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1.
Clin Transl Immunology ; 10(9): e1337, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527244

RESUMO

Objectives: The upper respiratory tract is the major entry site for Streptococcus pyogenes and influenza virus. Vaccine strategies that activate mucosal immunity could significantly reduce morbidity and mortality because of these pathogens. The severity of influenza is significantly greater if a streptococcal infection occurs during the viraemic period and generally viral infections complicated by a subsequent bacterial infection are known as super-infections. We describe an innovative vaccine strategy against influenza virus:S. pyogenes super-infection. Moreover, we provide the first description of a liposomal multi-pathogen-based platform that enables the incorporation of both viral and bacterial antigens into a vaccine and constitutes a transformative development. Methods: Specifically, we have explored a vaccination strategy with biocompatible liposomes that express conserved streptococcal and influenza A virus B-cell epitopes on their surface and contain encapsulated diphtheria toxoid as a source of T-cell help. The vaccine is adjuvanted by inclusion of the synthetic analogue of monophosphoryl lipid A, 3D-PHAD. Results: We observe that this vaccine construct induces an Immunoglobulin A (IgA) response in both mice and ferrets. Vaccination reduces viral load in ferrets from influenza challenge and protects mice from both pathogens. Notably, vaccination significantly reduces both mortality and morbidity associated with a super-infection. Conclusion: The vaccine design is modular and could be adapted to include B-cell epitopes from other mucosal pathogens where an IgA response is required for protection.

2.
mSphere ; 6(5): e0065921, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34585962

RESUMO

Infection with mosquito-borne arthritogenic alphaviruses, such as Ross River virus (RRV) and Barmah Forest virus (BFV), can lead to long-lasting rheumatic disease. Existing mouse models that recapitulate the disease signs and immunopathogenesis of acute RRV and BFV infection have consistently shown relevance to human disease. However, these mouse models, which chiefly model hindlimb dysfunction, may be prone to subjective interpretation when scoring disease. Assessment is therefore time-consuming and requires experienced users. The DigiGait system provides video-based measurements of movement, behavior, and gait dynamics in mice and small animals. Previous studies have shown DigiGait to be a reliable system to objectively quantify changes in gait in other models of pain and inflammation. Here, for the first time, we determine measurable differences in the gait of mice with infectious arthritis using the DigiGait system. Statistically significant differences in paw area and paw angle were detected during peak disease in RRV-infected mice. Significant differences in temporal gait parameters were also identified during the period of peak disease in RRV-infected mice. These trends were less obvious or absent in BFV-infected mice, which typically present with milder disease signs than RRV-infected mice. The DigiGait system therefore provides an objective model of variations in gait dynamics in mice acutely infected with RRV. DigiGait is likely to have further utility for murine models that develop severe forms of infectious arthritis resulting in hindlimb dysfunction like RRV. IMPORTANCE Mouse models that accurately replicate the immunopathogenesis and clinical disease of alphavirus infection are vital to the preclinical development of therapeutic strategies that target alphavirus infection and disease. Current models rely on subjective scoring made through experienced observation of infected mice. Here, we demonstrate how the DigiGait system, and interventions on mice to use this system, can make an efficient objective assessment of acute disease progression and changes in gait in alphavirus-infected mice. Our study highlights the importance of measuring gait parameters in the assessment of models of infectious arthritis.

3.
Cell Host Microbe ; 29(6): 894-903.e5, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-33989514

RESUMO

Babesia spp. are tick-transmitted intra-erythrocytic protozoan parasites that infect humans and animals, causing a flu-like illness and hemolytic anemia. There is currently no human vaccine available. People most at risk of severe disease are the elderly, immunosuppressed, and asplenic individuals. B. microti and B. divergens are the predominant species affecting humans. Here, we present a whole-parasite Babesia vaccine. To establish proof-of-principle, we employed chemically attenuated B. microti parasitized red blood cells from infected mice. To aid clinical translation, we produced liposomes containing killed parasite material. Vaccination significantly reduces peak parasitemia following challenge. B cells and anti-parasite antibodies do not significantly contribute to vaccine efficacy. Protection is abrogated by the removal of CD4+ T cells or macrophages prior to challenge. Importantly, splenectomized mice are protected by vaccination. To further facilitate translation, we prepared a culture-based liposomal vaccine and demonstrate that this performs as a universal vaccine inducing immunity against different human Babesia species.


