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1.
Cell ; 169(1): 58-71.e14, 2017 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-28340350

RESUMEN

Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a "polar claw" mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.


Asunto(s)
Células Asesinas Naturales/inmunología , Muromegalovirus/inmunología , Receptores de Células Asesinas Naturales/inmunología , Proteínas Virales/metabolismo , Animales , Antígenos Ly/metabolismo , Línea Celular , Células HEK293 , Interacciones Huésped-Patógeno , Humanos , Evasión Inmune , Inmunidad Innata , Ratones , Células 3T3 NIH , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Ratas
2.
Cell Commun Signal ; 22(1): 106, 2024 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-38336645

RESUMEN

Aquaporins (AQPs) are ubiquitous channel proteins that play a critical role in the homeostasis of the cellular environment by allowing the transit of water, chemicals, and ions. They can be found in many different types of cells and organs, including the lungs, eyes, brain, glands, and blood vessels. By controlling the osmotic water flux in processes like cell growth, energy metabolism, migration, adhesion, and proliferation, AQPs are capable of exerting their regulatory influence over a wide range of cellular processes. Tumour cells of varying sources express AQPs significantly, especially in malignant tumours with a high propensity for metastasis. New insights into the roles of AQPs in cell migration and proliferation reinforce the notion that AQPs are crucial players in tumour biology. AQPs have recently been shown to be a powerful tool in the fight against pathogenic antibodies and metastatic cell migration, despite the fact that the molecular processes of aquaporins in pathology are not entirely established. In this review, we shall discuss the several ways in which AQPs are expressed in the body, the unique roles they play in tumorigenesis, and the novel therapeutic approaches that could be adopted to treat carcinoma.


Asunto(s)
Acuaporinas , Neoplasias , Humanos , Neoplasias/patología , Carcinogénesis , Transformación Celular Neoplásica , Agua/metabolismo , Acuaporinas/química , Acuaporinas/metabolismo
3.
J Med Virol ; 95(1): e28412, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36527332

RESUMEN

Considering the global trend to confine the COVID-19 pandemic by applying various preventive health measures, preprocedural mouth rinsing has been proposed to mitigate the transmission risk of SARS-CoV-2 in dental clinics. The study aimed to investigate the effect of different mouth rinses on salivary viral load in COVID-19 patients. This study was a single-center, randomized, double-blind, six-parallel-group, placebo-controlled clinical trial that investigated the effect of four mouth rinses (1% povidone-iodine, 1.5% hydrogen peroxide, 0.075% cetylpyridinium chloride, and 80 ppm hypochlorous acid) on salivary SARS-CoV-2 viral load relative to the distilled water and no-rinse control groups. The viral load was measured by quantitative reverse transcription PCR (RT-qPCR) at baseline and 5, 30, and 60 min post rinsing. The viral load pattern within each mouth rinse group showed a reduction overtime; however, this reduction was only statistically significant in the hydrogen peroxide group. Further, a significant reduction in the viral load was observed between povidone-iodine, hydrogen peroxide, and cetylpyridinium chloride compared to the no-rinse group at 60 min, indicating their late antiviral potential. Interestingly, a similar statistically significant reduction was also observed in the distilled water control group compared to the no-rinse group at 60 min, proposing mechanical washing of the viral particles through the rinsing procedure. Therefore, results suggest using preprocedural mouth rinses, particularly hydrogen peroxide, as a risk-mitigation step before dental procedures, along with strict adherence to other infection control measures.


