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1.
Nature ; 623(7985): 149-156, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37880367

RESUMO

Host factors that mediate Leishmania genetic exchange are not well defined. Here we demonstrate that natural IgM (IgMn)1-4 antibodies mediate parasite genetic exchange by inducing the transient formation of a spherical parasite clump that promotes parasite fusion and hybrid formation. We establish that IgMn from Leishmania-free animals binds to the surface of Leishmania parasites to induce significant changes in the expression of parasite transcripts and proteins. Leishmania binding to IgMn is partially lost after glycosidase treatment, although parasite surface phosphoglycans, including lipophosphoglycan, are not required for IgMn-induced parasite clumping. Notably, the transient formation of parasite clumps is essential for Leishmania hybridization in vitro. In vivo, we observed a 12-fold increase in hybrid formation in sand flies provided a second blood meal containing IgMn compared with controls. Furthermore, the generation of recombinant progeny from mating hybrids and parental lines were only observed in sand flies provided with IgMn. Both in vitro and in vivo IgM-induced Leishmania crosses resulted in full genome hybrids that show equal patterns of biparental contribution. Leishmania co-option of a host natural antibody to facilitate mating in the insect vector establishes a new paradigm of parasite-host-vector interdependence that contributes to parasite diversity and fitness by promoting genetic exchange.


Assuntos
Interações Hospedeiro-Parasita , Imunoglobulina M , Leishmania , Psychodidae , Reprodução , Animais , Hibridização Genética , Imunoglobulina M/imunologia , Leishmania/genética , Leishmania/imunologia , Psychodidae/imunologia , Psychodidae/parasitologia , Reprodução/genética , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Regulação da Expressão Gênica , Glicosídeo Hidrolases/metabolismo
2.
PLoS Pathog ; 20(9): e1012527, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39250503

RESUMO

Intracellular pathogens that replicate in host myeloid cells have devised ways to inhibit the cell's killing machinery. Pyroptosis is one of the host strategies used to reduce the pathogen replicating niche and thereby control its expansion. The intracellular Leishmania parasites can survive and use neutrophils as a silent entry niche, favoring subsequent parasite dissemination into the host. Here, we show that Leishmania mexicana induces NLRP1- and caspase-1-dependent Gasdermin D (GSDMD)-mediated pyroptosis in neutrophils, a process critical to control the parasite-induced pathology. In the absence of GSDMD, we observe an increased number of infected dermal neutrophils two days post-infection. Using adoptive neutrophil transfer in neutropenic mice, we show that pyroptosis contributes to the regulation of the neutrophil niche early after infection. The critical role of neutrophil pyroptosis and its positive influence on the regulation of the disease outcome was further demonstrated following infection of mice with neutrophil-specific deletion of GSDMD. Thus, our study establishes neutrophil pyroptosis as a critical regulator of leishmaniasis pathology.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Leishmaniose Cutânea , Neutrófilos , Proteínas de Ligação a Fosfato , Piroptose , Animais , Neutrófilos/metabolismo , Neutrófilos/imunologia , Proteínas de Ligação a Fosfato/metabolismo , Camundongos , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/parasitologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Reguladoras de Apoptose/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Leishmania mexicana/imunologia , Gasderminas
3.
Proc Natl Acad Sci U S A ; 117(5): 2613-2621, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31964820

RESUMO

Tsetse-transmitted African trypanosomes must develop into mammalian-infectious metacyclic cells in the fly's salivary glands (SGs) before transmission to a new host. The molecular mechanisms that underlie this developmental process, known as metacyclogenesis, are poorly understood. Blocking the few metacyclic parasites deposited in saliva from further development in the mammal could prevent disease. To obtain an in-depth perspective of metacyclogenesis, we performed single-cell RNA sequencing (scRNA-seq) from a pool of 2,045 parasites collected from infected tsetse SGs. Our data revealed three major cell clusters that represent the epimastigote, and pre- and mature metacyclic trypanosome developmental stages. Individual cell level data also confirm that the metacyclic pool is diverse, and that each parasite expresses only one of the unique metacyclic variant surface glycoprotein (mVSG) coat protein transcripts identified. Further clustering of cells revealed a dynamic transcriptomic and metabolic landscape reflective of a developmental program leading to infectious metacyclic forms preadapted to survive in the mammalian host environment. We describe the expression profile of proteins that regulate gene expression and that potentially play a role in metacyclogenesis. We also report on a family of nonvariant surface proteins (Fam10) and demonstrate surface localization of one member (named SGM1.7) on mature metacyclic parasites. Vaccination of mice with recombinant SGM1.7 reduced parasitemia early in the infection. Future studies are warranted to investigate Fam10 family proteins as potential trypanosome transmission blocking vaccine antigens. Our experimental approach is translationally relevant for developing strategies to prevent other insect saliva-transmitted parasites from infecting and causing disease in mammalian hosts.


