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1.
Nat Immunol ; 21(7): 790-801, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32424361

RESUMO

Plasmodium parasite-specific antibodies are critical for protection against malaria, yet the development of long-lived and effective humoral immunity against Plasmodium takes many years and multiple rounds of infection and cure. Here, we report that the rapid development of short-lived plasmablasts during experimental malaria unexpectedly hindered parasite control by impeding germinal center responses. Metabolic hyperactivity of plasmablasts resulted in nutrient deprivation of the germinal center reaction, limiting the generation of memory B cell and long-lived plasma cell responses. Therapeutic administration of a single amino acid to experimentally infected mice was sufficient to overcome the metabolic constraints imposed by plasmablasts and enhanced parasite clearance and the formation of protective humoral immune memory responses. Thus, our studies not only challenge the current model describing the role and function of blood-stage Plasmodium-induced plasmablasts but they also reveal new targets and strategies to improve anti-Plasmodium humoral immunity.


Assuntos
Imunidade Humoral , Malária/imunologia , Plasmócitos/metabolismo , Plasmodium falciparum/imunologia , Adolescente , Adulto , Aminoácidos/administração & dosagem , Aminoácidos/metabolismo , Animais , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Anticorpos Antiprotozoários/metabolismo , Antimaláricos/administração & dosagem , DNA de Protozoário/isolamento & purificação , Modelos Animais de Doenças , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Interações Hospedeiro-Parasita/imunologia , Humanos , Malária/sangue , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Nutrientes/metabolismo , Plasmócitos/imunologia , Plasmócitos/parasitologia , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Estudo de Prova de Conceito , Adulto Jovem
2.
Immunity ; 42(3): 580-90, 2015 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-25786180

RESUMO

Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C') inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C' inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.


Assuntos
Anticorpos Antiprotozoários/biossíntese , Complemento C1q/metabolismo , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Merozoítos/imunologia , Parasitemia/prevenção & controle , Plasmodium falciparum/imunologia , Adolescente , Animais , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Criança , Pré-Escolar , Testes de Fixação de Complemento , Via Clássica do Complemento , Eritrócitos/imunologia , Eritrócitos/parasitologia , Feminino , Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Imunoglobulina G/biossíntese , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Masculino , Proteína 1 de Superfície de Merozoito/antagonistas & inibidores , Proteína 1 de Superfície de Merozoito/genética , Proteína 1 de Superfície de Merozoito/imunologia , Parasitemia/imunologia , Parasitemia/parasitologia , Estudos Prospectivos , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia
3.
Environ Res ; 244: 117940, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38101724

RESUMO

BACKGROUND: Vibrio spp. naturally occur in warm water with moderate salinity. Infections with non-cholera Vibrio (vibriosis) cause an estimated 80,000 illnesses and 100 fatalities each year in the United States. Climate associated changes to environmental parameters in aquatic ecosystems are largely promoting Vibrio growth, and increased incidence of vibriosis is being reported globally. However, vibriosis trends in the northeastern U.S. (e.g., Maryland) have not been evaluated since 2008. METHODS: Vibriosis case data for Maryland (2006-2019; n = 611) were obtained from the COVIS database. Incidence rates were calculated using U.S. Census Bureau population estimates for Maryland. A logistic regression model, including region, age group, race, gender, occupation, and exposure type, was used to estimate the likelihood of hospitalization. RESULTS: Comparing the 2006-2012 and 2013-2019 periods, there was a 39% (p = 0.01) increase in the average annual incidence rate (per 100,000 population) of vibriosis, with V. vulnificus infections seeing the greatest percentage increase (53%, p = 0.01), followed by V. parahaemolyticus (47%, p = 0.05). The number of hospitalizations increased by 58% (p = 0.01). Since 2010, there were more reported vibriosis cases with a hospital duration ≥10 days. Patients from the upper eastern shore region and those over the age of 65 were more likely (OR = 6.8 and 12.2) to be hospitalized compared to other patients. CONCLUSIONS: Long-term increases in Vibrio infections, notably V. vulnificus wound infections, are occurring in Maryland. This trend, along with increased rates in hospitalizations and average hospital durations, underscore the need to improve public awareness, water monitoring, post-harvest seafood interventions, and environmental forecasting ability.