Asunto(s)
COVID-19 , Antisépticos Bucales , Humanos , Antisépticos Bucales/uso terapéutico , SARS-CoV-2 , Peróxido de Hidrógeno , Povidona Yodada/uso terapéutico , Cetilpiridinio/uso terapéutico , Pandemias , Carga Viral , Agua
4.
Proc Natl Acad Sci U S A ; 115(45): 11579-11584, 2018 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-30249666

RESUMEN

Adaptive natural killer (NK) cell memory represents a new frontier in immunology. Work over the last decade has discovered and confirmed the existence of NK cells with antigen-specific memories, which had previously been considered a unique property of T and B cells. These findings have shown that antigen-specific NK cells gain their specificity without the use of RAG proteins, representing a novel mechanism for generating antigen specificity, but the details of this mechanism have remained a mystery. We have discovered that members of the Ly49 family of surface receptors are critically involved in both the sensitization and the challenge phases of an NK cell memory response, as is antigen presentation from their binding partner, the class I MHC. Moreover, we demonstrate that the Ly49-interacting component of a presented antigen dictates the specificity of the NK cell memory response, implicating Ly49 receptors themselves in antigen-specific recognition. Finally, we demonstrate that adaptive NK cell memories can protect against an otherwise lethal melanoma without T cell or B cell support. These findings offer insight into the mechanism behind NK cell antigen specificity and demonstrate the clinical potential of this adaptive immune cell.


Asunto(s)
Dermatitis por Contacto/prevención & control , Memoria Inmunológica , Células Asesinas Naturales/inmunología , Melanoma Experimental/terapia , Subfamilia A de Receptores Similares a Lectina de Células NK/genética , Péptidos/inmunología , Inmunidad Adaptativa/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Presentación de Antígeno , Vacunas contra el Cáncer/administración & dosificación , Dermatitis por Contacto/genética , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/patología , Dinitrofluorobenceno/administración & dosificación , Femenino , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Células Asesinas Naturales/citología , Células Asesinas Naturales/efectos de los fármacos , Masculino , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Subfamilia A de Receptores Similares a Lectina de Células NK/inmunología , Oxazoles/administración & dosificación , Péptidos/administración & dosificación , Péptidos/síntesis química , Vacunación
5.
PLoS Pathog ; 12(2): e1005446, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26928844

RESUMEN

The immune response to influenza virus infection comprises both innate and adaptive defenses. NK cells play an early role in the destruction of tumors and virally-infected cells. NK cells express a variety of inhibitory receptors, including those of the Ly49 family, which are functional homologs of human killer-cell immunoglobulin-like receptors (KIR). Like human KIR, Ly49 receptors inhibit NK cell-mediated lysis by binding to major histocompatibility complex class I (MHC-I) molecules that are expressed on normal cells. During NK cell maturation, the interaction of NK cell inhibitory Ly49 receptors with their MHC-I ligands results in two types of NK cells: licensed ("functional"), or unlicensed ("hypofunctional"). Despite being completely dysfunctional with regard to rejecting MHC-I-deficient cells, unlicensed NK cells represent up to half of the mature NK cell pool in rodents and humans, suggesting an alternative role for these cells in host defense. Here, we demonstrate that after influenza infection, MHC-I expression on lung epithelial cells is upregulated, and mice bearing unlicensed NK cells (Ly49-deficient NKCKD and MHC-I-deficient B2m-/- mice) survive the infection better than WT mice. Importantly, transgenic expression of an inhibitory self-MHC-I-specific Ly49 receptor in NKCKD mice restores WT influenza susceptibility, confirming a direct role for Ly49. Conversely, F(ab')2-mediated blockade of self-MHC-I-specific Ly49 inhibitory receptors protects WT mice from influenza virus infection. Mechanistically, perforin-deficient NKCKD mice succumb to influenza infection rapidly, indicating that direct cytotoxicity is necessary for unlicensed NK cell-mediated protection. Our findings demonstrate that Ly49:MHC-I interactions play a critical role in influenza virus pathogenesis. We suggest a similar role may be conserved in human KIR, and their blockade may be protective in humans.