Assuntos
Babesia microti/imunologia , Babesiose/imunologia , Babesiose/prevenção & controle , Avaliação Pré-Clínica de Medicamentos , Parasitemia/imunologia , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/uso terapêutico , Animais , Anticorpos Antiprotozoários/sangue , Linfócitos B/imunologia , Babesiose/parasitologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Imunidade , Lipossomos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Parasitemia/terapia , T-Linfocitopenia Idiopática CD4-Positiva/imunologia , Carrapatos/parasitologia
4.
mBio ; 12(2)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879586

RESUMO

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo, the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development.IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit's value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/etiologia , SARS-CoV-2/patogenicidade , Animais , COVID-19/patologia , COVID-19/virologia , Síndrome da Liberação de Citocina/etiologia , Modelos Animais de Doenças , Feminino , Interações entre Hospedeiro e Microrganismos , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Transgênicos , Pandemias , Pneumonia Viral/etiologia , Pneumonia Viral/virologia , Genética Reversa/métodos , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Tropismo Viral , Replicação Viral
5.
Lancet Infect Dis ; 21(5): e123-e133, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33160445

RESUMO

Mosquito-borne viruses, or arboviruses, have been part of the infectious disease landscape for centuries, and are often, but not exclusively, endemic to equatorial and subtropical regions of the world. The past two decades saw the re-emergence of arthritogenic alphaviruses, a genus of arboviruses that includes several members that cause severe arthritic disease. Recent outbreaks further highlight the substantial public health burden caused by these viruses. Arthritogenic alphaviruses are often reported in the context of focused outbreaks in specific regions (eg, Caribbean, southeast Asia, and Indian Ocean) and cause debilitating acute disease that can extend to chronic manifestations for years after infection. These viruses are classified among several antigenic complexes, span a range of hosts and mosquito vectors, and can be distributed along specific geographical locations. In this Review, we highlight key features of alphaviruses that are known to cause arthritic disease in humans and outline the present findings pertaining to classification, immunogenicity, pathogenesis, and experimental approaches aimed at limiting disease manifestations. Although the most prominent alphavirus outbreaks in the past 15 years featured chikungunya virus, and a large body of work has been dedicated to understanding chikungunya disease mechanisms, this Review will instead focus on other arthritogenic alphaviruses that have been identified globally and provide a comprehensive appraisal of present and future research directions.


Assuntos
Infecções por Alphavirus/epidemiologia , Infecções por Alphavirus/fisiopatologia , Infecções por Arbovirus/epidemiologia , Infecções por Arbovirus/fisiopatologia , Alphavirus/genética , Infecções por Alphavirus/diagnóstico , Infecções por Alphavirus/virologia , Animais , Infecções por Arbovirus/diagnóstico , Infecções por Arbovirus/virologia , Arbovírus/genética , Febre de Chikungunya , Vírus Chikungunya , Culicidae , Modelos Animais de Doenças , Variação Genética , Humanos , Mosquitos Vetores/virologia
6.
J Immunol ; 205(7): 1842-1856, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32839238

RESUMO

Follicular dendritic cells and macrophages have been strongly implicated in presentation of native Ag to B cells. This property has also occasionally been attributed to conventional dendritic cells (cDC) but is generally masked by their essential role in T cell priming. cDC can be divided into two main subsets, cDC1 and cDC2, with recent evidence suggesting that cDC2 are primarily responsible for initiating B cell and T follicular helper responses. This conclusion is, however, at odds with evidence that targeting Ag to Clec9A (DNGR1), expressed by cDC1, induces strong humoral responses. In this study, we reveal that murine cDC1 interact extensively with B cells at the border of B cell follicles and, when Ag is targeted to Clec9A, can display native Ag for B cell activation. This leads to efficient induction of humoral immunity. Our findings indicate that surface display of native Ag on cDC with access to both T and B cells is key to efficient humoral vaccination.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Lectinas Tipo C/metabolismo , Receptores Imunológicos/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Animais , Apresentação do Antígeno , Autoantígenos/imunologia , Autoantígenos/metabolismo , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Imunidade Humoral , Lectinas Tipo C/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/genética , Vacinação
7.
mBio ; 11(2)2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127460