Assuntos
Vibrioses , Vibrio parahaemolyticus , Vibrio vulnificus , Estados Unidos/epidemiologia , Humanos , Maryland/epidemiologia , Incidência , Ecossistema , Vibrioses/epidemiologia , Água
4.
Immunol Rev ; 293(1): 70-87, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674682

RESUMO

Malaria is a major global health problem. Despite decades of research, there is still no effective vaccine to prevent disease in the majority of people living in malaria-endemic regions. Additionally, drug treatment options are continually threatened by the emergence of drug-resistant parasites. Immune responses generated against Plasmodium parasites that cause malaria are generally not sufficient to prevent the establishment of infection and can even contribute to the development of disease, unless individuals have survived multiple infections. Research conducted in experimental models, controlled human malaria infection studies, and with malaria patients from disease-endemic areas indicate the rapid development of immunoregulatory pathways in response to Plasmodium infection. These "imprinted" immune responses limit inflammation, and likely prevent progression to severe disease manifestations. However, they also cause slow acquisition of immunity and possibly hamper the development of vaccine-mediated protection against disease. A major target for and mediator of the immunoregulatory pathways established during malaria are CD4+ T cells that play critical roles in priming phagocytic cells to capture and kill malaria parasites, as well as helping B cells produce functional anti-parasitic antibodies. In this review, we describe mechanisms of CD4+ T cell activation during malaria and discuss the immunoregulatory mechanisms that develop to dampen their anti-parasitic and pathological functions. We also offer some ideas about how host-directed approaches might be applied to modulate CD4+ T cell functions to improve vaccine responses and enhance development of natural immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interações Hospedeiro-Parasita/imunologia , Imunomodulação , Malária/imunologia , Plasmodium/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Ativação Linfocitária/imunologia , Malária/tratamento farmacológico , Malária/metabolismo , Malária/parasitologia , Camundongos , Terapia de Alvo Molecular , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Receptores Toll-Like/metabolismo
5.
Immunol Rev ; 293(1): 38-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31556468

RESUMO

Developing efficacious vaccines for human malaria caused by Plasmodium falciparum is a major global health priority, although this has proven to be immensely challenging over the decades. One major hindrance is the incomplete understanding of specific immune responses that confer protection against disease and/or infection. While antibodies to play a crucial role in malaria immunity, the functional mechanisms of these antibodies remain unclear as most research has primarily focused on the direct inhibitory or neutralizing activity of antibodies. Recently, there is a growing body of evidence that antibodies can also mediate effector functions through activating the complement system against multiple developmental stages of the parasite life cycle. These antibody-complement interactions can have detrimental consequences to parasite function and viability, and have been significantly associated with protection against clinical malaria in naturally acquired immunity, and emerging findings suggest these mechanisms could contribute to vaccine-induced immunity. In order to develop highly efficacious vaccines, strategies are needed that prioritize the induction of antibodies with enhanced functional activity, including the ability to activate complement. Here we review the role of complement in acquired immunity to malaria, and provide insights into how this knowledge could be used to harness complement in malaria vaccine development.


Assuntos
Proteínas do Sistema Complemento/imunologia , Interações Hospedeiro-Parasita/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Ativação do Complemento/imunologia , Modelos Animais de Doenças , Eritrócitos/imunologia , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Humanos , Imunidade Inata , Imunização Passiva , Vacinas Antimaláricas/administração & dosagem , Plasmodium falciparum/crescimento & desenvolvimento
6.
Emerg Infect Dis ; 29(6): 1183-1190, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37209671

RESUMO

Shiga toxin-producing Escherichia coli (STEC) causes acute diarrheal illness. To determine risk factors for non-O157 STEC infection, we enrolled 939 patients and 2,464 healthy controls in a case-control study conducted in 10 US sites. The highest population-attributable fractions for domestically acquired infections were for eating lettuce (39%), tomatoes (21%), or at a fast-food restaurant (23%). Exposures with 10%-19% population attributable fractions included eating at a table service restaurant, eating watermelon, eating chicken, pork, beef, or iceberg lettuce prepared in a restaurant, eating exotic fruit, taking acid-reducing medication, and living or working on or visiting a farm. Significant exposures with high individual-level risk (odds ratio >10) among those >1 year of age who did not travel internationally were all from farm animal environments. To markedly decrease the number of STEC-related illnesses, prevention measures should focus on decreasing contamination of produce and improving the safety of foods prepared in restaurants.