Assuntos
Insetos Vetores/parasitologia , Proteínas de Protozoários/genética , Trypanosoma brucei brucei/crescimento & desenvolvimento , Trypanosoma brucei brucei/genética , Moscas Tsé-Tsé/parasitologia , Animais , Feminino , Humanos , Estágios do Ciclo de Vida , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Protozoários/imunologia , RNA de Protozoário/genética , Glândulas Salivares/parasitologia , Análise de Sequência de RNA , Análise de Célula Única , Transcriptoma , Trypanosoma brucei brucei/imunologia , Tripanossomíase Africana/imunologia , Tripanossomíase Africana/parasitologia
4.
J Infect Dis ; 226(10): 1842-1851, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36052609

RESUMO

Incidence of visceral leishmaniasis (VL) in the Indian subcontinent (ISC) has declined by more than 95% since initiation of the elimination program in 2005. As the ISC transitions to the postelimination surveillance phase, an accurate measurement of human-vector contact is needed to assure long-term success. To develop this tool, we identified PagSP02 and PagSP06 from saliva of Phlebotomus argentipes, the vector of Leishmania donovani in the ISC, as immunodominant proteins in humans. We also established the absence of cross-reactivity with Phlebotomus papatasi saliva, the only other human-biting sand fly in the ISC. Importantly, by combining recombinant rPagSP02 and rPagSP06 we achieved greater antibody recognition and specificity than single salivary proteins. The receiver operating characteristics curve for rPagSP02 + rPagSP06 predicts exposure to Ph. argentipes bites with 90% specificity and 87% sensitivity compared to negative control sera (P >.0001). Overall, rPagSP02 + rPagSP06 provides an effective surveillance tool for monitoring vector control efforts after VL elimination.


Assuntos
Leishmania donovani , Leishmaniose Visceral , Phlebotomus , Animais , Humanos , Leishmaniose Visceral/epidemiologia , Leishmania donovani/genética , Proteínas e Peptídeos Salivares , Biomarcadores , Índia/epidemiologia
5.
Lancet ; 395(10242): 1998-2007, 2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32534628

RESUMO

BACKGROUND: In animal models, immunity to mosquito salivary proteins protects animals against mosquito-borne disease. These findings provide a rationale to vaccinate against mosquito saliva instead of the pathogen itself. To our knowledge, no vector salivary protein-based vaccine has been tested for safety and immunogenicity in humans. We aimed to assess the safety and immunogenicity of Anopheles gambiae saliva vaccine (AGS-v), a peptide-based vaccine derived from four A gambiae salivary proteins, in humans. METHODS: In this randomised, placebo-controlled, double-blind, phase 1 trial, participants were enrolled at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Participants were eligible if they were healthy adults, aged 18-50 years with no history of severe allergic reactions to mosquito bites. Participants were randomly assigned (1:1:1), using block randomisation and a computer-generated randomisation sequence, to treatment with either 200 nmol of AGS-v vaccine alone, 200 nmol of AGS-v with adjuvant (Montanide ISA 51), or sterile water as placebo. Participants and clinicians were masked to treatment assignment. Participants were given a subcutaneous injection of their allocated treatment at day 0 and day 21, followed by exposure to feeding by an uninfected Aedes aegypti mosquito at day 42 to assess subsequent risk to mosquito bites in a controlled setting. The primary endpoints were safety and immunogenicity at day 42 after the first immunisation. Participants who were given at least one dose of assigned treatment were assessed for the primary endpoints and analysis was by intention to treat. The trial was registered with ClinicalTrials.gov, NCT03055000, and is closed for accrual. FINDINGS: Between Feb 15 and Sept 10, 2017, we enrolled and randomly assigned 49 healthy adult participants to the adjuvanted vaccine (n=17), vaccine alone (n=16), or placebo group (n=16). Five participants did not complete the two-injection regimen with mosquito feeding at day 42, but were included in the safety analyses. No systemic safety concerns were identified; however, one participant in the adjuvanted vaccine group developed a grade 3 erythematous rash at the injection site. Pain, swelling, erythema, and itching were the most commonly reported local symptoms and were significantly increased in the adjuvanted vaccine group compared with both other treatment groups (nine [53%] of 17 participants in the adjuvanted vaccine group, two [13%] of 16 in the vaccine only group, and one [6%] of 16 in the placebo group; p=0·004). By day 42, participants who were given the adjuvanted vaccine had a significant increase in vaccine-specific total IgG antibodies compared with at baseline than did participants who were give vaccine only (absolute difference of log10-fold change of 0·64 [95% CI 0·39 to 0·89]; p=0·0002) and who were given placebo (0·62 [0·34 to 0·91]; p=0·0001). We saw a significant increase in IFN-γ production by peripheral blood mononuclear cells at day 42 in the adjuvanted vaccine group compared with in the placebo group (absolute difference of log10 ratio of vaccine peptide-stimulated vs negative control 0·17 [95% CI 0·061 to 0·27]; p=0·009) but we saw no difference between the IFN-γ production in the vaccine only group compared with the placebo group (0·022 [-0·072 to 0·116]; p=0·63). INTERPRETATION: AGS-v was well tolerated, and, when adjuvanted, immunogenic. These findings suggest that vector-targeted vaccine administration in humans is safe and could be a viable option for the increasing burden of vector-borne disease. FUNDING: Office of the Director and the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, and National Institutes of Health.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Transmissão de Doença Infecciosa/prevenção & controle , Imunogenicidade da Vacina/imunologia , Saliva/imunologia , Adjuvantes Imunológicos/efeitos adversos , Adulto , Animais , Anopheles/imunologia , Anopheles/metabolismo , Estudos de Casos e Controles , Método Duplo-Cego , Feminino , Humanos , Imunoglobulina G/imunologia , Injeções Subcutâneas/métodos , Leucócitos Mononucleares/imunologia , Masculino , Modelos Animais , Mosquitos Vetores/imunologia , Mosquitos Vetores/metabolismo , Placebos/administração & dosagem , Segurança , Vacinação/efeitos adversos , Vacinação/métodos
6.
BMC Genomics ; 21(1): 608, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887545