Asunto(s)
Antígenos Ly/metabolismo , Evasión Inmune , Virus de la Influenza A/inmunología , Células Asesinas Naturales/inmunología , Subfamilia A de Receptores Similares a Lectina de Células NK/metabolismo , Infecciones por Orthomyxoviridae/inmunología , Receptores KIR/metabolismo , Mucosa Respiratoria/inmunología , Animales , Antígenos Ly/genética , Línea Celular Tumoral , Células Cultivadas , Técnicas de Cocultivo , Cruzamientos Genéticos , Inmunidad Innata , Virus de la Influenza A/fisiología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Células Asesinas Naturales/virología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Ratones Noqueados , Ratones Transgénicos , Subfamilia A de Receptores Similares a Lectina de Células NK/agonistas , Subfamilia A de Receptores Similares a Lectina de Células NK/antagonistas & inhibidores , Subfamilia A de Receptores Similares a Lectina de Células NK/genética , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virología , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Receptores KIR/agonistas , Receptores KIR/antagonistas & inhibidores , Receptores KIR/genética , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Mucosa Respiratoria/virología , Organismos Libres de Patógenos Específicos , Análisis de Supervivencia , Microglobulina beta-2/genética , Microglobulina beta-2/metabolismo
6.
PLoS Pathog ; 12(11): e1006021, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27814389

RESUMEN

[This corrects the article DOI: 10.1371/journal.ppat.1005446.].

7.
J Immunol ; 197(6): 2325-37, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27511735

RESUMEN

NK cells play a major role in immune defense against human and murine CMV (MCMV) infection. Although the MCMV genome encodes for MHC class I-homologous decoy ligands for inhibitory NK cell receptors to evade detection, some mouse strains have evolved activating receptors, such as Ly49H, to recognize these ligands and initiate an immune response. In this study, we demonstrate that approximately half of the Ly49H-expressing (Ly49H(+)) NK cells in the spleen and liver of C57BL/6 mice also express the inhibitory NKR-P1B receptor. During MCMV infection, the NKR-P1B(-)Ly49H(+) NK cell subset proliferates to constitute the bulk of the NK cell population. This NK cell subset also confers better protection against MCMV infection compared with the NKR-P1B(+)Ly49H(+) subset. The two populations are composed of cells that differ in their surface expression of receptors such as Ly49C/I and NKG2A/C/E, as well as developmental markers, CD27 and CD11b, and the high-affinity IL-2R (CD25) following infection. Although the NKR-P1B(+) NK cells can produce effector molecules such as IFNs and granzymes, their proliferation is inhibited during infection. A similar phenotype in MCMV-infected Clr-b-deficient mice, which lack the ligand for NKR-P1B, suggests the involvement of ligands other than the host Clr-b. Most interestingly, genetic deficiency of the NKR-P1B, but not Clr-b, results in accelerated virus clearance and recovery from MCMV infection. This study is particularly significant because the mouse NKR-P1B:Clr-b receptor:ligand system represents the closest homolog of the human NKR-P1A:LLT1 system and may have a direct relevance to human CMV infection.


Asunto(s)
Infecciones por Herpesviridae/inmunología , Células Asesinas Naturales/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Animales , Ligandos , Ratones , Ratones Endogámicos C57BL , Muromegalovirus/inmunología , Muromegalovirus/fisiología , Subfamilia B de Receptores Similares a Lectina de Células NK/deficiencia , Subfamilia B de Receptores Similares a Lectina de Células NK/genética
8.
Blood ; 125(14): 2217-27, 2015 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-25612621

RESUMEN

NKR-P1B is a homodimeric type II transmembrane C-type lectinlike receptor that inhibits natural killer (NK) cell function upon interaction with its cognate C-type lectin-related ligand, Clr-b. The NKR-P1B:Clr-b interaction represents a major histocompatibility complex class I (MHC-I)-independent missing-self recognition system that monitors cellular Clr-b levels. We have generated NKR-P1B(B6)-deficient (Nkrp1b(-/-)) mice to study the role of NKR-P1B in NK cell development and function in vivo. NK cell inhibition by Clr-b is abolished in Nkrp1b(-/-) mice, confirming the inhibitory nature of NKR-P1B(B6). Inhibitory receptors also promote NK cell tolerance and responsiveness to stimulation; hence, NK cells expressing NKR-P1B(B6) and Ly49C/I display augmented responsiveness to activating signals vs NK cells expressing either or none of the receptors. In addition, Nkrp1b(-/-) mice are defective in rejecting cells lacking Clr-b, supporting a role for NKR-P1B(B6) in MHC-I-independent missing-self recognition of Clr-b in vivo. In contrast, MHC-I-dependent missing-self recognition is preserved in Nkrp1b(-/-) mice. Interestingly, spontaneous myc-induced B lymphoma cells may selectively use NKR-P1B:Clr-b interactions to escape immune surveillance by wild-type, but not Nkrp1b(-/-), NK cells. These data provide direct genetic evidence of a role for NKR-P1B in NK cell tolerance and MHC-I-independent missing-self recognition.