Assuntos
Infecções por Escherichia coli , Escherichia coli Shiga Toxigênica , Animais , Bovinos , Estados Unidos/epidemiologia , Infecções por Escherichia coli/epidemiologia , Estudos de Casos e Controles , Fatores de Risco , Diarreia/epidemiologia
7.
MMWR Morb Mortal Wkly Rep ; 72(26): 701-706, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37384552

RESUMO

Each year, infections from major foodborne pathogens are responsible for an estimated 9.4 million illnesses, 56,000 hospitalizations, and 1,350 deaths in the United States (1). To evaluate progress toward prevention of enteric infections in the United States, the Foodborne Diseases Active Surveillance Network (FoodNet) conducts surveillance for laboratory-diagnosed infections caused by eight pathogens transmitted commonly through food at 10 U.S. sites. During 2020-2021, FoodNet detected decreases in many infections that were due to behavioral modifications, public health interventions, and changes in health care-seeking and testing practices during the COVID-19 pandemic. This report presents preliminary estimates of pathogen-specific annual incidences during 2022, compared with average annual incidences during 2016-2018, the reference period for the U.S. Department of Health and Human Services' Healthy People 2030 targets (2). Many pandemic interventions ended by 2022, resulting in a resumption of outbreaks, international travel, and other factors leading to enteric infections. During 2022, annual incidences of illnesses caused by the pathogens Campylobacter, Salmonella, Shigella, and Listeria were similar to average annual incidences during 2016-2018; however, incidences of Shiga toxin-producing Escherichia coli (STEC), Yersinia, Vibrio, and Cyclospora illnesses were higher. Increasing culture-independent diagnostic test (CIDT) usage likely contributed to increased detection by identifying infections that would have remained undetected before widespread CIDT usage. Reducing pathogen contamination during poultry slaughter and processing of leafy greens requires collaboration among food growers and processors, retail stores, restaurants, and regulators.


Assuntos
COVID-19 , Doenças Transmitidas por Alimentos , Humanos , Animais , Incidência , Pandemias , Conduta Expectante , COVID-19/epidemiologia , Doenças Transmitidas por Alimentos/epidemiologia
8.
Foodborne Pathog Dis ; 20(4): 123-131, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37015074

RESUMO

Vibrio parahaemolyticus is the leading cause of seafood-related foodborne illness globally. In 2018, the U.S. federal, state, and local public health and regulatory partners investigated a multistate outbreak of V. parahaemolyticus infections linked to crabmeat that resulted in 26 ill people and nine hospitalizations. State and U.S. Food and Drug Administration (FDA) laboratories recovered V. parahaemolyticus, Salmonella spp., and Listeria monocytogenes isolates from crabmeat samples collected from various points of distribution and conducted phylogenetic analyses of whole-genome sequencing data. Federal, state, and local partners conducted traceback investigations to determine the source of crabmeat. Multiple Venezuelan processors that supplied various brands of crabmeat were identified, but a sole firm was not confirmed as the source of the outbreak. Travel restrictions between the United States and Venezuela prevented FDA officials from conducting on-site inspections of cooked crabmeat processors. Based on investigation findings, partners developed public communications advising consumers not to eat crabmeat imported from Venezuela and placed potentially implicated firms on import alerts. While some challenges limited the scope of the investigation, epidemiologic, traceback, and laboratory evidence identified the contaminated food and country of origin, and contributed to public health and regulatory actions, preventing additional illnesses. This multistate outbreak illustrates the importance of adhering to appropriate food safety practices and regulations for imported seafood.


Assuntos
Doenças Transmitidas por Alimentos , Vibrioses , Vibrio parahaemolyticus , Humanos , Estados Unidos/epidemiologia , Filogenia , Venezuela/epidemiologia , Doenças Transmitidas por Alimentos/epidemiologia , Vibrioses/epidemiologia , Surtos de Doenças
9.
Antimicrob Agents Chemother ; 66(1): e0158421, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34694880

RESUMO

Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants ages 18 to 55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for 3 days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether), and lumefantrine exposure were not affected by ruxolitinib coadministration. Ruxolitinib coadministration resulted in a 3-fold-greater pSTAT3 inhibition compared to placebo (geometric mean ratio = 3.01 [90% confidence interval = 2.14 to 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634.).