RESUMO

BACKGROUND: Sand flies are the vectors of Leishmania parasites. To develop in the sand fly midgut, Leishmania multiplies and undergoes various stage differentiations giving rise to the infective form, the metacyclic promastigotes. To determine the changes in sand fly midgut gene expression caused by the presence of Leishmania, we performed RNA-Seq of uninfected and Leishmania infantum-infected Lutzomyia longipalpis midguts from seven different libraries corresponding to time points which cover the various Leishmania developmental stages. RESULTS: The combined transcriptomes resulted in the de novo assembly of 13,841 sand fly midgut transcripts. Importantly, only 113 sand fly transcripts, about 1%, were differentially expressed in the presence of Leishmania parasites. Further, we observed distinct differentially expressed sand fly midgut transcripts corresponding to the presence of each of the various Leishmania stages suggesting that each parasite stage influences midgut gene expression in a specific manner. Two main patterns of sand fly gene expression modulation were noted. At early time points (days 1-4), more transcripts were down-regulated by Leishmania infection at large fold changes (> 32 fold). Among the down-regulated genes, the transcription factor Forkhead/HNF-3 and hormone degradation enzymes were differentially regulated on day 2 and appear to be the upstream regulators of nutrient transport, digestive enzymes, and peritrophic matrix proteins. Conversely, at later time points (days 6 onwards), most of the differentially expressed transcripts were up-regulated by Leishmania infection with small fold changes (< 32 fold). The molecular functions of these genes have been associated with the metabolism of lipids and detoxification of xenobiotics. CONCLUSION: Overall, our data suggest that the presence of Leishmania produces a limited change in the midgut transcript expression profile in sand flies. Further, Leishmania modulates sand fly gene expression early on in the developmental cycle in order to overcome the barriers imposed by the midgut, yet it behaves like a commensal at later time points where a massive number of parasites in the anterior midgut results only in modest changes in midgut gene expression.


Assuntos
Mucosa Intestinal/metabolismo , Leishmania/patogenicidade , Psychodidae/genética , Transcriptoma , Animais , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Hormônios de Inseto/genética , Hormônios de Inseto/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Insetos Vetores/genética , Insetos Vetores/crescimento & desenvolvimento , Insetos Vetores/parasitologia , Psychodidae/crescimento & desenvolvimento , Psychodidae/parasitologia
7.
Clin Infect Dis ; 68(12): 2036-2044, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-30239631