Asunto(s)
Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Lectinas Tipo C/fisiología , Linfoma de Células B/inmunología , Proteínas de la Membrana/fisiología , Subfamilia B de Receptores Similares a Lectina de Células NK/fisiología , Animales , Western Blotting , Células Cultivadas , Femenino , Citometría de Flujo , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Ligandos , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Masculino , Ratones , Ratones Endogámicos C57BL
9.
J Immunol ; 190(8): 3994-4004, 2013 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-23479228

RESUMEN

Plasmacytoid dendritic cells (pDC) are the major producers of type I IFN during the initial immune response to viral infection. Ly49Q, a C-type lectin-like receptor specific for MHC-I, possesses a cytoplasmic ITIM and is highly expressed on murine pDC. Using Ly49Q-deficient mice, we show that, regardless of strain background, this receptor is required for maximum IFN-α production by pDC. Furthermore, Ly49Q expression on pDC, but not myeloid dendritic cells, is necessary for optimal IL-12 secretion, MHC-II expression, activation of CD4(+) T cell proliferation, and nuclear translocation of the master IFN-α regulator IFN regulatory factor 7 in response to TLR9 agonists. In contrast, the absence of Ly49Q did not affect plasmacytoid dendritic cell-triggering receptor expressed on myeloid cells expression or pDC viability. Genetic complementation revealed that IFN-α production by pDC is dependent on an intact tyrosine residue in the Ly49Q cytoplasmic ITIM. However, pharmacological inhibitors and phosphatase-deficient mice indicate that Src homology 2 domain-containing phosphatase 1 (SHP)-1, SHP-2, and SHIP phosphatase activity is dispensable for this function. Finally, we observed that Ly49Q itself is downregulated on pDC in response to CpG exposure in an ITIM-independent manner. In conclusion, Ly49Q enhances TLR9-mediated signaling events, leading to IFN regulatory factor 7 nuclear translocation and expression of IFN-I genes in an ITIM-dependent manner that can proceed without the involvement of SHP-1, SHP-2, and SHIP.


Asunto(s)
Células Dendríticas/inmunología , Interferón-alfa/biosíntesis , Subfamilia A de Receptores Similares a Lectina de Células NK/fisiología , Animales , Células Dendríticas/metabolismo , Células Dendríticas/patología , Prueba de Complementación Genética/métodos , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Ratones Mutantes , Ratones Transgénicos , Oligodesoxirribonucleótidos/genética , Oligodesoxirribonucleótidos/farmacología , Estructura Terciaria de Proteína/genética , Transporte de Proteínas/genética , Transporte de Proteínas/inmunología
10.
J Immunol ; 191(11): 5722-9, 2013 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-24154624

