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1.
Cell ; 187(6): 1363-1373.e12, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38366591

RESUMEN

In response to the 2022 outbreak of mpox driven by unprecedented human-to-human monkeypox virus (MPXV) transmission, we designed BNT166, aiming to create a highly immunogenic, safe, accessible, and scalable next-generation vaccine against MPXV and related orthopoxviruses. To address the multiple viral forms and increase the breadth of immune response, two candidate multivalent mRNA vaccines were evaluated pre-clinically: a quadrivalent vaccine (BNT166a; encoding the MPXV antigens A35, B6, M1, H3) and a trivalent vaccine (BNT166c; without H3). Both candidates induced robust T cell responses and IgG antibodies in mice, including neutralizing antibodies to both MPXV and vaccinia virus. In challenge studies, BNT166a and BNT166c provided complete protection from vaccinia, clade I, and clade IIb MPXV. Furthermore, immunization with BNT166a was 100% effective at preventing death and at suppressing lesions in a lethal clade I MPXV challenge in cynomolgus macaques. These findings support the clinical evaluation of BNT166, now underway (NCT05988203).


Asunto(s)
Monkeypox virus , Mpox , Vacuna contra Viruela , Animales , Humanos , Ratones , Macaca fascicularis , Monkeypox virus/genética , Mpox/inmunología , Mpox/prevención & control , Vacunas Combinadas , Virus Vaccinia/genética
2.
Nature ; 563(7733): 705-709, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30464342

RESUMEN

Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of difficult-to-treat, often fatal infections in humans1,2. Most humans have antibodies against S. aureus, but these are highly variable and often not protective in immunocompromised patients3. Previous vaccine development programs have not been successful4. A large percentage of human antibodies against S. aureus target wall teichoic acid (WTA), a ribitol-phosphate (RboP) surface polymer modified with N-acetylglucosamine (GlcNAc)5,6. It is currently unknown whether the immune evasion capacities of MRSA are due to variation of dominant surface epitopes such as those associated with WTA. Here we show that a considerable proportion of the prominent healthcare-associated and livestock-associated MRSA clones CC5 and CC398, respectively, contain prophages that encode an alternative WTA glycosyltransferase. This enzyme, TarP, transfers GlcNAc to a different hydroxyl group of the WTA RboP than the standard enzyme TarS7, with important consequences for immune recognition. TarP-glycosylated WTA elicits 7.5-40-fold lower levels of immunoglobulin G in mice than TarS-modified WTA. Consistent with this, human sera contained only low levels of antibodies against TarP-modified WTA. Notably, mice immunized with TarS-modified WTA were not protected against infection with tarP-expressing MRSA, indicating that TarP is crucial for the capacity of S. aureus to evade host defences. High-resolution structural analyses of TarP bound to WTA components and uridine diphosphate GlcNAc (UDP-GlcNAc) explain the mechanism of altered RboP glycosylation and form a template for targeted inhibition of TarP. Our study reveals an immune evasion strategy of S. aureus based on averting the immunogenicity of its dominant glycoantigen WTA. These results will help with the identification of invariant S. aureus vaccine antigens and may enable the development of TarP inhibitors as a new strategy for rendering MRSA susceptible to human host defences.


Asunto(s)
Pared Celular/química , Pared Celular/inmunología , Evasión Inmune , Staphylococcus aureus Resistente a Meticilina/citología , Staphylococcus aureus Resistente a Meticilina/inmunología , Pentosafosfatos/inmunología , Ácidos Teicoicos/inmunología , Acetilglucosamina/química , Acetilglucosamina/metabolismo , Adulto , Animales , Bacteriófagos/patogenicidad , Femenino , Glicosilación , Glicosiltransferasas/metabolismo , Humanos , Masculino , Staphylococcus aureus Resistente a Meticilina/química , Ratones , Persona de Mediana Edad , Modelos Moleculares , Pentosafosfatos/química , Pentosafosfatos/metabolismo , Ácidos Teicoicos/química , Ácidos Teicoicos/metabolismo , Uridina Difosfato/química , Uridina Difosfato/metabolismo , Adulto Joven
3.
Exp Dermatol ; 31(3): 349-361, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34679243

