scholarly journals Development of a Novel Virus-Like Particle Vaccine Platform That Mimics the Immature Form of Alphavirus

2017 ◽  
Vol 24 (7) ◽  
Author(s):  
Akane Urakami ◽  
Atsuko Sakurai ◽  
Momoko Ishikawa ◽  
Moh Lan Yap ◽  
Yevel Flores-Garcia ◽  
...  
Keyword(s):  
Immune Responses ◽  
Malaria Infection ◽  
Protein A ◽  
Structural Proteins ◽  
Vaccine Platform ◽  
Content Type ◽  
Virus Like Particle ◽  
Immature Form ◽  
Novel Virus

ABSTRACT Virus-like particles (VLPs) are noninfectious multiprotein structures that are engineered to self-assemble from viral structural proteins. Here, we developed a novel VLP-based vaccine platform utilizing VLPs from the chikungunya virus. We identified two regions within the envelope protein, a structural component of chikungunya, where foreign antigens can be inserted without compromising VLP structure. Our VLP displays 480 copious copies of an inserted antigen on the VLP surface in a highly symmetric manner and is thus capable of inducing strong immune responses against any inserted antigen. Furthermore, by mimicking the structure of the immature form of the virus, we altered our VLP's in vivo dynamics and enhanced its immunogenicity. We used the circumsporozoite protein (CSP) of the Plasmodium falciparum malaria parasite as an antigen and demonstrated that our VLP-based vaccine elicits strong immune responses against CSP in animals. The sera from immunized monkeys protected mice from malaria infection. Likewise, mice vaccinated with P. yoelii CSP-containing VLPs were protected from an infectious sporozoite challenge. Hence, our uniquely engineered VLP platform can serve as a blueprint for the development of vaccines against other pathogens and diseases.

scholarly journals In VivoMechanisms Involved in Enhanced Protection Utilizing an Fc Receptor-Targeted Mucosal Vaccine Platform in a Bacterial Vaccine and Challenge Model

2014 ◽  
Vol 83 (1) ◽  
pp. 77-89 ◽  
Author(s):  
Constantine Bitsaktsis ◽  
Zulfia Babadjanova ◽  
Edmund J. Gosselin
Keyword(s):  
Immune Responses ◽  
Mucosal Vaccine ◽  
Effector Memory ◽  
Interleukin 12 ◽  
Nasal Passage ◽  
Dependent Manner ◽  
Vaccine Platform ◽  
Universal Vaccine ◽  
Content Type

Targeting antigens (Ag) to Fcγ receptors (FcγR) intranasally (i.n.) enhances immunogenicity and protection against intracellular and extracellular pathogens. Specifically, we have demonstrated that targeting fixed (inactivated)Francisella tularensis(iFT) organisms to FcR in mice i.n., with MAb-iFT immune complexes, enhancesF. tularensis-specific immune responses and protection againstF. tularensischallenge. Furthermore, traditional adjuvant is not required. In addition, we have demonstrated that the increased immunogenicity following the targeting of iFT to FcR is due, in part, to enhanced dendritic cell (DC) maturation, enhanced internalization, and processing and presentation of iFT by DCs, as well as neonatal FcR (FcRn)-enhanced trafficking of iFT from the nasal passage to the nasal mucosa-associated lymphoid tissue (NALT). Using this immunization and challenge model, we expanded on these studies to identify specificin vivoimmune responses impacted and enhanced by FcR targeting of iFT i.n. Specifically, the results of this study demonstrate for the first time that targeting iFT to FcR increases the frequency of activated DCs within the lungs of MAb-iFT-immunized mice subsequent toF. tularensisLVS challenge. In addition, the frequency and number of gamma interferon (IFN-γ)-secreting effector memory (EM) CD4+T cells elicited byF. tularensisinfection (postimmunization) is increased in an interleukin 12 (IL-12)-dependent manner. In summary, these studies build significantly upon previously published work utilizing this vaccine platform. We have identified a number of additional mechanisms by which this novel, adjuvant-independent, FcR-targeted mucosal vaccine approach enhances immunity and protection against infection, while further validating its potential as a universal vaccine platform against mucosal pathogens.

