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1.
Philos Trans A Math Phys Eng Sci ; 381(2248): 20220017, 2023 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-37031697

RESUMO

We investigate some concrete independence results for systems of reverse mathematics which emerge from monotonicity properties of number-theoretic functions. Natural properties of the less than or equal to relation with respect to sums of natural numbers lead to independence results for first-order Peano arithmetic. Natural properties of the less than or equal to relation with respect to sums and products of natural numbers lead to independence results for arithmetical transfinite recursion. By considering number-theoretic functions of arbitrary arities, we obtain independence results for systems beyond arithmetical transfinite recursion. We discuss how these embeddability relations are related to tree embeddability relations and we consider variants where the tree embeddability relation is not assumed to preserve infima. The findings of this paper are complementary to results on Kruskal-like theorems proved earlier by the first author. This article is part of the theme issue 'Modern perspectives in Proof Theory'.

2.
J Infect Dis ; 226(9): 1499-1509, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35451492

RESUMO

Herpes simplex virus (HSV) infection of the neonatal brain causes severe encephalitis and permanent neurologic deficits. However, infants infected with HSV at the time of birth follow varied clinical courses, with approximately half of infants experiencing only external infection of the skin rather than invasive neurologic disease. Understanding the cause of these divergent outcomes is essential to developing neuroprotective strategies. To directly assess the contribution of viral variation to neurovirulence, independent of human host factors, we evaluated clinical HSV isolates from neonates with different neurologic outcomes in neurologically relevant in vitro and in vivo models. We found that isolates taken from neonates with encephalitis are more neurovirulent in human neuronal culture and mouse models of HSV encephalitis, as compared to isolates collected from neonates with skin-limited disease. These findings suggest that inherent characteristics of the infecting HSV strain contribute to disease outcome following neonatal infection.


Assuntos
Doenças Transmissíveis , Encefalite por Herpes Simples , Herpes Simples , Animais , Camundongos , Recém-Nascido , Humanos , Herpesvirus Humano 2 , Encéfalo
3.
PLoS Pathog ; 16(7): e1008795, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32716975

RESUMO

HSV-1 causes 50% of first-time genital herpes infections in resource-rich countries and affects 190 million people worldwide. A prophylactic herpes vaccine is needed to protect against genital infections by both HSV-1 and HSV-2. Previously our laboratory developed a trivalent vaccine that targets glycoproteins C, D, and E present on the HSV-2 virion. We reported that this vaccine protects animals from genital disease and recurrent virus shedding following lethal HSV-2 challenge. Importantly the vaccine also generates cross-reactive antibodies that neutralize HSV-1, suggesting it may provide protection against HSV-1 infection. Here we compared the efficacy of this vaccine delivered as protein or nucleoside-modified mRNA immunogens against vaginal HSV-1 infection in mice. Both the protein and mRNA vaccines protected mice from HSV-1 disease; however, the mRNA vaccine provided better protection as measured by lower vaginal virus titers post-infection. In a second experiment, we compared protection provided by the mRNA vaccine against intravaginal challenge with HSV-1 or HSV-2. Vaccinated mice were totally protected against death, genital disease and infection of dorsal root ganglia caused by both viruses, but somewhat better protected against vaginal titers after HSV-2 infection. Overall, in the two experiments, the mRNA vaccine prevented death and genital disease in 54/54 (100%) mice infected with HSV-1 and 20/20 (100%) with HSV-2, and prevented HSV DNA from reaching the dorsal root ganglia, the site of virus latency, in 29/30 (97%) mice infected with HSV-1 and 10/10 (100%) with HSV-2. We consider the HSV-2 trivalent mRNA vaccine to be a promising candidate for clinical trials for prevention of both HSV-1 and HSV-2 genital herpes.