RESUMEN

Murine Ly49 receptors, which are expressed mainly on NK and NKT cells, interact with MHC class I (MHC-I) molecules with varying specificity. Differing reports of Ly49/MHC binding affinities may be affected by multiple factors, including cis versus trans competition and species origin of the MHC-I L chain (ß2-microglobulin). To determine the contribution of each of these factors, Ly49G, Ly49I, Ly49O, Ly49V, and Ly49Q receptors from the 129 mouse strain were expressed individually on human 293T cells or the mouse cell lines MHC-I-deficient C1498, H-2(b)-expressing MC57G, and H-2(k)-expressing L929. The capacity to bind to H-2D(b)- and H-2K(b)-soluble MHC-I tetramers containing either human or murine ß2-microglobulin L chains was tested for all five Ly49 receptors in all four cell lines. We found that most of these five inhibitory Ly49 receptors show binding for one or both self-MHC-I molecules in soluble tetramer binding assays when three conditions are fulfilled: 1) lack of competing cis interactions, 2) tetramer L chain is of mouse origin, and 3) Ly49 is expressed in mouse and not human cell lines. Furthermore, Ly49Q, the single known MHC-I receptor on plasmacytoid dendritic cells, was shown to bind H-2D(b) in addition to H-2K(b) when the above conditions were met, suggesting that Ly49Q functions as a pan-MHC-Ia receptor on plasmacytoid dendritic cells. In this study, we have optimized the parameters for soluble tetramer binding analyses to enhance future Ly49 ligand identification and to better evaluate specific contributions by different Ly49/MHC-I pairs to NK cell education and function.


Asunto(s)
Células Dendríticas/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Células Asesinas Naturales/inmunología , Subfamilia A de Receptores Similares a Lectina de Células NK/metabolismo , Células T Asesinas Naturales/inmunología , Animales , Diferenciación Celular , Separación Celular , Pruebas Inmunológicas de Citotoxicidad , Citometría de Flujo/métodos , Células HEK293 , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Ligandos , Ratones , Ratones Noqueados , Subfamilia A de Receptores Similares a Lectina de Células NK/genética , Subfamilia A de Receptores Similares a Lectina de Células NK/inmunología , Unión Proteica , Ingeniería de Proteínas , Especificidad de la Especie
11.
Front Immunol ; 15: 1350208, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38533510

RESUMEN

Colorectal cancer (CRC) is the third most common cancer globally and presents a significant challenge owing to its high mortality rate and the limitations of traditional treatment options such as surgery, radiotherapy, and chemotherapy. While these treatments are foundational, they are often poorly effective owing to tumor resistance. Immunotherapy is a groundbreaking alternative that has recently emerged and offers new hope for success by exploiting the body's own immune system. This article aims to provide an extensive review of clinical trials evaluating the efficacy of various immunotherapies, including CRC vaccines, chimeric antigen receptor T-cell therapies, and immune checkpoint inhibitors. We also discuss combining CRC vaccines with monoclonal antibodies, delve into preclinical studies of novel cancer vaccines, and assess the impact of these treatment methods on patient outcomes. This review seeks to provide a deeper understanding of the current state of CRC treatment by evaluating innovative treatments and their potential to redefine the prognosis of patients with CRC.


Asunto(s)
Vacunas contra el Cáncer , Neoplasias Colorrectales , Humanos , Inmunoterapia/métodos , Inmunoterapia Adoptiva , Resultado del Tratamiento
12.
Front Immunol ; 14: 1085940, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37063914

RESUMEN

Background: Cancer incidence and mortality are increasing rapidly worldwide, necessitating further investigation into developing and optimizing emergent cancer therapies. Oncolytic viruses such as vesicular stomatitis virus encoding interferon ß (VSV-IFNß) have attracted considerable attention, as they offer great efficacy and safety profiles. This systematic review aimed to determine and compare the efficacy profile between VSV-IFNß and non-treatment controls in preclinical cancer models. Methodology: The Embase and Medline databases were systematically searched for relevant studies using related key terms and Medical Subject Headings (MeSH). Titles, abstracts, and full texts were screened, and data from eligible articles were extracted by two groups independently and in duplicate (two reviewers per group). Disagreements were resolved by a fifth independent reviewer. The included articles were all preclinical (translational) in vivo English studies that investigated and compared the efficacy profile between VSV-IFNß and non-treatment controls in animal models. The risk of bias among the studies was assessed by two reviewers independently and in duplicate using SYRCLE's risk-of-bias tool for animal studies; disparities were addressed by a third independent reviewer. Results: After employing relevant MeSH and key terms, we identified 1598 articles. A total of 87 articles were either duplicates or conference proceedings and were thus excluded. Following title and abstract screening, 37 articles were included in the full-text assessment. Finally, 14 studies met the eligibility criteria. Forty-two experiments from the included studies examined the potential efficacy of VSV-IFNß through different routes of administration, including intratumoral, intraperitoneal, and intravenous routes. Thirty-seven experiments reported positive outcomes. Meanwhile, five experiments reported negative outcomes, three and two of which examined intratumoral and intravenous VSV-IFNß administration, respectively. Conclusion: Although the majority of the included studies support the promising potential of VSV-IFNß as an oncolytic virus, further research is necessary to ensure a safe and efficacious profile to translate its application into clinical trials. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022335418.