Assuntos
Antimaláricos , Malária Falciparum , Adolescente , Adulto , Antimaláricos/efeitos adversos , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Feminino , Fluorenos/uso terapêutico , Humanos , Lumefantrina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Nitrilas , Pirazóis , Pirimidinas , Método Simples-Cego , Adulto Jovem
10.
MMWR Morb Mortal Wkly Rep ; 71(21): 709-712, 2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35617142

RESUMO

Listeriosis is a serious infection usually caused by eating food contaminated with the bacterium Listeria monocytogenes. An estimated 1,600 persons become ill with listeriosis each year, among whom approximately 260 die. Persons at higher risk for listeriosis include pregnant persons and their newborns, adults aged ≥65 years, and persons with weakened immune systems. Persons with invasive listeriosis usually report symptoms starting 1-4 weeks after eating food contaminated with L. monocytogenes; however, some persons who become infected have reported symptoms starting as late as 70 days after exposure or as early as the same day of exposure (1). On January 29, 2021, PulseNet, the national molecular subtyping surveillance network coordinated by CDC, identified a multistate cluster of three L. monocytogenes infections: two from Maryland and one from Connecticut (2). CDC, the Food and Drug Administration (FDA), and state and local partners began an investigation on February 1, 2021. A total of 13 outbreak-related cases were eventually identified from four states. All patients reported Hispanic ethnicity; 12 patients were hospitalized, and one died. Rapid food testing and record collection by regulatory agencies enabled investigators to identify a brand of queso fresco made with pasteurized milk as the likely source of the outbreak, leading to an initial product recall on February 19, 2021. Fresh, soft Hispanic-style cheeses made with pasteurized milk are a well-documented source of listeriosis outbreaks. These cheeses can be contaminated with L. monocytogenes unless stringent hygienic controls are implemented, and the processing environment is monitored for contamination (3). U.S. public health agencies should establish or improve communications, including new methods of disseminating information that also effectively reach Hispanic populations, to emphasize the risk from eating fresh, soft Hispanic-style cheeses, even those made with pasteurized milk.


Assuntos
Queijo , Listeria monocytogenes , Listeriose , Adulto , Queijo/microbiologia , Surtos de Doenças , Feminino , Contaminação de Alimentos , Microbiologia de Alimentos , Hispânico ou Latino , Humanos , Recém-Nascido , Listeriose/epidemiologia , Gravidez , Estados Unidos/epidemiologia
11.
MMWR Morb Mortal Wkly Rep ; 71(40): 1260-1264, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36201372

RESUMO

To evaluate progress toward prevention of enteric infections in the United States, the Foodborne Diseases Active Surveillance Network (FoodNet) conducts active population-based surveillance for laboratory-diagnosed infections caused by Campylobacter, Cyclospora, Listeria, Salmonella, Shiga toxin-producing Escherichia coli (STEC), Shigella, Vibrio, and Yersinia at 10 U.S. sites. This report summarizes preliminary 2021 data and describes changes in annual incidence compared with the average annual incidence for 2016-2018, the reference period for the U.S. Department of Health and Human Services' (HHS) Healthy People 2030 goals for some pathogens (1). During 2021, the incidence of infections caused by Salmonella decreased, incidence of infections caused by Cyclospora, Yersinia, and Vibrio increased, and incidence of infections caused by other pathogens did not change. As in 2020, behavioral modifications and public health interventions implemented to control the COVID-19 pandemic might have decreased transmission of enteric infections (2). Other factors (e.g., increased use of telemedicine and continued increase in use of culture-independent diagnostic tests [CIDTs]) might have altered their detection or reporting (2). Much work remains to achieve HHS Healthy People 2030 goals, particularly for Salmonella infections, which are frequently attributed to poultry products and produce, and Campylobacter infections, which are frequently attributed to chicken products (3).