Assuntos
Proteção Cruzada/imunologia , Herpes Genital , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 2/imunologia , Vacinas contra Herpesvirus/imunologia , Latência Viral/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Feminino , Herpes Genital/virologia , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro , Proteínas do Envelope Viral/imunologia
4.
J Virol ; 94(11)2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188735

RESUMO

Herpes simplex virus (HSV) can cause severe infection in neonates leading to mortality and lifelong morbidity. Prophylactic approaches, such as maternal immunization, could prevent neonatal HSV (nHSV) infection by providing protective immunity and preventing perinatal transmission. We previously showed that maternal immunization with a replication-defective HSV vaccine candidate, dl5-29, leads to transfer of virus-specific antibodies into the neonatal circulation and protects against nHSV neurological sequela and mortality (C. D. Patel, I. M. Backes, S. A. Taylor, Y. Jiang, et al., Sci Transl Med, 11:eaau6039, 2019, https://doi.org/10.1126/scitranslmed.aau6039). In this study, we evaluated the efficacy of maternal immunization with an experimental trivalent (gC2, gD2, and gE2) subunit vaccine to protect against nHSV. Using a murine model of nHSV, we demonstrated that maternal immunization with the trivalent vaccine protected offspring against nHSV-disseminated disease and mortality. In addition, offspring of immunized dams were substantially protected from behavioral pathology following HSV infection. This study supports the idea that maternal immunization is a viable strategy for the prevention of neonatal infections.IMPORTANCE Herpes simplex virus is among the most serious infections of newborns. Current antiviral therapies can prevent mortality if infection is recognized early and treated promptly. Most children who survive nHSV develop lifelong neurological and behavioral deficits, despite aggressive antiviral treatment. We propose that maternal immunization could provide protection against HSV for both mother and baby. To this end, we used a trivalent glycoprotein vaccine candidate to demonstrate that offspring are protected from nHSV following maternal immunization. Significantly, this approach protected offspring from long-term behavioral morbidity. Our results emphasize the importance of providing protective immunity to neonates during this window of vulnerability.


Assuntos
Herpes Simples , Herpesvirus Humano 1/imunologia , Complicações Infecciosas na Gravidez , Animais , Animais Recém-Nascidos , Linhagem Celular , Criança , Herpes Simples/imunologia , Herpes Simples/prevenção & controle , Humanos , Recém-Nascido , Camundongos , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/prevenção & controle , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/farmacologia
5.
PLoS Pathog ; 14(5): e1007095, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29791513

RESUMO

Herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit antigen is included in many preclinical candidate vaccines. The rationale for including gD2 is to produce antibodies that block crucial gD2 epitopes involved in virus entry and cell-to-cell spread. HSV-2 gD2 was the only antigen in the Herpevac Trial for Women that protected against HSV-1 genital infection but not HSV-2. In that trial, a correlation was detected between gD2 ELISA titers and protection against HSV-1, supporting the importance of antibodies. A possible explanation for the lack of protection against HSV-2 was that HSV-2 neutralization titers were low, four-fold lower than to HSV-1. Here, we evaluated neutralization titers and epitope-specific antibody responses to crucial gD2 epitopes involved in virus entry and cell-to-cell spread as correlates of immune protection against genital lesions in immunized guinea pigs. We detected a strong correlation between neutralizing antibodies and protection against genital disease. We used a high throughput biosensor competition assay to measure epitope-specific responses to seven crucial gD2 linear and conformational epitopes involved in virus entry and spread. Some animals produced antibodies to most crucial epitopes while others produced antibodies to few. The number of epitopes recognized by guinea pig immune serum correlated with protection against genital lesions. We confirmed the importance of antibodies to each crucial epitope using monoclonal antibody passive transfer that improved survival and reduced genital disease in mice after HSV-2 genital challenge. We re-evaluated our prior study of epitope-specific antibody responses in women in the Herpevac Trial. Humans produced antibodies that blocked significantly fewer crucial gD2 epitopes than guinea pigs, and antibody responses in humans to some linear epitopes were virtually absent. Neutralizing antibody titers and epitope-specific antibody responses are important immune parameters to evaluate in future Phase I/II prophylactic human vaccine trials that contain gD2 antigen.