RESUMO

BACKGROUND: Visceral leishmaniasis (VL), due to Leishmania infantum, is a persistent intracellular parasitic infection transmitted by the bite of infected sand flies. Symptomatic VL has been reported in U.S. soldiers with Iraq deployment. Untreated symptomatic VL can be fatal; asymptomatic VL (AVL) may establish a lifelong risk of reactivation. We report prevalence and AVL risk factors in Operation Iraqi Freedom (OIF) deployers during 2002-11. METHODS: Healthy soldiers exposed to VL endemic areas in Iraq and 50 controls who never traveled to endemic regions were recruited through military healthcare facilities (2015-17). Responses to a risk factor survey and blood samples were obtained. Leishmania research diagnostics utilized included enzyme-linked immunosorbent assay (ELISA), rk39 test strips, quantitative polymerase chain reaction (PCR), and interferon gamma release (IGRA) assays. Statistical analyses included Fisher exact test, Pearson χ2 test, Mann-Whitney U test, and logistic regression. RESULTS: 200 deployed subjects were enrolled, mostly males (84.0%), of white ethnicity (79.0%), and median age 41 (range 24-61) years. 64% were seropositive for Phlebotomus alexandri saliva antibodies. Prevalence of AVL (any positive test result) was 39/200 (19.5%, 95% confidence interval 14.4%-25.8%). Two (1.0%) PCR, 10 (5%) ELISA, and 28 (14%) IGRA samples were positive. Travel to Ninewa governorate increased risk for AVL (P = .01). CONCLUSION: AVL was identified in 19.5% of OIF deployers; travel to northwest Iraq correlated with infection. Further studies are needed to inform risk for reactivation VL in US veterans and to target additional blood safety and surveillance measures.


Assuntos
Infecções Assintomáticas , Leishmania infantum , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/parasitologia , Militares , Adulto , Feminino , Geografia , Humanos , Iraque/epidemiologia , Leishmaniose Visceral/diagnóstico , Masculino , Pessoa de Meia-Idade , Vigilância em Saúde Pública , Estados Unidos/epidemiologia , Adulto Jovem
8.
PLoS Pathog ; 13(1): e1006130, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28095465

RESUMO

Differentiation of extracellular Leishmania promastigotes within their sand fly vector, termed metacyclogenesis, is considered to be essential for parasites to regain mammalian host infectivity. Metacyclogenesis is accompanied by changes in the local parasite environment, including secretion of complex glycoconjugates within the promastigote secretory gel and colonization and degradation of the sand fly stomodeal valve. Deletion of the stage-regulated HASP and SHERP genes on chromosome 23 of Leishmania major is known to stall metacyclogenesis in the sand fly but not in in vitro culture. Here, parasite mutants deficient in specific genes within the HASP/SHERP chromosomal region have been used to investigate their role in metacyclogenesis, parasite transmission and establishment of infection. Metacyclogenesis was stalled in HASP/SHERP mutants in vivo and, although still capable of osmotaxis, these mutants failed to secrete promastigote secretory gel, correlating with a lack of parasite accumulation in the thoracic midgut and failure to colonise the stomodeal valve. These defects prevented parasite transmission to a new mammalian host. Sand fly midgut homogenates modulated parasite behaviour in vitro, suggesting a role for molecular interactions between parasite and vector in Leishmania development within the sand fly. For the first time, stage-regulated expression of the small HASPA proteins in Leishmania (Leishmania) has been demonstrated: HASPA2 is expressed only in extracellular promastigotes and HASPA1 only in intracellular amastigotes. Despite its lack of expression in amastigotes, replacement of HASPA2 into the null locus background delays onset of pathology in BALB/c mice. This HASPA2-dependent effect is reversed by HASPA1 gene addition, suggesting that the HASPAs may have a role in host immunomodulation.


Assuntos
Interações Hospedeiro-Parasita/fisiologia , Leishmania major/patogenicidade , Leishmaniose/transmissão , Proteínas de Protozoários/metabolismo , Virulência/fisiologia , Animais , Antígenos de Protozoários/metabolismo , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Imunofluorescência , Immunoblotting , Insetos Vetores/parasitologia , Leishmania major/crescimento & desenvolvimento , Leishmaniose/genética , Camundongos , Camundongos Endogâmicos BALB C , Reação em Cadeia da Polimerase , Psychodidae/parasitologia
9.
J Infect Dis ; 218(1): 7-15, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29617849

RESUMO

Arthropod-borne viruses (arboviruses) are taxonomically diverse causes of significant morbidity and mortality. In recent decades, important mosquito-borne viruses such as West Nile, chikungunya, dengue, and Zika have re-emerged and spread widely, in some cases pandemically, to cause serious public health emergencies. There are no licensed vaccines against most of these viruses, and vaccine development and use has been complicated by the number of different viruses to protect against, by subtype and strain variation, and by the inability to predict when and where outbreaks will occur. A new approach to preventing arboviral diseases is suggested by the observation that arthropod saliva facilitates transmission of pathogens, including leishmania parasites, Borrelia burgdorferi, and some arboviruses. Viruses carried within mosquito saliva may more easily initiate host infection by taking advantage of the host's innate and adaptive immune responses to saliva. This provides a rationale for creating vaccines against mosquito salivary proteins, rather than against only the virus proteins contained within the saliva. As proof of principle, immunization with sand fly salivary antigens to prevent leishmania infection has shown promising results in animal models. A similar approach using salivary proteins of important vector mosquitoes, such as Aedes aegypti, might protect against multiple mosquito-borne viral infections.