Assuntos
COVID-19 , Doenças Transmitidas por Alimentos , Vibrio , Doenças Transmitidas por Alimentos/epidemiologia , Humanos , Incidência , Pandemias , Vigilância da População , Salmonella , Estados Unidos/epidemiologia , Conduta Expectante
12.
J Infect Dis ; 224(7): 1128-1138, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32236404

RESUMO

BACKGROUND: RTS,S is the leading malaria vaccine candidate but only confers partial efficacy against malaria in children. RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection; however, it is unclear how these protective antibodies function. METHODS: We quantified the induction of functional anti-CSP antibody responses in healthy malaria-naive adults (N = 45) vaccinated with RTS,S/AS01. This included the ability to mediate effector functions via the fragment crystallizable (Fc) region, such as interacting with human complement proteins and Fcγ-receptors (FcγRs) that are expressed on immune cells, which promote various immunological functions. RESULTS: Our major findings were (1) RTS,S-induced antibodies mediated Fc-dependent effector functions, (2) functional antibodies were generally highest after the second vaccine dose, (3) functional antibodies targeted multiple regions of CSP, (4) participants with higher levels of functional antibodies had a reduced probability of developing parasitemia following homologous challenge (P < .05), and (5) nonprotected subjects had higher levels of anti-CSP IgM. CONCLUSIONS: Our data suggest a role for Fc-dependent antibody effector functions in RTS,S-induced immunity. Enhancing the induction of these functional activities may be a strategy to improve the protective efficacy of RTS,S or other malaria vaccines. CLINICAL TRIALS REGISTRATION: NCT00075049.


Assuntos
Anticorpos Antiprotozoários/sangue , Vacinas Antimaláricas/administração & dosagem , Malária/prevenção & controle , Eficácia de Vacinas , Antígenos de Protozoários , Humanos , Malária/sangue , Vacinas Antimaláricas/imunologia , Proteínas de Protozoários
13.
Immunol Cell Biol ; 99(2): 126-129, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33152796

RESUMO

We discuss the study by McNamara et al., who report that low levels of antigen-specific antibodies in serum can limit the boosting of antibody and B-cell responses following immunization with live attenuated malaria sporozoites.


Assuntos
Vacinas Antimaláricas , Malária , Animais , Anticorpos Antiprotozoários , Epitopos , Malária/prevenção & controle , Esporozoítos/imunologia
14.
BMC Med ; 19(1): 201, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34425801

RESUMO

BACKGROUND: The pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells (pRBCs) in the placenta, contributing to poor pregnancy outcomes. Parasite accumulation is primarily mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). Magnitude of IgG to pRBCs has been associated with reduced risk of MiP in some studies, but associations have been inconsistent. Further, antibody effector mechanisms are poorly understood, and the role of antibody complement interactions is unknown. METHODS: Studying a longitudinal cohort of pregnant women (n=302) from a malaria-endemic province in Papua New Guinea (PNG), we measured the ability of antibodies to fix and activate complement using placental binding pRBCs and PfEMP1 recombinant domains. We determined antibody-mediated complement inhibition of pRBC binding to the placental receptor, chondroitin sulfate A (CSA), and associations with protection against placental parasitemia. RESULTS: Some women acquired antibodies that effectively promoted complement fixation on placental-binding pRBCs. Complement fixation correlated with IgG1 and IgG3 antibodies, which dominated the response. There was, however, limited evidence for membrane attack complex activity or pRBC lysis or killing. Importantly, a higher magnitude of complement fixing antibodies was prospectively associated with reduced odds of placental infection at delivery. Using genetically modified P. falciparum and recombinant PfEMP1 domains, we found that complement-fixing antibodies primarily targeted a specific variant of PfEMP1 (known as VAR2CSA). Furthermore, complement enhanced the ability of antibodies to inhibit pRBC binding to CSA, which was primarily mediated by complement C1q protein. CONCLUSIONS: These findings provide new insights into mechanisms mediating immunity to MiP and reveal potential new strategies for developing malaria vaccines that harness antibody-complement interactions.