Assuntos
Anticorpos Antivirais/imunologia , Herpes Genital/prevenção & controle , Vacinas contra o Vírus do Herpes Simples/imunologia , Simplexvirus/imunologia , Proteínas do Envelope Viral/imunologia , Internalização do Vírus , Animais , Anticorpos Antivirais/sangue , Chlorocebus aethiops , Epitopos/imunologia , Feminino , Cobaias , Imunização Passiva , Imunoglobulina G/sangue , Imunoglobulina G/isolamento & purificação , Camundongos , Camundongos Endogâmicos BALB C , Células Vero
6.
Med Sci Monit ; 26: e928754, 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33188161

RESUMO

BACKGROUND A lethal synergism between the influenza virus and Streptococcus pneumoniae has been identified. However, bacterial coinfection is considered relatively infrequent in hospitalized patients with COVID-19, and the co-prevalence of Streptococcus pneumoniae is low. MATERIAL AND METHODS We retrospectively analyzed the clinical characteristics and outcomes of patients subsequently admitted to AMITA Health Saint Francis Hospital between March 1 and June 30, 2020, with documented SARS-CoV-2 and S. pneumoniae coinfection. RESULTS We identified 11 patients with S. pneumoniae coinfection. The median age was 77 years (interquartile range [IQR], 74-82 years), 45.5% (5/11) were males, 54.5% (6/11) were white, and 90.9% (10/11) were long-term care facility (LTCF) residents. The median length of stay was 7 days (IQR, 6-8 days). Among 11 patients, 4 were discharged in stable condition and 7 had died, resulting in an inpatient mortality rate of 64%. CONCLUSIONS At our center, 11 patients with COVID-19 pneumonia who had confirmed infection with SARS-CoV-2 were diagnosed with Streptococcus pneumoniae infection while in hospital. All patients had pneumonia confirmed on imaging and a nonspecific increase in markers of inflammation. The in-hospital mortality rate of 64% (7 patients) was higher in this group than in previous reports. This study highlights the importance of monitoring bacterial coinfection in patients with viral lung infection due to SARS-CoV-2.


Assuntos
COVID-19/epidemiologia , Coinfecção/epidemiologia , Pneumonia Pneumocócica/epidemiologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/microbiologia , Coinfecção/diagnóstico , Coinfecção/imunologia , Coinfecção/microbiologia , Conjuntos de Dados como Assunto , Feminino , Mortalidade Hospitalar , Hospitalização , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pandemias , Pneumonia Pneumocócica/diagnóstico , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/microbiologia , Estudos Retrospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/isolamento & purificação
7.
PLoS Pathog ; 13(1): e1006141, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28103319

RESUMO

A genital herpes vaccine is urgently needed to prevent pain and suffering, reduce the incidence of neonatal herpes, and decrease the risk of HIV acquisition and transmission that accompanies genital infection. We evaluated a trivalent HSV-2 subunit antigen vaccine administered with CpG and alum in rhesus macaques and guinea pigs. The vaccine contains glycoproteins C, D and E (gC2, gD2, gE2) to block virus entry by gD2 and immune evasion by gC2 and gE2. In rhesus macaques, the trivalent vaccine induced plasma and mucosa neutralizing antibodies, antibodies that block gC2 and gE2 immune evasion activities, and stimulated CD4 T cell responses. After intravaginal challenge, a self-limited vaginal infection of brief duration was detected by histopathology and immunohistochemistry in naïve, but not in trivalent immunized macaques. Vaccine efficacy was evaluated in female guinea pigs. Animals were mock immunized, or immunized with gD2, the trivalent vaccine or the trivalent vaccine followed by a booster dose of gD2 (trivalent + gD2). The trivalent and trivalent + gD2 groups were 97% and 99% efficacious, respectively in preventing genital lesions and both outperformed gD2 alone. As a marker of transmission risk, vaginal swabs were evaluated daily for HSV-2 DNA and replication competent virus between five and seven weeks after challenge. HSV-2 DNA shedding was reduced in all groups compared with mock. Shedding of replication competent virus occurred on fewer days in the trivalent than gD2 immunized animals while the trivalent + gD2 group had no shedding of replication competent virus. Overall, the trivalent group had genital lesions on < 1% days and shedding of replication competent virus on 0.2% days. The vaccine has outstanding potential for prevention of genital herpes in humans.