RESUMO

Arthritogenic alphaviruses such as Ross River and Chikungunya viruses cause debilitating muscle and joint pain and pose significant challenges in the light of recent outbreaks. How host immune responses are orchestrated after alphaviral infections and lead to musculoskeletal inflammation remains poorly understood. Here, we show that myositis induced by Ross River virus (RRV) infection is driven by CD11bhi Ly6Chi inflammatory monocytes and followed by the establishment of a CD11bhi Ly6Clo CX3CR1+ macrophage population in the muscle upon recovery. Selective modulation of CD11bhi Ly6Chi monocyte migration to infected muscle using immune-modifying microparticles (IMP) reduced disease score, tissue damage, and inflammation and promoted the accumulation of CX3CR1+ macrophages, enhancing recovery and resolution. Here, we detail the role of immune pathology, describing a poorly characterized muscle macrophage subset as part of the dynamics of alphavirus-induced myositis and tissue recovery and identify IMP as an effective immunomodulatory approach. Given the lack of specific treatments available for alphavirus-induced pathologies, this study highlights a therapeutic potential for simple immune modulation by IMP in infected individuals in the event of large alphavirus outbreaks.IMPORTANCE Arthritogenic alphaviruses cause debilitating inflammatory disease, and current therapies are restricted to palliative approaches. Here, we show that following monocyte-driven muscle inflammation, tissue recovery is associated with the accumulation of CX3CR1+ macrophages in the muscle. Modulating inflammatory monocyte infiltration using immune-modifying microparticles (IMP) reduced tissue damage and inflammation and enhanced the formation of tissue repair-associated CX3CR1+ macrophages in the muscle. This shows that modulating key effectors of viral inflammation using microparticles can alter the outcome of disease by facilitating the accumulation of macrophage subsets associated with tissue repair.


Assuntos
Infecções por Alphavirus/metabolismo , Infecções por Alphavirus/virologia , Receptor 1 de Quimiocina CX3C/genética , Monócitos/metabolismo , Miosite/etiologia , Miosite/metabolismo , Cicatrização , Infecções por Alphavirus/patologia , Animais , Biomarcadores , Biópsia , Receptor 1 de Quimiocina CX3C/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Imunomodulação/genética , Imunofenotipagem , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/virologia , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/virologia , Miosite/patologia
8.
Front Immunol ; 11: 304, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194557

RESUMO

Chikungunya virus (CHIKV) is the causative pathogen of chikungunya fever, a mosquito-borne viral disease causing highly debilitating arthralgia that can persist for months and progress to chronic arthritis. Our previous studies have identified the CHIKV live-attenuated vaccine candidate CHIKV-NoLS. Like most live-attenuated vaccines, attenuated replication of CHIKV-NoLS has the potential to limit scalable production. To overcome production limits, as well as other drawbacks of live-attenuated vaccines, we developed an in vivo liposome RNA delivery system to deliver the self-replicating RNA genome of CHIKV-NoLS directly into mice, allowing the recipients' body to produce the live-attenuated vaccine particles. CAF01 liposomes were able to deliver replication-competent CHIKV-NoLS RNA in vitro. Immunodeficient AG129 mice inoculated with liposome-delivered CHIKV-NoLS RNA developed viremia and disease signs representative of this lethal model of CHIKV infection, demonstrating de novo vaccine particle production in vivo. In immunocompetent C57BL/6 mice, liposome-delivered CHIKV-NoLS RNA inoculation was associated with reduced IgM and IgG levels with low antibody CHIKV-neutralizing capacity, compared to vaccination with the original live-attenuated vaccine CHIKV-NoLS. One dose of liposome-delivered CHIKV-NoLS RNA did not provide systemic protection from CHIKV wild-type (WT) challenge but was found to promote an early onset of severe CHIKV-induced footpad swelling. Liposome-delivered CHIKV-NoLS RNA inoculation did, however, provide local protection from CHIKV-WT challenge in the ipsilateral foot after one dose. Results suggest that in the presence of low CHIKV-specific neutralizing antibody levels, local inflammatory responses, likely brought on by liposome adjuvants, have a role in the protection of CHIKV-induced footpad swelling in the ipsilateral foot of mice inoculated with liposome-delivered CHIKV-NoLS RNA. Low IgG and CHIKV-specific neutralizing antibody levels may be responsible for early onset of severe swelling in the feet of CHIKV-WT-challenged mice. These results support previous studies that suggest CHIKV is vulnerable to antibody-mediated enhancement of disease. Further studies using booster regimes aim to demonstrate the potential for liposomes to deliver the self-replicating RNA genome of live-attenuated vaccines and offer a novel immunization strategy.