Assuntos
Aedes/imunologia , Infecções por Arbovirus/prevenção & controle , Transmissão de Doença Infecciosa/prevenção & controle , Mosquitos Vetores/imunologia , Saliva/imunologia , Vacinas/imunologia , Vacinas/isolamento & purificação , Animais , Descoberta de Drogas/tendências , Mosquitos Vetores/virologia
10.
PLoS Pathog ; 11(4): e1004646, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25856431

RESUMO

The impact of the microbiota on the immune status of its host is a source of intense research and publicity. In comparison, the effect of arthropod microbiota on vector-borne infectious diseases has received little attention. A better understanding of the vector microbiota in relation to mammalian host immune responses is vital, as it can lead to strategies that affect transmission and improve vaccine design in a field of research where few vaccines exist and effective treatment is rare. Recent demonstrations of how microbiota decrease pathogen development in arthropods, and thus alter vector permissiveness to vector-borne diseases (VBDs), have led to renewed interest. However, hypotheses on the interactions between the arthropod-derived microbiota and the mammalian hosts have yet to be addressed. Advances in DNA sequencing technology, increased yield and falling costs, mean that these studies are now feasible for many microbiologists and entomologists. Here, we distill current knowledge and put forward key questions and experimental designs to shed light on this burgeoning research topic.


Assuntos
Vetores Artrópodes/microbiologia , Artrópodes/microbiologia , Transmissão de Doença Infecciosa , Microbiota , Animais , Humanos
11.
J Infect Dis ; 213(11): 1752-61, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26768257

RESUMO

Canine leishmaniasis (CanL) is a chronic fatal disease of dogs and a major source of human infection through propagation of parasites in vectors. Here, we infected 8 beagles through multiple experimental vector transmissions with Leishmania infantum-infected Lutzomyia longipalpis. CanL clinical signs varied, although live parasites were recovered from all dog spleens. Splenic parasite burdens correlated positively with Leishmania-specific interleukin 10 levels, negatively with Leishmania-specific interferon γ and interleukin 2 levels, and negatively with Leishmania skin test reactivity. A key finding was parasite persistence for 6 months in lesions observed at the bite sites in all dogs. These recrudesced following a second transmission performed at a distal site. Notably, sand flies efficiently acquired parasites after feeding on lesions at the primary bite site. In this study, controlled vector transmissions identify a potentially unappreciated role for skin at infectious bite sites in dogs with CanL, providing a new perspective regarding the mechanism of Leishmania transmissibility to vector sand flies.


Assuntos
Doenças do Cão/parasitologia , Insetos Vetores/parasitologia , Leishmania infantum , Leishmaniose Visceral/veterinária , Psychodidae/parasitologia , Animais , Reservatórios de Doenças/veterinária , Doenças do Cão/imunologia , Doenças do Cão/patologia , Doenças do Cão/transmissão , Cães , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Mordeduras e Picadas de Insetos/parasitologia , Mordeduras e Picadas de Insetos/patologia , Mordeduras e Picadas de Insetos/veterinária , Interferon gama/metabolismo , Leishmania infantum/isolamento & purificação , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/patologia , Leishmaniose Visceral/transmissão , Pele/parasitologia , Baço/parasitologia
12.
FASEB J ; 29(1): 11-24, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25300620

RESUMO

In Leishmania mexicana parasites, a unique glucose transporter, LmxGT1, is selectively targeted to the flagellar membrane, suggesting a possible sensory role that is often associated with ciliary membrane proteins. Expression of LmxGT1 is down-regulated ∼20-fold by increasing cell density but is up-regulated ∼50-fold by depleting glucose from the medium, and the permease is strongly down-regulated when flagellated insect-stage promastigotes invade mammalian macrophages and transform into intracellular amastigotes. Regulation of LmxGT1 expression by glucose and during the lifecycle operates at the level of protein stability. Significantly, a ∆lmxgt1 null mutant, grown in abundant glucose, undergoes catastrophic loss of viability when parasites deplete glucose from the medium, a property not exhibited by wild-type or add-back lines. These results suggest that LmxGT1 may function as a glucose sensor that allows parasites to enter the stationary phase when they deplete glucose and that in the absence of this sensor, parasites do not maintain viability when they run out of glucose. However, alternate roles for LmxGT1 in monitoring glucose availability are considered. The absence of known sensory receptors with defined ligands and biologic functions in Leishmania and related kinetoplastid parasites underscores the potential significance of these observations.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Leishmania mexicana/metabolismo , Proteínas de Protozoários/metabolismo , Animais , Linhagem Celular , Feminino , Flagelos/metabolismo , Regulação da Expressão Gênica , Genes de Protozoários , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Leishmania mexicana/genética , Leishmania mexicana/patogenicidade , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Proteínas de Protozoários/genética , Psychodidae/parasitologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo
13.
Immunol Rev ; 239(1): 237-70, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21198676