Assuntos
Herpes Simples/imunologia , Herpesvirus Humano 2/imunologia , Vacinas contra Herpesvirus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Cobaias , Humanos , Imuno-Histoquímica , Macaca mulatta , Reação em Cadeia da Polimerase , Vacinas de Subunidades Antigênicas/imunologia
8.
J Virol ; 89(16): 8497-509, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26041292

RESUMO

UNLABELLED: We evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while the UL19 and UL47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing UL19 and UL47 stimulated human and murine CD4(+) and CD8(+) T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/gD2, with CpG and alum as adjuvants; (iii) immunized with the UL19/UL47 adenovirus vectors; or (iv) immunized with the combination of gC2/gD2-CpG/alum and the UL19/UL47 adenovirus vectors. Immunization with gC2/gD2 produced potent neutralizing antibodies, while UL19 and UL47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and UL19/UL47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/gD2-only group and none in the combined group developed acute disease. No animals in the gC2/gD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/gD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/gD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/gD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens UL19 and UL47 to the gC2/gD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/gD2 in the guinea pig model. IMPORTANCE: HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (gD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) would enhance the protection provided by the gC2/gD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/gD2 and UL19/UL47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.


Assuntos
Antígenos Virais/imunologia , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas Virais/biossíntese , Adenoviridae , Animais , Anticorpos Antivirais/imunologia , Western Blotting , Linfócitos T CD4-Positivos/imunologia , Proteínas do Capsídeo/imunologia , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Vetores Genéticos/imunologia , Cobaias , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real
9.
Arch Virol ; 161(11): 3203-13, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27568015

RESUMO

Herpes simplex virus type 1 (HSV-1) glycoprotein E (gE), glycoprotein I (gI), and Us9 promote efficient anterograde axonal transport of virus from the neuron cytoplasm to the axon terminus. HSV-1 and PRV gE and gI form a heterodimer that is required for anterograde transport, but an association that includes Us9 has not been demonstrated. NS-gE380 is an HSV-1 mutant that has five amino acids inserted after gE residue 380, rendering it defective in anterograde axonal transport. We demonstrated that gE, gI and Us9 form a trimolecular complex in Vero cells infected with NS-gE380 virus in which gE binds to both Us9 and gI. We detected the complex using immunoprecipitation with anti-gE or anti-gI monoclonal antibodies in the presence of ionic detergents. Under these conditions, Us9 did not associate with gE in cells infected with wild-type HSV-1; however, using a nonionic detergent, TritonX-100, an association between Us9 and gE was detected in immunoprecipitates of both wild-type and NS-gE380-infected cells. The results suggest that the interaction between Us9 and gE is weak and disrupted by ionic detergents in wild-type infected cells. We postulate that the tight interaction between Us9 and gE leads to the anterograde spread defect in the NS-gE380 virus.


Assuntos
Herpesvirus Humano 1/fisiologia , Lipoproteínas/metabolismo , Fosfoproteínas/metabolismo , Mapeamento de Interação de Proteínas , Proteínas do Envelope Viral/metabolismo , Proteínas Virais/metabolismo , Animais , Chlorocebus aethiops , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular , Ligação Proteica , Células Vero
10.
Sens Actuators B Chem ; 229: 232-238, 2016 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-26900258

RESUMO

Nucleic acid amplification-based diagnostics offer rapid, sensitive, and specific means for detecting and monitoring the progression of infectious diseases. However, this method typically requires extensive sample preparation, expensive instruments, and trained personnel. All of which hinder its use in resource-limited settings, where many infectious diseases are endemic. Here, we report on a simple, inexpensive, minimally-instrumented, smart cup platform for rapid, quantitative molecular diagnostics of pathogens at the point of care. Our smart cup takes advantage of water-triggered, exothermic chemical reaction to supply heat for the nucleic acid-based, isothermal amplification. The amplification temperature is regulated with a phase-change material (PCM). The PCM maintains the amplification reactor at a constant temperature, typically, 60-65°C, when ambient temperatures range from 12 to 35°C. To eliminate the need for an optical detector and minimize cost, we use the smartphone's flashlight to excite the fluorescent dye and the phone camera to record real-time fluorescence emission during the amplification process. The smartphone can concurrently monitor multiple amplification reactors and analyze the recorded data. Our smart cup's utility was demonstrated by amplifying and quantifying herpes simplex virus type 2 (HSV-2) with LAMP assay in our custom-made microfluidic diagnostic chip. We have consistently detected as few as 100 copies of HSV-2 viral DNA per sample. Our system does not require any lab facilities and is suitable for use at home, in the field, and in the clinic, as well as in resource-poor settings, where access to sophisticated laboratories is impractical, unaffordable, or nonexistent.