RESUMEN

Staphylococcus aureus colonization is abundant on the skin of atopic dermatitis (AD) patients where it contributes to skin inflammation. S. aureus produces virulence factors that distinguish it from commensal skin bacteria such as S. epidermidis and S. lugdunensis. However, it has remained unclear, which of these virulence factors have the strongest impact on AD. Membrane vesicles (MVs) are released by pathogenic bacteria and might play an essential role in the long-distance delivery of bacterial effectors such as virulence factors. We show that MVs are also released by skin commensals in a similar quantity and membrane lipid amount as those from pathogenic S. aureus. Interestingly, MVs from skin commensals can protect against S. aureus skin colonization by conditioning human skin for enhanced defence. In contrast, MVs released by S. aureus are able to induce CXCL8 and TNF-α in primary human keratinocytes, recruit neutrophils and induce neutrophil extracellular traps, which enhance S. aureus skin colonization. CXCL8 induction is TLR2- and NFkB-dependent and the induction level correlates with the membrane lipid and protein A content of the MVs. Interestingly, MVs of S. aureus strains from the lesional skin of AD patients show an enhanced membrane lipid and protein A content compared to the strains from the non-lesional sites and have an enhanced proinflammatory potential. Our data underline the complex interplay in host- and bacterial derived factors in S. aureus skin colonization and the important role of bacterial derived MVs and their membrane lipid and protein A content in skin inflammatory disorders.


Asunto(s)
Dermatitis Atópica , Infecciones Estafilocócicas , Bacterias , Humanos , Inmunidad Innata , Lípidos de la Membrana , Piel/patología , Staphylococcus aureus/fisiología , Factores de Virulencia
4.
J Infect Dis ; 221(4): 668-678, 2020 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-31573600

RESUMEN

BACKGROUND: Formyl-peptide receptors (FPRs) are important pattern recognition receptors that sense specific bacterial peptides. Formyl-peptide receptors are highly expressed on neutrophils and monocytes, and their activation promotes the migration of phagocytes to sites of infection. It is currently unknown whether FPRs may also influence subsequent processes such as bacterial phagocytosis and killing. Staphylococcus aureus, especially highly pathogenic community-acquired methicillin-resistant S aureus strains, release high amounts of FPR2 ligands, the phenol-soluble modulins. METHODS: We demonstrate that FPR activation leads to upregulation of complement receptors 1 and 3 as well as FCγ receptor I on neutrophils and, consequently, increased opsonic phagocytosis of S aureus and other pathogens. RESULTS: Increased phagocytosis promotes killing of S aureus and interleukin-8 release by neutrophils. CONCLUSIONS: We show here for the first time that FPRs govern opsonic phagocytosis. Manipulation of FPR2 activation could open new therapeutic opportunities against bacterial pathogens.


Asunto(s)
Infecciones Comunitarias Adquiridas/metabolismo , Staphylococcus aureus Resistente a Meticilina/metabolismo , Fagocitosis/efectos de los fármacos , Receptores de Formil Péptido/metabolismo , Receptores de Lipoxina/metabolismo , Infecciones Estafilocócicas/metabolismo , Donantes de Sangre , Células Cultivadas , Infecciones Comunitarias Adquiridas/microbiología , Humanos , Interleucina-8/metabolismo , Antígeno de Macrófago-1/metabolismo , Neutrófilos/metabolismo , Receptores de Complemento 3b/metabolismo , Receptores de Formil Péptido/antagonistas & inhibidores , Receptores de IgG/metabolismo , Receptores de Lipoxina/antagonistas & inhibidores , Receptores de Reconocimiento de Patrones/metabolismo , Infecciones Estafilocócicas/microbiología
5.
Front Cell Infect Microbiol ; 11: 785833, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34926327