Asunto(s)
Interferón beta , Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Animales , Neoplasias/terapia , Virus Oncolíticos/genética , Virus de la Estomatitis Vesicular Indiana , Vesiculovirus/genética , Interferón beta/uso terapéutico
13.
Front Mol Biosci ; 10: 1190669, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37255540

RESUMEN

The use of oncolytic viruses (OVs) in combination with cytokines, such as IL-12, is a promising approach for cancer treatment that addresses the limitations of current standard treatments and traditional cancer immunotherapies. IL-12, a proinflammatory cytokine, triggers intracellular signaling pathways that lead to increased apoptosis of tumor cells and enhanced antitumor activity of immune cells via IFN-γ induction, making this cytokine a promising candidate for cancer therapy. Targeted expression of IL-12 within tumors has been shown to play a crucial role in tumor eradication. The recent development of oncolytic viruses enables targeted delivery and expression of IL-12 at the tumor site, thereby addressing the systemic toxicities associated with traditional cancer therapy. In this study, we constructed an oncolytic virus, VSVΔ51M, based on the commercially available VSV wild-type backbone and further modified it to express human IL-12. Our preclinical data confirmed the safety and limited toxicity of the modified virus, VSV-Δ51M-hIL-12, supporting its potential use for clinical development.

14.
Front Bioeng Biotechnol ; 11: 1150892, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37528991

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic imposes an urgent and continued need for the development of safe and cost-effective vaccines to induce preventive responses for limiting major outbreaks around the world. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we repurposed the VSV∆51M oncolytic virus platform to express the spike receptor-binding domain (RBD) antigen. In this study, we report the development and characterization of the VSV∆51M-RBD vaccine. Our findings demonstrate successful expression of the RBD gene by the VSV∆51M-RBD virus, inducing anti-RBD responses without attenuating the virus. Moreover, the VSV∆51M-RBD vaccine exhibited safety, immunogenicity, and the potential to serve as a safe and effective alternative or complementary platform to current COVID-19 vaccines.

15.
One Health ; 17: 100601, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37520847

RESUMEN

High seroprevalence rates of several phleboviruses have been reported in domestic animals and humans in sandfly-infested regions. Sandfly Fever Sicilian virus (SFSV) and Toscana virus (TOSV) are two of these viruses commonly transmitted by Phlebotomus sandflies. While SFSV can cause rapidly resolving mild febrile illness, TOSV could involve the central nervous system (CNS), causing diseases ranging from aseptic meningitis to meningoencephalitis. Sandfly-associated phleboviruses have not been investigated before in Saudi Arabia and are potential causes of infection given the prevalence of sandflies in the country. Here, we investigated the seroprevalence of SFSV and TOSV in the western region of Saudi Arabia in samples collected from blood donors, livestock animals, and animal handlers. An overall seroprevalence of 9.4% and 0.8% was found in humans for SFSV and TOSV, respectively. Seropositivity was significantly higher in non-Saudis compared to Saudis and increased significantly with age especially for SFSV. The highest seropositivity rate was among samples collected from animal handlers. Specifically, in blood donors, 6.4% and 0.7% tested positive for SFSV and TOSV nAbs, respectively. Animal handlers showed higher seroprevalence rates of 16% and 1% for anti-SFSV and anti-TOSV nAbs, respectively, suggesting that contact with livestock animals could be a risk factor. Indeed, sera from livestock animals showed seropositivity of 53.3% and 4.4% in cows, 27.5% and 7.8% in sheep, 2.2% and 0.0% in goats, and 10.0% and 2.3% in camels for SFSV and TOSV, respectively. Together, these results suggest that both SFSV and TOSV are circulating in the western region of Saudi Arabia in humans and livestock animals, albeit at different rates, and that age and contact with livestock animals could represent risk factors for infection with these viruses.