Assuntos
Febre de Chikungunya/prevenção & controle , Vírus Chikungunya/imunologia , RNA Viral/administração & dosagem , Vacinas Virais/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vírus Chikungunya/genética , Feminino , Genoma Viral , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Vacinas Virais/imunologia
9.
Saudi J Kidney Dis Transpl ; 31(1): 200-208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32129214

RESUMO

Urinary tract infection (UTI) is one of the most common bacterial infections among children. It is noted that the risk of renal damage from UTI is the greatest in children younger than five years, thus early diagnosis and prompt treatment are important. The aim of this study was to assess the incidence of UTI in children attending pediatric outpatient clinics in Zagazig and Tanta University Hospitals as tertiary care hospitals. Furthermore, we attempted to determine related risk factors, isolate the organisms that cause UTI in children, and study their antibiotic susceptibility patterns. This cross-sectional descriptive study was conducted on 1200 toddlers and children, (754 boys and 446 girls) aged between 30 months and seven years attending the pediatric outpatient clinics of Zagazig and Tanta University Hospitals. All patient groups were subjected to full medical history, physical examination, dipstick analysis by using both nitrite and leukocyte esterase (LE) detectors, microscopic examinations, and urine culture for cases with the positive LE, positive nitrite dipstick test for urine or positive for both LE and nitrite. The incidence of UTI among children included in the current study was 7%. Positive LE was seen in 112 (9.3%), nitrite positivity was seen in 94 (7.8%), and both LE and nitrite positivity in 34 (2.8%). Escherichia coli was the most common organism. Cefotaxime and amikacin were the most common sensitive antibiotics to the isolates.


Assuntos
Infecções Urinárias , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/microbiologia , Criança , Pré-Escolar , Estudos Transversais , Farmacorresistência Bacteriana , Egito , Feminino , Humanos , Incidência , Masculino , Fatores de Risco , Centros de Atenção Terciária , Infecções Urinárias/diagnóstico , Infecções Urinárias/epidemiologia , Infecções Urinárias/microbiologia
10.
Cell Immunol ; 350: 103913, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30992120

RESUMO

Intravital imaging of cutaneous immune responses has revealed intricate links between the skin's structural properties, the immune cells that reside therein, and the carefully orchestrated migratory dynamics that enable rapid sensing and subsequent elimination of skin pathogens. In particular, the development of 2-photon intravital microscopy (2P-IVM), which enables the excitation of fluorescent molecules within deep tissue with minimal light scattering and tissue damage, has proven an invaluable tool in the characterization of different cell subset's roles in skin infection. The ability to visualize cells, tissue structures, pathogens and track migratory dynamics at designated times following infection, or during inflammatory responses has been crucial in defining how immune responses in the skin are coordinated, either locally or in concert with circulating immune cells. Skin pathogens affect millions of people worldwide, and skin infections leading to cutaneous pathology have a considerable impact on the quality of life and longevity of people affected. In contrast, pathogens that infect the skin to later cause systemic illness, such as malaria parasites and a variety of arthropod-borne viruses, or infection in distant anatomical sites are a significant cause of morbidity and mortality worldwide. Here, we review recent advances and seminal studies that employed intravital imaging to characterize key immune response mechanisms in the context of viral, bacterial and parasitic skin infections, and provide insights on skin pathogens of global significance that would benefit from such investigative approaches.


Assuntos
Microscopia Intravital/métodos , Dermatopatias Infecciosas/diagnóstico por imagem , Dermatopatias Infecciosas/imunologia , Animais , Derme/diagnóstico por imagem , Derme/imunologia , Epiderme/diagnóstico por imagem , Epiderme/imunologia , Humanos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Camundongos , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Qualidade de Vida , Pele/diagnóstico por imagem , Pele/imunologia , Dermatopatias Infecciosas/microbiologia
12.
J Maxillofac Oral Surg ; 18(2): 288-292, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30996553

RESUMO

Introduction: Primary surgery of cleft lip and palate has dramatically improved with technical and material advances. Some adults who previously underwent surgery still have upper lip deformities or extensive scar, and they are occasionally seen for secondary treatment. Cases: In our study, a total of five patients with secondary deformity of the upper lip with the scarred tissue with paucity of the muscle in the midline were operated using the modified Abbe flap. Conclusion: With this technique, we were able to achieve the bulk in the midline over the upper lip and the functional integrity of the muscle was maintained.