RESUMEN

The human innate immune system is equipped with multiple mechanisms to detect microbe-associated molecular patterns (MAMPs) to fight bacterial infections. The metabolite short-chain fatty acids (SCFAs) acetate, propionate and butyrate are released by multiple bacteria or are food ingredients. SCFA production, especially acetate production, is usually essential for bacteria, and knockout of pathways involved in acetate production strongly impairs bacterial fitness. Because host organisms use SCFAs as MAMPs and alter immune reactions in response to SCFAs, interventions that modulate SCFA levels can be a new strategy for infection control. The interaction between SCFAs and host cells has been primarily investigated in the intestinal lumen because of the high local levels of SCFAs released by bacterial microbiome members. However, members of not only the intestinal microbiome but also the skin microbiome produce SCFAs, which are known ligands of the seven-transmembrane G-protein-coupled receptor FFAR2. In addition to enterocytes, FFAR2 is expressed on other human cell types, including leukocytes, especially neutrophils. This finding is in line with other research that determined that targeted activation of FFAR2 diminishes susceptibility toward various types of infection by bacteria such as Klebsiella pneumonia, Citrobacter rodentium, and Staphylococcus aureus but also by viruses such as respiratory syncytial and influenza viruses. Thus, our immune system appears to be able to use FFAR2-dependent detection of SCFAs for perceiving and even averting severe infections. We summarize recent advances in understanding the role of SCFAs and FFAR2 in various infection types and propose the manipulation of this receptor as an additional therapeutic strategy to fight infections.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Citrobacter rodentium , Ácidos Grasos Volátiles , Humanos , Neutrófilos
6.
Commun Biol ; 4(1): 928, 2021 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-34330996

RESUMEN

Bacterial sepsis is a major cause of mortality resulting from inadequate immune responses to systemic infection. Effective immunomodulatory approaches are urgently needed but it has remained elusive, which targets might be suitable for intervention. Increased expression of the G-protein-coupled receptor GPR43, which is known to govern intestinal responses to acetate, has been associated with sepsis patient survival but the mechanisms behind this observation have remained unclear. We show that elevated serum acetate concentrations prime neutrophils in a GPR43-dependent fashion, leading to enhanced neutrophil chemotaxis, oxidative burst, cytokine release and upregulation of phagocytic receptors. Consequently, acetate priming improved the capacity of human neutrophils to eliminate methicillin-resistant Staphylococcus aureus. Acetate administration increased mouse serum acetate concentrations and primed neutrophils. Notably, it rescued wild-type mice from severe S. aureus sepsis and reduced bacterial numbers in peripheral organs by several magnitudes. Acetate treatment improved the sepsis course even when applied several hours after onset of the infection, which recommends GPR43 as a potential target for sepsis therapy. Our study indicates that the severity of sepsis depends on transient neutrophil priming by appropriate blood acetate concentrations. Therapeutic interventions based on GPR43 stimulation could become valuable strategies for reducing sepsis-associated morbidity and mortality.


Asunto(s)
Acetatos/metabolismo , Staphylococcus aureus Resistente a Meticilina/fisiología , Neutrófilos/inmunología , Receptores Acoplados a Proteínas G/genética , Sepsis/inmunología , Infecciones Estafilocócicas/inmunología , Receptores Acoplados a Proteínas G/inmunología , Sepsis/genética , Infecciones Estafilocócicas/genética
7.
Front Immunol ; 12: 701093, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34552584