11.
J Virol ; 88(15): 8421-32, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24829358

RESUMO

UNLABELLED: Herpes simplex virus 2 (HSV-2) subunit antigen vaccines targeting virus entry molecules have failed to prevent genital herpes in human trials. Our approach is to include a virus entry molecule and add antigens that block HSV-2 immune evasion. HSV-2 glycoprotein C (gC2) is an immune evasion molecule that inhibits complement. We previously reported that adding gC2 to gD2 improved vaccine efficacy compared to the efficacy of either antigen alone in mice and guinea pigs. Here we demonstrate that HSV-2 glycoprotein E (gE2) functions as an immune evasion molecule by binding the IgG Fc domain. HSV-2 gE2 is synergistic with gC2 in protecting the virus from antibody and complement neutralization. Antibodies produced by immunization with gE2 blocked gE2-mediated IgG Fc binding and cell-to-cell spread. Mice immunized with gE2 were only partially protected against HSV-2 vaginal challenge in mice; however, when gE2 was added to gC2/gD2 to form a trivalent vaccine, neutralizing antibody titers with and without complement were significantly higher than those produced by gD2 alone. Importantly, the trivalent vaccine protected the dorsal root ganglia (DRG) of 32/33 (97%) mice between days 2 and 7 postchallenge, compared with 27/33 (82%) in the gD2 group. The HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than in those immunized with gD2 alone. The extent of DRG protection using the trivalent vaccine was better than what we previously reported for gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion. IMPORTANCE: Herpes simplex virus is the most common cause of genital ulcer disease worldwide. Infection results in emotional distress for infected individuals and their partners, is life threatening for infants exposed to herpes during childbirth, and greatly increases the risk of individuals acquiring and transmitting HIV infection. A vaccine that prevents genital herpes infection will have major public health benefits. Our vaccine approach includes strategies to prevent the virus from evading immune attack. Mice were immunized with a trivalent vaccine containing an antigen that induces antibodies to block virus entry and two antigens that induce antibodies that block immune evasion from antibody and complement. Immunized mice demonstrated no genital disease, and 32/33 (97%) animals had no evidence of infection of dorsal root ganglia, suggesting that the vaccine may prevent the establishment of latency and recurrent infections.


Assuntos
Herpes Genital/prevenção & controle , Herpesvirus Humano 2/imunologia , Vacinas contra Herpesvirus/imunologia , Evasão da Resposta Imune , Proteínas do Envelope Viral/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , DNA Viral/análise , DNA Viral/genética , Modelos Animais de Doenças , Feminino , Herpes Genital/imunologia , Vacinas contra Herpesvirus/administração & dosagem , Vacinas contra Herpesvirus/genética , Camundongos , Camundongos Endogâmicos BALB C , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Proteínas do Envelope Viral/metabolismo , Carga Viral
12.
J Virol ; 88(4): 2000-10, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24284325

RESUMO

A prophylactic vaccine for genital herpes disease remains an elusive goal. We report the results of two studies performed collaboratively in different laboratories that assessed immunogenicity and vaccine efficacy in herpes simplex virus 1 (HSV-1)-seropositive guinea pigs immunized and subsequently challenged intravaginally with HSV-2. In study 1, HSV-2 glycoproteins C (gC2) and D (gD2) were produced in baculovirus and administered intramuscularly as monovalent or bivalent vaccines with CpG and alum. In study 2, gD2 was produced in CHO cells and given intramuscularly with monophosphoryl lipid A (MPL) and alum, or gC2 and gD2 were produced in glycoengineered Pichia pastoris and administered intramuscularly as a bivalent vaccine with Iscomatrix and alum to HSV-1-naive or -seropositive guinea pigs. In both studies, immunization boosted neutralizing antibody responses to HSV-1 and HSV-2. In study 1, immunization with gC2, gD2, or both immunogens significantly reduced the frequency of genital lesions, with the bivalent vaccine showing the greatest protection. In study 2, both vaccines were highly protective against genital disease in naive and HSV-1-seropositive animals. Comparisons between gD2 and gC2/gD2 in study 2 must be interpreted cautiously, because different adjuvants, gD2 doses, and antigen production methods were used; however, significant differences invariably favored the bivalent vaccine. Immunization of naive animals with gC2/gD2 significantly reduced the number of days of vaginal shedding of HSV-2 DNA compared with that for mock-immunized animals. Surprisingly, in both studies, immunization of HSV-1-seropositive animals had little effect on recurrent vaginal shedding of HSV-2 DNA, despite significantly reducing genital disease.