scholarly journals Seroprevalence of Antibodies against Pkn1, a Novel Potential Immunogen, inChlamydia trachomatis-InfectedMacaca nemestrinaand Human Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Achchhe L. Patel ◽  
Prashant K. Mishra ◽  
Divya Sachdev ◽  
Uma Chaudhary ◽  
Dorothy L. Patton ◽  
...  
Keyword(s):  
Immune Responses ◽  
Genital Tract ◽  
Protein A ◽  
Macaca Nemestrina ◽  
Sexually Transmitted ◽  
Host Immune Responses ◽  
Bioinformatic Tools ◽  
Genital Tract Infections ◽  
Tract Infections

Chlamydia trachomatis(CT) is an important cause of sexually transmitted genital tract infections (STIs) and trachoma. Despite major research into chlamydial pathogenesis and host immune responses, immunoprotection has been hampered by the incomplete understanding of protective immunity in the genital tract. Characterized vaccine candidates have shown variable efficacy ranging from no protection to partial protectionin vivo. It is therefore a research priority to identify novel chlamydial antigens that may elicit protective immune responses against CT infection. In the present study we assessed the seroprevalence of antibodies against protein kinase1 (Pkn1), DNA ligaseA (LigA), and major outer membrane protein A (OmpA) following natural CT infection in humans and in experimentally induced CT infection inMacaca nemestrina. Antigenic stretches of Pkn1, LigA, and OmpA were identified using bioinformatic tools.Pkn1,LigA, andOmpAgenes were cloned in bacterial expression vector and purified by affinity chromatography. Our results demonstrate significantly high seroprevalence of antibodies against purified Pkn1 and OmpA in sera obtained from the macaque animal model and human patients infected with CT. In contrast no significant seroreactivity was observed for LigA. The seroprevalence of antibodies against Pkn1 suggest that nonsurface chlamydial proteins could also be important for developing vaccines forC. trachomatis.

scholarly journals A Novel Carbon Monoxide-Releasing Molecule Fully Protects Mice from Severe Malaria

2011 ◽  
Vol 56 (3) ◽  
pp. 1281-1290 ◽  
Author(s):  
Ana C. Pena ◽  
Nuno Penacho ◽  
Liliana Mancio-Silva ◽  
Rita Neres ◽  
João D. Seixas ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Severe Malaria ◽  
Adjuvant Treatment ◽  
Malaria Infection ◽  
Severe Disease ◽  
Inhalation Therapy ◽  
Heme Oxygenase 1 ◽  
Primary Therapy ◽  
Content Type

ABSTRACTSevere forms of malaria infection, such as cerebral malaria (CM) and acute lung injury (ALI), are mainly caused by the apicomplexan parasitePlasmodium falciparum. Primary therapy with quinine or artemisinin derivatives is generally effective in controllingP. falciparumparasitemia, but mortality from CM and other forms of severe malaria remains unacceptably high. Herein, we report the design and synthesis of a novel carbon monoxide-releasing molecule (CO-RM; ALF492) that fully protects mice against experimental CM (ECM) and ALI. ALF492 enables controlled CO deliveryin vivowithout affecting oxygen transport by hemoglobin, the major limitation in CO inhalation therapy. The protective effect is CO dependent and induces the expression of heme oxygenase-1, which contributes to the observed protection. Importantly, when used in combination with the antimalarial drug artesunate, ALF492 is an effective adjunctive and adjuvant treatment for ECM, conferring protection after the onset of severe disease. This study paves the way for the potential use of CO-RMs, such as ALF492, as adjunctive/adjuvant treatment in severe forms of malaria infection.

scholarly journals Protein A-Specific Monoclonal Antibodies and Prevention of Staphylococcus aureus Disease in Mice

2012 ◽  
Vol 80 (10) ◽  
pp. 3460-3470 ◽  
Author(s):  
Hwan Keun Kim ◽  
Carla Emolo ◽  
Andrea C. DeDent ◽  
Fabiana Falugi ◽  
Dominique M. Missiakas ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibodies ◽  
Immune Responses ◽  
B Cell ◽  
Protein A ◽  
Abscess Formation ◽  
Staphylococcal Protein A ◽  
Content Type ◽  
Humoral Immune ◽  
Binding Domains