13.
Viruses ; 11(3)2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909385

RESUMO

Arthritogenic alphaviruses are a group of medically important arboviruses that cause inflammatory musculoskeletal disease in humans with debilitating symptoms, such as arthralgia, arthritis, and myalgia. The arthritogenic, or Old World, alphaviruses are capable of causing explosive outbreaks, with some viruses of major global concern. At present, there are no specific therapeutics or commercially available vaccines available to prevent alphaviral disease. Infected patients are typically treated with analgesics and non-steroidal anti-inflammatory drugs to provide often inadequate symptomatic relief. Studies to determine the mechanisms of arthritogenic alphaviral disease have highlighted the role of the host immune system in disease pathogenesis. This review discusses the current knowledge of the innate immune response to acute alphavirus infection and alphavirus-induced immunopathology. Therapeutic strategies to treat arthritogenic alphavirus disease by targeting the host immune response are also examined.


Assuntos
Infecções por Alphavirus/tratamento farmacológico , Artralgia/tratamento farmacológico , Artralgia/virologia , Imunidade Inata , Inflamação/tratamento farmacológico , Alphavirus/efeitos dos fármacos , Infecções por Alphavirus/complicações , Infecções por Alphavirus/imunologia , Animais , Artrite/tratamento farmacológico , Artrite/virologia , Febre de Chikungunya/tratamento farmacológico , Vírus Chikungunya/efeitos dos fármacos , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Camundongos , Mialgia/tratamento farmacológico , Mialgia/virologia
14.
Arthritis Rheumatol ; 71(7): 1185-1190, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30747500

RESUMO

OBJECTIVE: Arthritogenic alphaviruses, such as Ross River virus (RRV) and chikungunya virus (CHIKV), particularly affect joints of the extremities and can lead to debilitating and potentially chronic polyarthritis/polyarthralgia. The innate immune response of the host plays a crucial role in inducing proinflammatory host factors, leading to tissue destruction and bone loss in the joints. This study was performed to assess how the inhibition of interleukin-1ß (IL-1ß) signaling using the clinical rheumatoid arthritis drug anakinra influences bone loss in mice with arthritogenic alphavirus infections. METHODS: Mice (n = 5 per group) were infected with RRV or CHIKV and then treated with anakinra. Weight gain and disease severity were measured, tissue viral titers were determined, and histologic changes in joint tissues were assessed. RESULTS: Anakinra therapy reduced RRV- and CHIKV-induced bone loss in this murine model (P < 0.001 and P < 0.05, respectively). Histologic analysis of the knee joint showed that treatment with anakinra decreased epiphyseal growth plate thinning, loss of epiphyseal bone volume, and osteoclastogenesis in the tibia. Importantly, pharmacologic IL-1 receptor (IL-1R) blockade did not improve other clinical features, including disease score, weight loss, or viremia. CONCLUSION: The present findings suggest that anakinra therapy may reduce bone loss in experimental murine models of RRV and CHIKV. Further investigations are needed to assess the potential therapeutic benefits of anakinra in patients with arthritogenic alphavirus disease.


Assuntos
Antirreumáticos/farmacologia , Artrite Infecciosa/patologia , Febre de Chikungunya/patologia , Lâmina de Crescimento/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/antagonistas & inibidores , Osteogênese/efeitos dos fármacos , Tíbia/efeitos dos fármacos , Infecções por Alphavirus/imunologia , Infecções por Alphavirus/patologia , Infecções por Alphavirus/fisiopatologia , Animais , Artrite Infecciosa/imunologia , Artrite Infecciosa/fisiopatologia , Artrite Infecciosa/virologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Febre de Chikungunya/imunologia , Febre de Chikungunya/fisiopatologia , Vírus Chikungunya , Lâmina de Crescimento/patologia , Interleucina-1beta/imunologia , Articulação do Joelho , Camundongos , Vírus do Rio Ross , Tíbia/patologia
15.
Vaccines (Basel) ; 7(1)2018 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-30583514