16.
Front Immunol ; 13: 944452, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36311781

RESUMEN

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor of the central nervous system and has a very poor prognosis. The current standard of care for patients with GBM involves surgical resection, radiotherapy, and chemotherapy. Unfortunately, conventional therapies have not resulted in significant improvements in the survival outcomes of patients with GBM; therefore, the overall mortality rate remains high. Immunotherapy is a type of cancer treatment that helps the immune system to fight cancer and has shown success in different types of aggressive cancers. Recently, healthcare providers have been actively investigating various immunotherapeutic approaches to treat GBM. We reviewed the most promising immunotherapy candidates for glioblastoma that have achieved encouraging results in clinical trials, focusing on immune checkpoint inhibitors, oncolytic viruses, nonreplicating viral vectors, and chimeric antigen receptor (CAR) immunotherapies.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Receptores Quiméricos de Antígenos , Humanos , Glioblastoma/patología , Inmunoterapia/métodos , Neoplasias Encefálicas/patología , Pronóstico , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/uso terapéutico , Factores Inmunológicos/uso terapéutico
17.
Nat Commun ; 13(1): 7272, 2022 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-36433992

RESUMEN

Alveolar macrophages (AM) hold lung homeostasis intact. In addition to the defense against inhaled pathogens and deleterious inflammation, AM also maintain pulmonary surfactant homeostasis, a vital lung function that prevents pulmonary alveolar proteinosis. Signals transmitted between AM and pneumocytes of the pulmonary niche coordinate these specialized functions. However, the mechanisms that guide the metabolic homeostasis of AM remain largely elusive. We show that the NK cell-associated receptor, NKR-P1B, is expressed by AM and is essential for metabolic programming. Nkrp1b-/- mice are vulnerable to pneumococcal infection due to an age-dependent collapse in the number of AM and the formation of lipid-laden AM. The AM of Nkrp1b-/- mice show increased uptake but defective metabolism of surfactant lipids. We identify a physical relay between AM and alveolar type-II pneumocytes that is dependent on pneumocyte Clr-g expression. These findings implicate the NKR-P1B:Clr-g signaling axis in AM-pneumocyte communication as being important for maintaining metabolism in AM.


Asunto(s)
Proteinosis Alveolar Pulmonar , Surfactantes Pulmonares , Ratones , Animales , Macrófagos Alveolares/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Proteinosis Alveolar Pulmonar/metabolismo , Surfactantes Pulmonares/metabolismo , Muerte Celular
18.
Viruses ; 13(7)2021 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-34372618

RESUMEN

Healthcare workers (HCWs) are at high risk for SARS-CoV-2 infection compared to the general population. Here, we aimed to evaluate and characterize the SARS-CoV-2 seropositivity rate in randomly collected samples among HCWs from the largest referral hospitals and quarantine sites during the peak of the COVID-19 epidemic in the city of Jeddah, the second largest city in Saudi Arabia, using a cross-sectional analytic study design. Out of 693 participants recruited from 29 June to 10 August 2020, 223 (32.2%, 95% CI: 28.8-35.8) were found to be confirmed seropositive for SARS-CoV-2 antibodies, and among those 197 (88.3%) had never been diagnosed with COVID-19. Seropositivity was not significantly associated with participants reporting COVID-19 compatible symptoms as most seropositive HCW participants 140 (62.8%) were asymptomatic. The large proportion of asymptomatic SARS-CoV-2 cases detected in our study demands periodic testing as a general hospital policy.