ABSTRACTStaphylococcus aureusis a leading cause of human soft tissue infections and bacterial sepsis. The emergence of antibiotic-resistant strains (methicillin-resistantS. aureus[MRSA]) has prompted research into staphylococcal vaccines and preventive measures. The envelope ofS. aureusis decorated with staphylococcal protein A (SpA), which captures the Fcγ portion of immunoglobulins to prevent opsonophagocytosis and associates with the Fab portion of VH3-type B cell receptors to trigger B cell superantigen activity. Nontoxigenic protein A (SpAKKAA), when used as an immunogen in mice, stimulates humoral immune responses that neutralize the Fcγ and the VH3+Fab binding activities of SpA and provide protection from staphylococcal abscess formation in mice. Here, we isolated monoclonal antibodies (MAbs) against SpAKKAAthat, by binding to the triple-helical bundle fold of its immunoglobulin binding domains (IgBDs), neutralize the Fcγ and Fab binding activities of SpA. SpAKKAAMAbs promoted opsonophagocytic killing of MRSA in mouse and human blood, provided protection from abscess formation, and stimulated pathogen-specific immune responses in a mouse model of staphylococcal disease. Thus, SpAKKAAMAbs may be useful for the prevention and therapy of staphylococcal disease in humans.

scholarly journals Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA): a study protocol to investigate in vivo Plasmodium falciparum malaria parasite growth in the context of pre-existing immunity

2018 ◽  
Vol 3 ◽  
pp. 155 ◽  
Author(s):  
Melissa C. Kapulu ◽  
Patricia Njuguna ◽  
Mainga M. Hamaluba ◽  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Parasite Growth ◽  
Host Immunity ◽  
Human Malaria ◽  
Controlled Human Malaria Infection ◽  
Adult Volunteers

Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy.  We will use controlled human malaria infection (CHMI) studies with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo.  Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and extracted DNA will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. Registration: ClinicalTrials.gov identifier NCT02739763.

scholarly journals Schistosoma mansoni Infection Impairs Antimalaria Treatment and Immune Responses of Rhesus Macaques Infected with Mosquito-Borne Plasmodium coatneyi

2012 ◽  
Vol 80 (11) ◽  
pp. 3821-3827 ◽  
Author(s):  
Amma A. Semenya ◽  
JoAnn S. Sullivan ◽  
John W. Barnwell ◽  
W. Evan Secor
Keyword(s):  
Immune Responses ◽  
Schistosoma Mansoni ◽  
Malaria Infection ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
Content Type ◽  
Macaque Model ◽  
Malaria Parasitemia ◽  
Intravenous Inoculation ◽  
Plasmodium Coatneyi

ABSTRACTMalaria and schistosomiasis are the world's two most important parasitic infections in terms of distribution, morbidity, and mortality. In areas wherePlasmodiumandSchistosomaspecies are both endemic, coinfections are commonplace. Mouse models demonstrate that schistosomiasis worsens a malaria infection; however, just as mice and humans differ greatly, the murine-infectingPlasmodiumspecies differ as much from those that infect humans. Research into human coinfections (Schistosoma haematobium-Plasmodium falciparumversusSchistosoma mansoni-P. falciparum) has produced conflicting results. The rhesus macaque model provides a helpful tool for understanding the role ofS. mansonion malaria parasitemia and antimalarial immune responses usingPlasmodium coatneyi, a malaria species that closely resemblesP. falciparuminfection in humans. Eight rhesus macaques were exposed toS. mansonicercariae. Eight weeks later, these animals plus 8 additional macaques were exposed to malaria either through bites of infected mosquitos or intravenous inoculation. When malaria infection was initiated from mosquito bites, coinfected animals displayed increased malaria parasitemia, decreased hematocrit levels, and suppressed malaria-specific antibody responses compared to those of malaria infection alone. However, macaques infected by intravenous inoculation with erythrocytic-stage parasites did not display these same differences in parasitemia, hematocrit, or antibody responses between the two groups. Use of the macaque model provides information that begins to unravel differences in pathological and immunological outcomes observed between humans withP. falciparumthat are coinfected withS. mansoniorS. haematobium. Our results suggest that migration of malaria parasites through livers harboring schistosome eggs may alter host immune responses and infection outcomes.

scholarly journals Efficacy of Azithromycin in a Mouse Pneumonia Model against Hospital-Acquired Methicillin-Resistant Staphylococcus aureus