Assuntos
Herpes Genital/prevenção & controle , Herpesvirus Humano 1/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas Virais/farmacologia , Análise de Variância , Animais , Anticorpos Neutralizantes/imunologia , Baculoviridae , Células CHO , Cricetinae , Cricetulus , Ensaio de Imunoadsorção Enzimática , Feminino , Cobaias , Injeções Intramusculares , Lipídeo A/análogos & derivados , Pichia , Reação em Cadeia da Polimerase em Tempo Real , Vacinas Virais/administração & dosagem
14.
J Infect Dis ; 210(4): 571-5, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24652496

RESUMO

The Herpevac Trial evaluated a herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit vaccine to prevent genital herpes. Unexpectedly, the vaccine protected against genital HSV-1 infection but not genital HSV-2 infection. We evaluated sera from 30 women seronegative for HSV-1 and HSV-2 who were immunized with gD2 in the Herpevac Trial. Neutralizing antibody titers to HSV-1 were 3.5-fold higher than those to HSV-2 (P < .001). HSV-2 gC2 and gE2 on the virus blocked neutralization by gD2 antibody, while HSV-1 gC1 and gE1 did not block neutralization by gD2 antibody. The higher neutralizing antibody titers to HSV-1 offer an explanation for the Herpevac results, and shielding neutralizing domains provides a potential mechanism.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 2/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Feminino , Herpes Genital/imunologia , Herpes Genital/prevenção & controle , Herpes Simples/imunologia , Herpes Simples/prevenção & controle , Humanos , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia
15.
J Trop Pediatr ; 60(1): 27-32, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23982829

RESUMO

BACKGROUND: Failure to thrive (FTT) is a sign of tuberculosis (TB) and human immunodeficiency virus (HIV) infection. We assessed TB and HIV prevalence in children with FTT at one clinic in Botswana. METHODS: In July 2010, we screened all children attending a 'Well Child' clinic for FTT. Children with FTT were referred to a paediatrician who: (i) assessed causes of FTT, (ii) evaluated for HIV and TB and (iii) reviewed the patient chart for evaluations for TB and HIV. RESULTS: Of 919 children screened, 176 (19%) had FTT. One hundred eighteen (67%) children saw a paediatrician, and of these, 95 (81%) completed the TB evaluation. TB was newly diagnosed in 6 of 95 (6%). At review, HIV status was known in 23 of 118 (19%). Ninety-five had an unknown HIV status. Forty-five (47%) tested for HIV; all tested HIV-negative. CONCLUSION: TB and HIV screening among children with FTT diagnosed TB in 6% of cases completing an evaluation, but no new HIV infections.


Assuntos
Insuficiência de Crescimento/etiologia , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Programas de Rastreamento/métodos , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Botsuana/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/epidemiologia , Feminino , Seguimentos , Infecções por HIV/complicações , Humanos , Lactente , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Ambulatório Hospitalar , Prevalência , Fatores Socioeconômicos , Tuberculose/complicações , População Urbana/estatística & dados numéricos
16.
CEN Case Rep ; 13(1): 59-65, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37273129