RESUMEN

Neutrophil granulocytes act as a first line of defense against pathogenic staphylococci. However, Staphylococcus aureus has a remarkable capacity to survive neutrophil killing, which distinguishes it from the less-pathogenic Staphylococcus epidermidis. Both species release phenol-soluble modulin (PSM) toxins, which activate the neutrophil formyl-peptide receptor 2 (FPR2) to promote neutrophil influx and phagocytosis, and which disrupt neutrophils or their phagosomal membranes at high concentrations. We show here that the neutrophil serine proteases (NSPs) neutrophil elastase, cathepsin G and proteinase 3, which are released into the extracellular space or the phagosome upon neutrophil FPR2 stimulation, effectively degrade PSMs thereby preventing their capacity to activate and destroy neutrophils. Notably, S. aureus, but not S. epidermidis, secretes potent NSP-inhibitory proteins, Eap, EapH1, EapH2, which prevented the degradation of PSMs by NSPs. Accordingly, a S. aureus mutant lacking all three NSP inhibitory proteins was less effective in activating and destroying neutrophils and it survived less well in the presence of neutrophils than the parental strain. We show that Eap proteins promote pathology via PSM-mediated FPR2 activation since murine intraperitoneal infection with the S. aureus parental but not with the NSP inhibitors mutant strain, led to a significantly higher bacterial load in the peritoneum and kidneys of mFpr2-/- compared to wild-type mice. These data demonstrate that NSPs can very effectively detoxify some of the most potent staphylococcal toxins and that the prominent human pathogen S. aureus has developed efficient inhibitors to preserve PSM functions. Preventing PSM degradation during infection represents an important survival strategy to ensure FPR2 activation.


Asunto(s)
Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/metabolismo , Evasión Inmune/inmunología , Neutrófilos/inmunología , Staphylococcus aureus/metabolismo , Animales , Células Cultivadas , Humanos , Ratones , Ratones Endogámicos C57BL , Neutrófilos/enzimología , Serina Proteasas/inmunología , Serina Proteasas/metabolismo , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/inmunología
8.
mBio ; 9(6)2018 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-30459192

RESUMEN

The innate immune system uses Toll-like receptor (TLR) 2 to detect conserved bacterial lipoproteins of invading pathogens. The lipid anchor attaches lipoproteins to the cytoplasmic membrane and prevents their release from the bacterial cell envelope. How bacteria release lipoproteins and how these molecules reach TLR2 remain unknown. Staphylococcus aureus has been described to liberate membrane vesicles. The composition, mode of release, and relevance for microbe-host interaction of such membrane vesicles have remained ambiguous. We recently reported that S. aureus can release lipoproteins only when surfactant-like small peptides, the phenol-soluble modulins (PSMs), are expressed. Here we demonstrate that PSM peptides promote the release of membrane vesicles from the cytoplasmic membrane of S. aureus via an increase in membrane fluidity, and we provide evidence that the bacterial turgor is the driving force for vesicle budding under hypotonic osmotic conditions. Intriguingly, the majority of lipoproteins are released by S. aureus as components of membrane vesicles, and this process depends on surfactant-like molecules such as PSMs. Vesicle disruption at high detergent concentrations promotes the capacity of lipoproteins to activate TLR2. These results reveal that vesicle release by bacterium-derived surfactants is required for TLR2-mediated inflammation.IMPORTANCE Our study highlights the roles of surfactant-like molecules in bacterial inflammation with important implications for the prevention and therapy of inflammatory disorders. It describes a potential pathway for the transfer of hydrophobic bacterial lipoproteins, the major TLR2 agonists, from the cytoplasmic membrane of Gram-positive bacteria to the TLR2 receptor at the surface of host cells. Moreover, our study reveals a molecular mechanism that explains how cytoplasmic and membrane-embedded bacterial proteins can be released by bacterial cells without using any of the typical protein secretion routes, thereby contributing to our understanding of the processes used by bacteria to communicate with host organisms and the environment.


Asunto(s)
Proteínas Bacterianas/metabolismo , Vesículas Extracelulares/metabolismo , Interacciones Microbiota-Huesped/inmunología , Lipoproteínas/metabolismo , Staphylococcus aureus/metabolismo , Receptor Toll-Like 2/inmunología , Células HEK293 , Humanos , Inflamación , Solubilidad , Infecciones Estafilocócicas/inmunología , Tensoactivos , Receptor Toll-Like 2/genética
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