RESUMO

The neglected tropical diseases (NTDs) represent a group of parasitic and related infectious diseases such as amebiasis, Chagas disease, cysticercosis, echinococcosis, hookworm, leishmaniasis, and schistosomiasis. Together, these conditions are considered the most common infections in low- and middle-income countries, where they produce a level of global disability and human suffering equivalent to better known conditions such as human immunodeficiency virus/acquired immunodeficiency syndrome and malaria. Despite their global public health importance, progress on developing vaccines for NTD pathogens has lagged because of some key technical hurdles and the fact that these infections occur almost exclusively in the world's poorest people living below the World Bank poverty line. In the absence of financial incentives for new products, the multinational pharmaceutical companies have not embarked on substantive research and development programs for the neglected tropical disease vaccines. Here, we review the current status of scientific and technical progress in the development of new neglected tropical disease vaccines, highlighting the successes that have been achieved (cysticercosis and echinococcosis) and identifying the challenges and opportunities for development of new vaccines for NTDs. Also highlighted are the contributions being made by non-profit product development partnerships that are working to overcome some of the economic challenges in vaccine manufacture, clinical testing, and global access.


Assuntos
Doenças Negligenciadas/imunologia , Doenças Parasitárias/imunologia , Doenças Parasitárias/prevenção & controle , Vacinas Protozoárias , Vacinas , Animais , Modelos Animais de Doenças , Helmintíase/imunologia , Helmintíase/prevenção & controle , Helmintíase/terapia , Humanos , Enteropatias Parasitárias/imunologia , Enteropatias Parasitárias/prevenção & controle , Enteropatias Parasitárias/terapia , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/prevenção & controle , Doenças Negligenciadas/terapia , Doenças Parasitárias/epidemiologia , Doenças Parasitárias/terapia , Áreas de Pobreza , Infecções por Protozoários/imunologia , Infecções por Protozoários/prevenção & controle , Infecções por Protozoários/terapia , Vacinas Protozoárias/imunologia , Medicina Tropical , Vacinas/imunologia
14.
Infect Immun ; 82(7): 2736-45, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24733091

RESUMO

Cutaneous leishmaniasis is a sand fly-transmitted disease characterized by skin ulcers that carry significant scarring and social stigmatization. Over the past years, there has been cumulative evidence that immunity to specific sand fly salivary proteins confers a significant level of protection against leishmaniasis. In this study, we used an attenuated strain of Listeria monocytogenes as a vaccine expression system for LJM11, a sand fly salivary protein identified as a good vaccine candidate. We observed that mice were best protected against an intradermal needle challenge with Leishmania major and sand fly saliva when vaccinated intravenously. However, this protection was short-lived. Importantly, groups of vaccinated mice were protected long term when challenged with infected sand flies. Protection correlated with smaller lesion size, fewer scars, and better parasite control between 2 and 6 weeks postchallenge compared to the control group of mice vaccinated with the parent L. monocytogenes strain not expressing LJM11. Moreover, protection correlated with high numbers of CD4(+), gamma interferon-positive (IFN-γ(+)), tumor necrosis factor alpha-positive/negative (TNF-α(+/-)), interleukin-10-negative (IL-10(-)) cells and low numbers of CD4(+) IFN-γ(+/-) TNF-α(-) IL-10(+) T cells at 2 weeks postchallenge. Overall, our data indicate that delivery of LJM11 by Listeria is a promising vaccination strategy against cutaneous leishmaniasis inducing long-term protection against ulcer formation following a natural challenge with infected sand flies.