Assuntos
Malária Falciparum , Complicações Parasitárias na Gravidez , Anticorpos Antiprotozoários , Antígenos de Protozoários , Eritrócitos , Feminino , Humanos , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Parasitemia , Placenta , Plasmodium falciparum , Gravidez , Resultado da Gravidez , Gestantes
15.
BMC Med ; 19(1): 293, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34802442

RESUMO

BACKGROUND: There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes. METHODS: The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 105 (2 subjects), or 3 × 106 viable parasites (4 subjects). Parasitemia was measured using qPCR; immunogenicity was determined using standard assays. Parasites were rescued into culture for in vitro analyses (genome sequencing, cytoadhesion assays, scanning electron microscopy, var gene expression). RESULTS: None of the subjects who were administered with 1800 or 1.8 × 105 parasites developed parasitemia; 3/4 subjects administered 3× 106 parasites developed significant parasitemia, first detected on days 13, 18, and 22. One of these three subjects developed symptoms of malaria simultaneously with influenza B (day 17; 14,022 parasites/mL); one subject developed mild symptoms on day 28 (19,956 parasites/mL); and one subject remained asymptomatic up to day 35 (5046 parasites/mL). Parasitemia rapidly cleared with artemether/lumefantrine. Parasitemia induced a parasite-specific antibody and cell-mediated immune response. Parasites cultured ex vivo exhibited genotypic and phenotypic properties similar to inoculated parasites, although the var gene expression profile changed during growth in vivo. CONCLUSIONS: This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp- strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (number: ACTRN12617000824369 ; date: 06 June 2017).


Assuntos
Antimaláricos , Vacinas Antimaláricas , Malária Falciparum , Malária , Antimaláricos/uso terapêutico , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Austrália , Humanos , Malária/tratamento farmacológico , Vacinas Antimaláricas/efeitos adversos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Masculino , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Desenvolvimento de Vacinas , Vacinas Atenuadas/efeitos adversos
16.
MMWR Morb Mortal Wkly Rep ; 70(38): 1332-1336, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34555002

RESUMO

Foodborne illnesses are a substantial and largely preventable public health problem; before 2020 the incidence of most infections transmitted commonly through food had not declined for many years. To evaluate progress toward prevention of foodborne illnesses in the United States, the Foodborne Diseases Active Surveillance Network (FoodNet) of CDC's Emerging Infections Program monitors the incidence of laboratory-diagnosed infections caused by eight pathogens transmitted commonly through food reported by 10 U.S. sites.* FoodNet is a collaboration among CDC, 10 state health departments, the U.S. Department of Agriculture's Food Safety and Inspection Service (USDA-FSIS), and the Food and Drug Administration. This report summarizes preliminary 2020 data and describes changes in incidence with those during 2017-2019. During 2020, observed incidences of infections caused by enteric pathogens decreased 26% compared with 2017-2019; infections associated with international travel decreased markedly. The extent to which these reductions reflect actual decreases in illness or decreases in case detection is unknown. On March 13, 2020, the United States declared a national emergency in response to the COVID-19 pandemic. After the declaration, state and local officials implemented stay-at-home orders, restaurant closures, school and child care center closures, and other public health interventions to slow the spread of SARS-CoV-2, the virus that causes COVID-19 (1). Federal travel restrictions were declared (1). These widespread interventions as well as other changes to daily life and hygiene behaviors, including increased handwashing, have likely changed exposures to foodborne pathogens. Other factors, such as changes in health care delivery, health care-seeking behaviors, and laboratory testing practices, might have decreased the detection of enteric infections. As the pandemic continues, surveillance of illness combined with data from other sources might help to elucidate the factors that led to the large changes in 2020; this understanding could lead to improved strategies to prevent illness. To reduce the incidence of these infections concerted efforts are needed, from farm to processing plant to restaurants and homes. Consumers can reduce their risk of foodborne illness by following safe food-handling and preparation recommendations.