RESUMO

Calciphylaxis, also known as Calcific uremic arteriolopathy (CUA), is a serious disorder that presents with skin necrosis due to calcification of dermal and subcutaneous adipose tissue capillaries and arterioles. The condition occurs primarily in patients with end-stage renal disease (ESRD) on dialysis, and it carries high morbidity and mortality, primarily due to sepsis, with an estimated six-month survival of approximately 50%. Although there are no high-quality studies to guide the optimal treatment approach for patients with calciphylaxis, many retrospective studies and case series support treatment with sodium thiosulfate (STS). Despite the frequent use of STS as an off-label treatment, data regarding its safety and efficacy are limited. STS has generally been considered a safe drug with mild side effects. However, severe metabolic acidosis associated with STS is a rare and life-threatening complication of STS treatment and is often unpredictable. Herein, we report a 64-year-old female with ESRD on peritoneal dialysis (PD) who presented with a profound high anion gap metabolic acidosis and severe hyperkalemia while on STS treatment for CUA. No other etiology for her severe metabolic acidosis other than STS was identified. ESRD patients receiving STS should be monitored closely for this side effect. Dose reduction, increasing the duration of infusion, or even discontinuing STS treatment should be considered if severe metabolic acidosis develops.


Assuntos
Acidose , Calciofilaxia , Falência Renal Crônica , Tiossulfatos , Feminino , Humanos , Pessoa de Meia-Idade , Calciofilaxia/diagnóstico , Calciofilaxia/tratamento farmacológico , Calciofilaxia/etiologia , Diálise Renal/efeitos adversos , Estudos Retrospectivos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Acidose/etiologia
17.
Cardiol Res ; 15(2): 125-128, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38645826

RESUMO

Background: Atrial septal defects can allow right to left shunting of venous blood which presents clinically as platypnea-orthodeoxia syndrome. It is believed that concomitant presence of aortic root pathologies increases the likelihood of shunting. Methods: The study included a review of 510 articles listed in PubMed of patients with platypnea-orthodeoxia syndrome. Case reports of patients with extra-cardiac etiologies of platypnea-orthodeoxia were excluded. Results: We reviewed 191 case reports, and 98 cases (51.3%) had evidence of concomitant aortic root pathology. Furthermore, of the remaining 93 case reports, 69 ones excluded any mention of the nature of the aortic root altogether, further suggesting that this is an underreported number. Conclusions: There is a high prevalence of aortic root pathologies in patients with platypnea-orthodeoxia syndrome secondary to intra-cardiac shunts. In patients with unexplained hypoxemia and incidental finding of aortic root pathology, it may be worthwhile to obtain postural oxygen saturation measurements to exclude intra-cardiac shunts as the potential cause.

18.
J Virol ; 86(8): 4586-98, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22318147

RESUMO

A herpes simplex virus 2 (HSV-2) glycoprotein E deletion mutant (gE2-del virus) was evaluated as a replication-competent, attenuated live virus vaccine candidate. The gE2-del virus is defective in epithelial cell-to-axon spread and in anterograde transport from the neuron cell body to the axon terminus. In BALB/c and SCID mice, the gE2-del virus caused no death or disease after vaginal, intravascular, or intramuscular inoculation and was 5 orders of magnitude less virulent than wild-type virus when inoculated directly into the brain. No infectious gE2-del virus was recovered from dorsal root ganglia (DRG) after multiple routes of inoculation; however, gE2-del DNA was detected by PCR in lumbosacral DRG at a low copy number in some mice. Importantly, no recurrent vaginal shedding of gE2-del DNA was detected in immunized guinea pigs. Intramuscular immunization outperformed subcutaneous immunization in all parameters evaluated, although individual differences were not significant, and two intramuscular immunizations were more protective than one. Immunized animals had reduced vaginal disease, vaginal titers, DRG infection, recurrent genital lesions, and recurrent vaginal shedding of HSV-2 DNA; however, protection was incomplete. A combined modality immunization using live virus and HSV-2 glycoprotein C and D subunit antigens in guinea pigs did not totally eliminate recurrent lesions or recurrent vaginal shedding of HSV-2 DNA. The gE2-del virus used as an immunotherapeutic vaccine in previously HSV-2-infected guinea pigs greatly reduced the frequency of recurrent genital lesions. Therefore, the gE2-del virus is safe, other than when injected at high titer into the brain, and is efficacious as a prophylactic and immunotherapeutic vaccine.