Assuntos
Proteínas de Insetos/imunologia , Leishmania major/imunologia , Leishmaniose Cutânea/prevenção & controle , Listeria monocytogenes , Psychodidae/fisiologia , Proteínas e Peptídeos Salivares/imunologia , Animais , Mordeduras e Picadas/imunologia , Mordeduras e Picadas/parasitologia , Orelha Externa/imunologia , Orelha Externa/parasitologia , Insetos Vetores/parasitologia , Vacinas contra Leishmaniose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/classificação , Vacinas Sintéticas
16.
J Infect Dis ; 207(8): 1328-38, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23288926

RESUMO

BACKGROUND: Visceral leishmaniasis (VL) is transmitted by sand flies. Protection of needle-challenged vaccinated mice was abrogated in vector-initiated cutaneous leishmaniasis, highlighting the importance of developing natural transmission models for VL. METHODS: We used Lutzomyia longipalpis to transmit Leishmania infantum or Leishmania donovani to hamsters. Vector-initiated infections were monitored and compared with intracardiac infections. Body weights were recorded weekly. Organ parasite loads and parasite pick-up by flies were assessed in sick hamsters. RESULTS: Vector-transmitted L. infantum and L. donovani caused ≥5-fold increase in spleen weight compared with uninfected organs and had geometric mean parasite loads (GMPL) comparable to intracardiac inoculation of 10(7)-10(8) parasites, although vector-initiated disease progression was slower and weight loss was greater. Only vector-initiated L. infantum infections caused cutaneous lesions at transmission and distal sites. Importantly, 45.6%, 50.0%, and 33.3% of sand flies feeding on ear, mouth, and testicular lesions, respectively, were parasite-positive. Successful transmission was associated with a high mean percent of metacyclics (66%-82%) rather than total GMPL (2.0 × 10(4)-8.0 × 10(4)) per midgut. CONCLUSIONS: This model provides an improved platform to study initial immune events at the bite site, parasite tropism, and pathogenesis and to test drugs and vaccines against naturally acquired VL.


Assuntos
Modelos Animais de Doenças , Mordeduras e Picadas de Insetos/parasitologia , Insetos Vetores/parasitologia , Leishmaniose Visceral/patologia , Psychodidae/parasitologia , Animais , Peso Corporal , Cricetinae , Progressão da Doença , Leishmania donovani/patogenicidade , Leishmania infantum/patogenicidade , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Leishmaniose Cutânea/transmissão , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/transmissão , Masculino , Tamanho do Órgão , Carga Parasitária , Baço/parasitologia , Baço/patologia
17.
mBio ; 15(8): e0107924, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-38995021

RESUMO

Surveillance and sustained control of visceral leishmaniasis (VL) require reliable serodiagnostic tools. rK39, the gold standard antigen for VL diagnosis, is limited by its documented poor sensitivity in certain endemic regions, such as East Africa, and by the longevity of its antibodies, making it difficult to distinguish active from cured infections. In a recent publication in mBio, Roberts et al. (A. J. Roberts, H.B. Ong, S. Clare, C. Brandt, et al., mBio 15:e00859-24, 2024, https://doi.org/10.1128/mbio.00859-24) identified new immunogenic Leishmania candidates in dogs and humans. In dogs, combined antigens LdBPK_290790.1 + LdBPK_362700.1 (D4 +D46) distinguished symptomatic from asymptomatic infections. For humans, LdBPK_323600.1 (D36) antigen produced short-lived antibodies and performed well in patient cohorts from Bangladesh and Ethiopia, but not Kenya. This study adds promising new candidates to our serodiagnostic toolbox but highlights the need for more antigen discovery studies that may have to be focused on regional performance.


Assuntos
Anticorpos Antiprotozoários , Antígenos de Protozoários , Doenças do Cão , Leishmaniose Visceral , Testes Sorológicos , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/veterinária , Leishmaniose Visceral/imunologia , Cães , Animais , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/genética , Testes Sorológicos/métodos , Humanos , Doenças do Cão/diagnóstico , Doenças do Cão/parasitologia , Doenças do Cão/imunologia , Anticorpos Antiprotozoários/sangue , Sensibilidade e Especificidade , Etiópia
18.
Res Sq ; 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39070615

RESUMO

Phlebotomus argentipes is the established vector of leishmaniasis in the Indian sub-continent. Antibodies to sand fly salivary antigens are biomarkers for vector-host exposure in leishmaniasis-endemic regions. Ph. argentipes transmits Leishmania donovani in Sri Lanka, primarily causing cutaneous leishmaniasis (CL). Our study compared the performance of salivary gland homogenate (SGH) from a lab-reared local strain of Ph. argentipes females to a composite recombinant salivary biomarker (rPagSP02 + rPagSP06) in a CL-endemic population. Sera from 546 healthy individuals, 30 CL patients, and 15 non-endemic individuals were collected. Western blot analysis of Ph. argentipes SGH identified immunogenic bands between 15 kDa and 67 kDa, with bands of predicted molecular weight õf 15 kDa (SP02) and ~28-30 kDa (SP06) as the major antibody targets. Indirect ELISAs using SGH or rPagSP02 + rPagSP06 antigens showed high sensitivity (96.7%) and specificity (100%), detecting comparable seropositivity in endemic populations. rPagSP02 + rPagSP06 exhibited enhanced discriminatory ability, supported by a strong positive correlation (r = 0.869) with SGH. Our findings indicate that the composite rPagSP02 + rPagSP06 salivary biomarker effectively identifies Ph. argentipes exposure in individuals living in Sri Lanka, showing promising potential for use in surveillance. These findings should be further validated to confirm the epidemiological applications in leishmaniasis-endemic regions.

