where activity of PVL is found to be restricted to fewer species than that of HlgCB. Overexpression of various mammalian C5a receptors in HEK cells confirms that cytotoxicity toward neutrophils is driven by species-specific interactions of the toxins with C5aR1. By taking advantage of the species-specific engagement of the toxins with their receptors, we demonstrate that PVL and HlgCB differentially interact with human C5aR1 and C5aR2. In addition, binding studies illustrate that different parts of the receptor are involved in the initial binding of the toxin and the subsequent formation of lytic pores. These findings allow a better understanding of the molecular mechanism of pore formation. Finally, we show that the toxicity of PVL, but not of HlgCB, is neutralized by various C5aR1 antagonists. This study offers directions for the development of improved preclinical models for infection, as well as for the design of drugs antagonizing leukocidin toxicity.