Assuntos
Deleção de Genes , Vacinas contra o Vírus do Herpes Simples/imunologia , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/imunologia , Neurônios/virologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linhagem Celular , Chlorocebus aethiops , DNA Viral , Feminino , Gânglios Espinais/virologia , Cobaias , Herpes Genital/mortalidade , Herpes Genital/prevenção & controle , Herpes Genital/terapia , Herpes Simples/mortalidade , Herpes Simples/prevenção & controle , Herpes Simples/terapia , Vacinas contra o Vírus do Herpes Simples/administração & dosagem , Vacinas contra o Vírus do Herpes Simples/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Medula Espinal/virologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia
19.
J Med Cases ; 14(4): 141-147, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37188296

RESUMO

Non-tuberculous mycobacteria (NTM) are ubiquitous organisms in the environment that can potentially cause a range of pulmonary and extrapulmonary infections in humans. Epidemiological risk factors and the host's immune status determine the susceptibility to various clinical syndromes caused by different NTM species. Non-tuberculous mycobacteria pulmonary disease (NTM-PD) is primarily reported in patients with underlying lung disease. These infections often pose a significant disease burden on affected patients as they are often chronic, difficult to treat, and necessitate long-term multi-drug therapy. Mycobacterium avium complex (MAC) is the most common causative pathogen of NTM-PD in the USA, followed by Mycobacterium kansasii (M. kansasii). Less common species in the USA include Mycobacterium xenopi (M. xenopi), Mycobacterium abscessus, and others, largely depending upon the geographic location and exposure to species-specific predisposing risks. In this case series, the authors report on three elderly patients with chronic lung diseases who had pulmonary NTM disease caused by M. xenopi and MAC. The patients were encountered in both inpatient and outpatient settings from a community-based hospital in the midwestern USA. The clinical and radiological features of NTM-PD masqueraded as malignancy and posed a diagnostic dilemma. The epidemiology, clinical and radiological features, diagnosis, and management of NTM-PD are reviewed in this report.

20.
Viruses ; 15(4)2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-37112875

RESUMO

Herpes simplex virus (HSV) requires four essential virion glycoproteins-gD, gH, gL, and gB-for virus entry and cell fusion. To initiate fusion, the receptor binding protein gD interacts with one of two major cell receptors, HVEM or nectin-1. Once gD binds to a receptor, fusion is carried out by the gH/gL heterodimer and gB. A comparison of free and receptor-bound gD crystal structures revealed that receptor binding domains are located within residues in the N-terminus and core of gD. Problematically, the C-terminus lies across and occludes these binding sites. Consequentially, the C-terminus must relocate to allow for both receptor binding and the subsequent gD interaction with the regulatory complex gH/gL. We previously constructed a disulfide bonded (K190C/A277C) protein that locked the C-terminus to the gD core. Importantly, this mutant protein bound receptor but failed to trigger fusion, effectively separating receptor binding and gH/gL interaction. Here, we show that "unlocking" gD by reducing the disulfide bond restored not only gH/gL interaction but fusion activity as well, confirming the importance of C-terminal movement in triggering the fusion cascade. We characterize these changes, showing that the C-terminus region exposed by unlocking is: (1) a gH/gL binding site; (2) contains epitopes for a group (competition community) of monoclonal antibodies (Mabs) that block gH/gL binding to gD and cell-cell fusion. Here, we generated 14 mutations within the gD C-terminus to identify residues important for the interaction with gH/gL and the key conformational changes involved in fusion. As one example, we found that gD L268N was antigenically correct in that it bound most Mabs but was impaired in fusion, exhibited compromised binding of MC14 (a Mab that blocks both gD-gH/gL interaction and fusion), and failed to bind truncated gH/gL, all events that are associated with the inhibition of C-terminus movement. We conclude that, within the C-terminus, residue 268 is essential for gH/gL binding and induction of conformational changes and serves as a flexible inflection point in the critical movement of the gD C-terminus.


Assuntos
Simplexvirus , Proteínas do Envelope Viral , Simplexvirus/genética , Proteínas do Envelope Viral/metabolismo , Ligação Proteica , Glicoproteínas/metabolismo , Dissulfetos , Internalização do Vírus
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