19.
Parasit Vectors ; 17(1): 11, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38183132

RESUMO

BACKGROUND: Vector sand fly colonies are a critical component of studies aimed at improving the understanding of the neglected tropical disease leishmaniasis and alleviating its global impact. However, among laboratory-colonized arthropod vectors of infectious diseases, the labor-intensive nature of sand fly rearing coupled with the low number of colonies worldwide has generally discouraged the widespread use of sand flies in laboratory settings. Among the different factors associated with the low productivity of sand fly colonies, mite infestations are a significant factor. Sand fly colonies are prone to infestation by mites, and the physical interactions between sand flies and mites and metabolites have a negative impact on sand fly larval development. METHODS: Mites were collected from sand fly larval rearing pots and morphologically identified using taxonomic keys. Upon identification, they were photographed with a scanning electron microscope. Several mite control measures were adopted in two different laboratories, one at the Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases-National Institutes of Health (Rockville, MD, USA), and the other at the University of Calgary (Calgary, AB, Canada). RESULTS: The mite species associated with sand fly colonies in the two laboratories were morphologically identified as Tyrophagus sp. and Stratiolaelaps scimitus. While complete eradication of mites in sand fly colonies is considered unrealistic, drastically reducing their population has been associated with higher sand fly productivity. CONCLUSIONS: We report a case of detrimental interaction between sand flies and Tyrophagus sp. and S. scimitus in a closed laboratory sand fly colony, discuss their impact on sand fly production and provide guidelines for limiting the mite population size in a closed laboratory colony leading to improved sand fly yields.


Assuntos
Infestações por Ácaros , Ácaros , Phlebotomus , Psychodidae , Doenças Transmitidas por Vetores , Estados Unidos , Animais , Laboratórios
20.
Front Immunol ; 15: 1335307, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38633260

RESUMO

Introduction: Cutaneous leishmaniasis is a neglected vector-borne parasitic disease prevalent in 92 countries with approximately one million new infections annually. Interactions between vector saliva and the human host alter the response to infection and outcome of disease. Methods: To characterize the human immunological responses developed against saliva of Phlebotomus duboscqi, a Leishmania major (L. major) vector, we repeatedly exposed the arms of 14 healthy U.S volunteers to uninfected P. duboscqi bites. Blood was collected a week after each exposure and used to assess total IgG antibodies against the proteins of P. duboscqi salivary gland homogenate (SGH) and the levels of IFN-gamma and IL-10 from peripheral blood mononuclear cells (PBMCs) stimulated with SGH or recombinant sand fly proteins. We analyzed skin punch biopsies of the human volunteer arms from the insect bite site and control skin site after multiple P. duboscqi exposures (four volunteers) using immunohistochemical staining. Results: A variety of immediate insect bite skin reactions were observed. Late skin reactions to insect bites were characterized by macular hyperpigmentation and/or erythematous papules. Hematoxylin and eosin staining showed moderate mononuclear skin infiltrate with eosinophils in those challenged recently (within 2 months), eosinophils were not seen in biopsies with recall challenge (6 month post bites). An increase in plasma antigen-specific IgG responses to SGH was observed over time. Western Blot results showed strong plasma reactivity to five P. duboscqi salivary proteins. Importantly, volunteers developed a cellular immunity characterized by the secretion of IFN-gamma upon PBMC stimulation with P. duboscqi SGH and recombinant antigens. Discussion: Our results demonstrate that humans mounted a local and systemic immune response against P. duboscqi salivary proteins. Specifically, PduM02/SP15-like and PduM73/adenosine deaminase recombinant salivary proteins triggered a Th1 type immune response that might be considered in future development of a potential Leishmania vaccine.


Assuntos
Mordeduras e Picadas de Insetos , Phlebotomus , Animais , Humanos , Phlebotomus/parasitologia , Leucócitos Mononucleares , Imunidade Celular , Antígenos , Imunoglobulina G , Proteínas e Peptídeos Salivares
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