RESUMO

Our previous investigation of the nucleolar localisation sequence (NoLS) of chikungunya virus (CHIKV) capsid protein demonstrated the role of capsid in CHIKV virulence. Mutating the NoLS of capsid in CHIKV led to the development of a unique live-attenuated CHIKV vaccine candidate, termed CHIKV-NoLS. CHIKV-NoLS-immunised mice developed long-term immunity from CHIKV infection after a single dose. To further evaluate CHIKV-NoLS attenuation and suitability as a vaccine, we examined the footpad of inoculated mice for underlying CHIKV-NoLS-induced immunopathology by histological and flow cytometric analysis. In comparison to CHIKV-WT-infected mice, CHIKV-NoLS-inoculated mice exhibited minimal inflammation and tissue damage. To examine the stability of attenuation, the plaque phenotype and replication kinetics of CHIKV-NoLS were determined following extended in vitro passage. The average plaque size of CHIKV-NoLS remained notably smaller than CHIKV-WT after extended passage and attenuated replication was maintained. To examine thermostability, CHIKV-NoLS was stored at 21 °C, 4 °C, -20 °C and -80 °C and infectious CHIKV-NoLS quantified up to 84 days. The infectious titre of CHIKV-NoLS remains stable after 56 days when stored at either -20 °C or -80 °C. Interestingly, unlike CHIKV-WT, the infectious titre of CHIKV-NoLS is not sensitive to freeze thaw cycles. These data further demonstrate preclinical safety and stability of CHIKV-NoLS.

16.
J Cancer Res Ther ; 14(3): 583-586, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29893322

RESUMO

Objective: The purpose of this study was to identify human Cytomegalovirus (HCMV) in tissue blocks obtained from patients with nasopharyngeal carcinoma (NPC). Materials and Methods: Formalin-fixed paraffin wax processed NPC tissue were obtained from 150 tissue blocks and retrospectively investigated for the presence of HCMV using polymerase chain reaction. Results: Of the 150 NPC tissue specimens, HCMV was identified in 53/150 (35.3%) of the samples. Out of the 53 samples infected with HCMV, 33/97 (34%) were among males and 20/53 (37.7%) were among females. Of the 53 positive samples, 36/53 (68%) were found to harbor Epstein-Barr virus (EBV). Conclusion: The present study has shown a relatively considerable association between HCMV and NPC. The great majority of samples sheltering HCMV were also found to hide EBV, which proposes the potentiality of EBV over HCMV.


Assuntos
Carcinoma/virologia , Citomegalovirus/isolamento & purificação , DNA Viral/isolamento & purificação , Neoplasias Nasofaríngeas/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/genética , Carcinoma/patologia , Citomegalovirus/genética , Citomegalovirus/patogenicidade , DNA Viral/genética , Feminino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 4/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Inclusão em Parafina , Reação em Cadeia da Polimerase
17.
Nat Immunol ; 19(2): 183-191, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29311695

RESUMO

Although tissue-resident memory T cells (TRM cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin TRM cells engaged virus-infected cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary TRM cells formed from pre-existing TRM cells, as well as from precursors recruited from the circulation. Newly recruited antigen-specific or bystander TRM cells were generated in the skin without displacement of the pre-existing TRM cell pool. Thus, pre-existing skin TRM cell populations are not displaced after subsequent infections, which enables multiple TRM cell specificities to be stably maintained within the tissue.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Pele/imunologia , Animais , Proliferação de Células/fisiologia , Herpes Simples/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
18.
J Family Med Prim Care ; 7(6): 1548-1554, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30613557

RESUMO

Background: Every minute, an accident occurs in Saudi Arabia, causing 39,000 injuries and 7,000 deaths annually. Facial trauma or maxillofacial trauma (MFT) is a frequent presentation of road traffic accidents (RTAs), ranging from simple nasal fractures to gross or severe maxillofacial injuries. Methods: A total number of 237 patients were included in this prospective study from May 2013 to January 2018. The following medical details were recorded for each case, gender, age, fracture location, the presence of scalp laceration, the presence of brain damage, type of brain damage, shock degree, Glasgow Coma Scale (GCS), number of units used for blood transfusions for documentation of patient survival rate. We followed up the patients in their first appointment after 21 days of patient discharge from the hospital. Results: Majority of the patients were young male adults. A total of 59.1% of patients had cerebral damage, 38% (n = 90) of patients had at least, one scalp laceration, 43.5% (n = 103) of patients had some degree of shock, whereas 27.8% of the recruited patients needed at least 1 unit of blood transfusion. A total of 14.3% of the patients died as a result of their injuries, and the survival rate was 85.7%. Conclusions: Kingdom of Saudi Arabia (KSA) is having a high incidence of RTAs leading to high mortality rate. Therefore, it requires a sound evaluation of the risk factors for RTAs and establishment of guidelines to decrease the incidence of road traffic injuries and reduce health-care burden. Road safety campaigns focused on young population can help reduce RTAs and subsequent mortalities. Prompt arrival at the hospital, early diagnosis, and timely management of maxillofacial fractures and brain damages by skilled physicians will lower mortality rate in KSA..