Assuntos
COVID-19/epidemiologia , Microbiologia de Alimentos/estatística & dados numéricos , Parasitologia de Alimentos/estatística & dados numéricos , Doenças Transmitidas por Alimentos/epidemiologia , Pandemias , Conduta Expectante , Adolescente , Criança , Pré-Escolar , Doenças Transmitidas por Alimentos/microbiologia , Doenças Transmitidas por Alimentos/parasitologia , Humanos , Incidência , Lactente , Estados Unidos/epidemiologia
17.
Malar J ; 20(1): 97, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33593383

RESUMO

BACKGROUND: Plasmodium falciparum malaria increases plasma levels of the cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic factor associated with dendritic cell (DC) expansion. It is unknown if the zoonotic parasite Plasmodium knowlesi impacts Flt3L or DC in human malaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection. METHODS: Plasma Flt3L concentration and blood CD141+ DC, CD1c+ DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected with P. falciparum and in Malaysian patients with uncomplicated (ii) P. falciparum or (iii) P. knowlesi malaria. RESULTS: Plasmodium knowlesi caused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acute P. falciparum and P. knowlesi malaria with no increase in a subclinical experimental infection. Circulating CD141+ DCs, CD1c+ DCs and pDCs declined in all adults tested, for the first time extending the finding of DC subset decline in acute malaria to the zoonotic parasite P. knowlesi. CONCLUSIONS: In adults, submicroscopic Plasmodium infection causes no change in plasma Flt3L but does reduce circulating DCs. Plasma Flt3L concentrations increase in acute malaria, yet this increase is insufficient to restore or expand circulating CD141+ DCs, CD1c+ DCs or pDCs. These data imply that haematopoietic factors, yet to be identified and not Flt3L, involved in the sensing/maintenance of circulating DC are impacted by malaria and a submicroscopic infection. The zoonotic P. knowlesi is similar to other Plasmodium spp in compromising DC in adult malaria.


Assuntos
Células Dendríticas/metabolismo , Malária/parasitologia , Proteínas de Membrana/sangue , Doença Aguda , Adulto , Feminino , Humanos , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Plasma/química , Plasmodium falciparum/fisiologia , Plasmodium knowlesi/fisiologia , Adulto Jovem
18.
Epidemiol Infect ; 150: e16, 2021 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-35060456

RESUMO

Leafy green vegetables are a common source of Shiga toxin-producing Escherichia coli O157:H7 (STEC O157) foodborne illness outbreaks. Ruminant animals, primarily cattle, are the major reservoir of STEC O157. Epidemiological, traceback and field investigations were conducted to identify potential outbreak sources. Product and environmental samples were tested for STEC. A reoccurring strain of STEC O157 caused two multistate outbreaks linked to romaine lettuce in 2018 and 2019, resulting in 234 illnesses in 33 states. Over 80% of patients interviewed consumed romaine lettuce before illness. The romaine lettuce was sourced from two California growing regions: Santa Maria and Salinas Valley in 2018 and Salinas Valley in 2019. The outbreak strain was isolated from environmental samples collected at sites >90 miles apart across growing regions, as well as from romaine-containing products in 2019. Although the definitive route of romaine contamination was undetermined, use of a contaminated agricultural water reservoir in 2018 and contamination from cattle grazing on adjacent land in 2019 were suspected as possible factors. Preventing lettuce contamination from growth to consumption is imperative to preventing illness. These outbreaks highlight the need to further understand mechanisms of romaine contamination, including the role of environmental or animal reservoirs for STEC O157.


Assuntos
Surtos de Doenças , Infecções por Escherichia coli/epidemiologia , Escherichia coli O157/isolamento & purificação , Doenças Transmitidas por Alimentos/epidemiologia , Lactuca/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Infecções por Escherichia coli/microbiologia , Escherichia coli O157/genética , Feminino , Microbiologia de Alimentos , Doenças Transmitidas por Alimentos/microbiologia , Genoma Bacteriano/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Adulto Jovem
19.
Environ Health ; 20(1): 105, 2021 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-34537076