Asunto(s)
COVID-19/epidemiología , SARS-CoV-2/inmunología , Adulto , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales/inmunología , Infecciones Asintomáticas , COVID-19/inmunología , COVID-19/virología , Prueba Serológica para COVID-19 , Chlorocebus aethiops , Estudios Transversales , Femenino , Personal de Salud/estadística & datos numéricos , Humanos , Control de Infecciones , Masculino , Persona de Mediana Edad , Cuarentena , Derivación y Consulta , Arabia Saudita/epidemiología , Estudios Seroepidemiológicos , Células Vero
19.
Front Immunol ; 11: 1986, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32983137

RESUMEN

Monoclonal antibodies (mAbs) have become one of the most important classes of biopharmaceutical products, and they continue to dominate the universe of biopharmaceutical markets in terms of approval and sales. They are the most profitable single product class, where they represent six of the top ten selling drugs. At the beginning of the 1990s, an in vitro antibody selection technology known as antibody phage display was developed by John McCafferty and Sir. Gregory Winter that enabled the discovery of human antibodies for diverse applications, particularly antibody-based drugs. They created combinatorial antibody libraries on filamentous phage to be utilized for generating antigen specific antibodies in a matter of weeks. Since then, more than 70 phage-derived antibodies entered clinical studies and 14 of them have been approved. These antibodies are indicated for cancer, and non-cancer medical conditions, such as inflammatory, optical, infectious, or immunological diseases. This review will illustrate the utility of phage display as a powerful platform for therapeutic antibodies discovery and describe in detail all the approved mAbs derived from phage display.


Asunto(s)
Anticuerpos Monoclonales , Técnicas de Visualización de Superficie Celular , Desarrollo de Medicamentos/métodos , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Especificidad de Anticuerpos/genética , Especificidad de Anticuerpos/inmunología , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Ingeniería Genética , Ensayos Analíticos de Alto Rendimiento , Humanos , Terapia Molecular Dirigida , Investigación Biomédica Traslacional , Resultado del Tratamiento
20.
Sci Rep ; 10(1): 5095, 2020 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-32198420

RESUMEN

The mode of action for oncolytic viruses (OVs) in cancer treatment is thought to depend on a direct initial cytotoxic effect against infected tumor cells and subsequent activation of immune cell responses directed against the neoplasm. To study both of these effects in a mouse model of glioblastoma (GBM), we employed murine GBM cells engineered to constitutively express the type I Herpes Simplex Virus (HSV1) HSV-1 receptor, nectin-1, to allow for more efficient infection and replication by oncolytic HSV (oHSV). These cells were further engineered with a surrogate tumor antigen to facilitate assays of T cell activity. We utilized MRI-based volumetrics to measure GBM responses after injection with the oHSV and bioluminescent imaging (BLI) to determine oHSV replicative kinetics in the injected tumor mass. We found increased infiltration of both surrogate tumor antigen- and oHSV antigen-specific CD8+ T cells within 7 days after oHSV injection. There was no increase in tumor infiltrating CD8+ T cells expressing "exhaustion" markers, yet oHSV infection led to a reduction in PD-1+ CD8+ T cells in injected GBMs and an increase in IFNγ+ CD8+ T cells. There was a significant direct correlation between oHSV-mediated reduction in GBM volume and increased infiltration of both viral and tumor antigen-specific CD8+ T cells, as well as oHSV intratumoral gene activity. These findings imply that CD8+ T cell cytotoxicity against both tumor and viral antigens as well as intratumoral oHSV gene expression are important in oHSV-mediated GBM therapy.


Asunto(s)
Antígenos de Neoplasias/inmunología , Antígenos Virales/inmunología , Neoplasias Encefálicas/inmunología , Glioblastoma/inmunología , Viroterapia Oncolítica/métodos , Linfocitos T Citotóxicos/inmunología , Animales , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Línea Celular Tumoral , Modelos Animales de Enfermedad , Glioblastoma/patología , Glioblastoma/terapia , Herpesvirus Humano 1/inmunología , Humanos , Interferón gamma/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Virus Oncolíticos , Receptores Virales/genética , Receptores Virales/inmunología
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