19.
J Virol ; 92(3)2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29142130

RESUMO

Resolution of virus infections depends on the priming of virus-specific CD8+ T cells by dendritic cells (DC). While this process requires major histocompatibility complex (MHC) class I-restricted antigen presentation by DC, the relative contribution to CD8+ T cell priming by infected DC is less clear. We have addressed this question in the context of a peripheral infection with herpes simplex virus 1 (HSV). Assessing the endogenous, polyclonal HSV-specific CD8+ T cell response, we found that effective in vivo T cell priming depended on the presence of DC subsets specialized in cross-presentation, while Langerhans cells and plasmacytoid DC were dispensable. Utilizing a novel mouse model that allows for the in vivo elimination of infected DC, we also demonstrated in vivo that this requirement for cross-presenting DC was not related to their infection but instead reflected their capacity to cross-present HSV-derived antigen. Taking the results together, this study shows that infected DC are not required for effective CD8+ T cell priming during a peripheral virus infection.IMPORTANCE The ability of some DC to present viral antigen to CD8+ T cells without being infected is thought to enable the host to induce killer T cells even when viruses evade or kill infected DC. However, direct experimental in vivo proof for this notion has remained elusive. The work described in this study characterizes the role that different DC play in the induction of virus-specific killer T cell responses and, critically, introduces a novel mouse model that allows for the selective elimination of infected DC in vivo Our finding that HSV-specific CD8+ T cells can be fully primed in the absence of DC infection shows that cross-presentation by DC is indeed sufficient for effective CD8+ T cell priming during a peripheral virus infection.


Assuntos
Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada , Células Dendríticas/imunologia , Herpes Simples/imunologia , Animais , Apresentação do Antígeno , Linfócitos T CD8-Positivos/citologia , Células Dendríticas/citologia , Citometria de Fluxo , Herpesvirus Humano 1 , Camundongos , Camundongos Endogâmicos C57BL
20.
Arthritis Rheumatol ; 70(4): 484-495, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29287308

RESUMO

In the past decade, arboviruses-arthropod-borne viruses-have been the focus of public health institutions worldwide following a spate of devastating outbreaks. Chikungunya virus, an arbovirus that belongs to the alphavirus genus, is a reemerging arthritogenic virus that has caused explosive outbreaks since 2006, notably on Réunion Island, and more recently in the Caribbean, South America, India, and Southeast Asia. The severity of arthritic disease caused by chikungunya virus has prompted public health authorities in affected countries to develop specific guidelines to tackle this pathogen. Chikungunya virus disease manifests first as an acute stage of severe joint inflammation and febrile illness, which later progresses to a chronic stage, during which patients may experience debilitating and persisting articular pain for extended periods. This review aims to provide a broad perspective on current knowledge of chikungunya virus pathogenesis by identifying key clinical and experimental studies that have contributed to our understanding of chikungunya virus to date. In addition, the review explores the practical aspects of treatment and management of both acute and chronic chikungunya virus based on clinical experience during chikungunya virus outbreaks. Finally, recent findings on potential therapeutic solutions-from antiviral agents to immunomodulators-are reviewed to provide both viral immunologists and clinical rheumatologists with a balanced perspective on the nature of a reemerging arboviral disease of significant public health concern, and insight into future therapeutic approaches to better address the treatment and management of chikungunya virus.


Assuntos
Antivirais/uso terapêutico , Artrite Infecciosa/patologia , Febre de Chikungunya/patologia , Vírus Chikungunya , Fatores Imunológicos/uso terapêutico , Artrite Infecciosa/terapia , Artrite Infecciosa/virologia , Febre de Chikungunya/terapia , Febre de Chikungunya/virologia , Humanos , Inflamação
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