RESUMO

BACKGROUND: Infections with nontyphoidal Salmonella cause an estimated 19,336 hospitalizations each year in the United States. Sources of infection can vary by state and include animal and plant-based foods, as well as environmental reservoirs. Several studies have recognized the importance of increased ambient temperature and precipitation in the spread and persistence of Salmonella in soil and food. However, the impact of extreme weather events on Salmonella infection rates among the most prevalent serovars, has not been fully evaluated across distinct U.S. regions. METHODS: To address this knowledge gap, we obtained Salmonella case data for S. Enteriditis, S. Typhimurium, S. Newport, and S. Javiana (2004-2014; n = 32,951) from the Foodborne Diseases Active Surveillance Network (FoodNet), and weather data from the National Climatic Data Center (1960-2014). Extreme heat and precipitation events for the study period (2004-2014) were identified using location and calendar day specific 95th percentile thresholds derived using a 30-year baseline (1960-1989). Negative binomial generalized estimating equations were used to evaluate the association between exposure to extreme events and salmonellosis rates. RESULTS: We observed that extreme heat exposure was associated with increased rates of infection with S. Newport in Maryland (Incidence Rate Ratio (IRR): 1.07, 95% Confidence Interval (CI): 1.01, 1.14), and Tennessee (IRR: 1.06, 95% CI: 1.04, 1.09), both FoodNet sites with high densities of animal feeding operations (e.g., broiler chickens and cattle). Extreme precipitation events were also associated with increased rates of S. Javiana infections, by 22% in Connecticut (IRR: 1.22, 95% CI: 1.10, 1.35) and by 5% in Georgia (IRR: 1.05, 95% CI: 1.01, 1.08), respectively. In addition, there was an 11% (IRR: 1.11, 95% CI: 1.04-1.18) increased rate of S. Newport infections in Maryland associated with extreme precipitation events. CONCLUSIONS: Overall, our study suggests a stronger association between extreme precipitation events, compared to extreme heat, and salmonellosis across multiple U.S. regions. In addition, the rates of infection with Salmonella serovars that persist in environmental or plant-based reservoirs, such as S. Javiana and S. Newport, appear to be of particular significance regarding increased heat and rainfall events.


Assuntos
Mudança Climática , Clima Extremo , Doenças Transmitidas por Alimentos/epidemiologia , Infecções por Salmonella/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Monitoramento Epidemiológico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Risco , Estados Unidos , Adulto Jovem
20.
Environ Res ; 188: 109773, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32559686

RESUMO

Campylobacter is a leading cause of bacterial foodborne illness in the United States. Campylobacter infections have most often been associated with food-related risk factors, such as the consumption of poultry and raw milk. Socioeconomic, agricultural and environmental factors, including drinking water source, can also influence the risk of campylobacteriosis. Approximately 19% of Maryland residents rely on private wells as their sole source of water. Given that the federal Safe Drinking Water Act does not regulate the water quality of private wells, these could be important non-foodborne transmission pathways for Campylobacter. To address this issue, data on the number of culture-confirmed cases of Campylobacter infection in Maryland between 2007 and 2016 were obtained from the Foodborne Diseases Active Surveillance Network. Cases were linked by zip code with data from the Maryland well permits registry, the 2010 U.S. Census, the 2016 American Community Survey, and the USDA Agricultural Census. Campylobacteriosis incidence rates and well prevalence were calculated by zip code. Negative binomial regression models were then constructed to evaluate the association between the prevalence of private wells, presence/absence of animal feeding operations and the incidence of campylobacteriosis across the physiographic provinces in Maryland. From 2007 to 2016, a total of 5746 cases of campylobacteriosis were reported in Maryland, and annual incidence rates ranged from 6.65 to 11.59 per 100,000 people. In our statewide analysis, a significant positive association was observed between well prevalence and increased campylobacteriosis incidence at the zip code level (Incidence Rate Ratio (IRR) = 1.35, 95% Confidence Interval (CI) = 1.11, 1.63). A significant positive association was also observed between well prevalence and increased campylobacteriosis incidence in the Appalachian and Coastal provinces of Maryland (IRR = 2.94, 95% CI = 1.11, 7.76 and IRR = 1.70, 95% CI = 1.25, 2.31, respectively). The presence of broiler chicken operations, increasing median age and percentage of residents living in poverty were also significantly associated with campylobacteriosis incidence at the zip code level in some physiographic provinces in Maryland. To our knowledge, these are the first US data to demonstrate an association between prevalence of private wells and campylobacteriosis incidence at the zip code level.


Assuntos
Infecções por Campylobacter , Campylobacter , Água Potável , Doenças Transmitidas por Alimentos , Animais , Infecções por Campylobacter/epidemiologia , Galinhas , Doenças Transmitidas por Alimentos/epidemiologia , Humanos , Incidência , Maryland/epidemiologia , Estados Unidos/epidemiologia , Conduta Expectante
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