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Yu Yamashita ◽  
Kentaro Nagaoka ◽  
Hiroki Kimura ◽  
Masaru Suzuki ◽  
Satoshi Konno ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Protein A ◽  
Lavage Fluid ◽  
Suppressive Effect ◽  
The Other ◽  
Staphylococcal Protein A ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACT The use of macrolides against pneumonia has been reported to improve survival; however, little is known about their efficacy against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. In this study, we investigated the effect of azithromycin (AZM) and compared it with that of vancomycin (VCM) and daptomycin (DAP) in a murine model of MRSA pneumonia. Mice were infected with MRSA by intratracheal injection and then treated with AZM, VCM, or DAP. The therapeutic effect of AZM, in combination or not with the other drugs, was compared in vivo, whereas the effect of AZM on MRSA growth and toxin mRNA expression was evaluated in vitro. In vivo, the AZM-treated group showed significantly longer survival and fewer bacteria in the lungs 24 h after infection than the untreated group, as well as the other anti-MRSA drug groups. No significant decrease in cytokine levels (interleukin-6 [IL-6] and macrophage inflammatory protein-2 [MIP-2]) in bronchoalveolar lavage fluid or toxin expression levels (α-hemolysin [Hla] and staphylococcal protein A [Spa]) was observed following AZM treatment. In vitro, AZM suppressed the growth of MRSA in late log phase but not in stationary phase. No suppressive effect against toxin production was observed following AZM treatment in vitro. In conclusion, contrary to the situation in vitro, AZM was effective against MRSA growth in vivo in our pneumonia model, substantially improving survival. The suppressive effect on MRSA growth at the initial stage of pneumonia could underlie the potential mechanism of AZM action against MRSA pneumonia.

scholarly journals Inhibition of Local Immune Responses by the Frog-Killing Fungus Batrachochytrium dendrobatidis

2014 ◽  
Vol 82 (11) ◽  
pp. 4698-4706 ◽  
Author(s):  
J. Scott Fites ◽  
Laura K. Reinert ◽  
Timothy M. Chappell ◽  
Louise A. Rollins-Smith
Keyword(s):  
Immune Responses ◽  
Batrachochytrium Dendrobatidis ◽  
Single Injection ◽  
Delayed Type Hypersensitivity ◽  
Chytrid Fungus ◽  
Content Type ◽  
Adaptive Immune ◽  
Secondary Injection

ABSTRACTAmphibians are suffering unprecedented global declines. A leading cause is the infectious disease chytridiomycosis caused by the chytrid fungusBatrachochytrium dendrobatidis. Chytridiomycosis is a skin disease which disrupts transport of essential ions leading to death. Soluble factors produced byB. dendrobatidisimpair amphibian and mammalian lymphocytesin vitro, but previous studies have not shown the effects of these inhibitory factorsin vivo. To demonstratein vivoinhibition of immunity byB. dendrobatidis, a modified delayed-type-hypersensitivity (DTH) protocol was developed to induce innate and adaptive inflammatory swelling in the feet ofXenopus laevisby injection of killed bacteria or phytohemagglutinin (PHA). Compared to previous protocols for PHA injection in amphibians, this method induced up to 20-fold greater inflammatory swelling. Using this new protocol, we measured DTH responses induced by killed bacteria or PHA in the presence ofB. dendrobatidissupernatants. Swelling induced by single injection of PHA or killed bacteria was not significantly affected byB. dendrobatidissupernatants. However, swelling caused by a secondary injection of PHA, was significantly reduced byB. dendrobatidissupernatants. As previously describedin vitro, factors fromB. dendrobatidisappear to inhibit lymphocyte-mediated inflammatory swelling but not swelling caused by an inducer of innate leukocytes. This suggests thatB. dendrobatidisis capable of inhibiting lymphocytes in a localized response to prevent adaptive immune responses in the skin. The modified protocol used to induce inflammatory swelling in the present study may be more effective than previous methods to investigate amphibian immune competence, particularly in nonmodel species.

scholarly journals The Plasmodium falciparum Cell-Traversal Protein for Ookinetes and Sporozoites as a Candidate for Preerythrocytic and Transmission-Blocking Vaccines

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Diego A. Espinosa ◽  
Joel Vega-Rodriguez ◽  
Yevel Flores-Garcia ◽  
Amy R. Noe ◽  
Christian Muñoz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Monoclonal Antibodies ◽  
Immune Responses ◽  
Passive Immunization ◽  
Content Type ◽  
Adjuvant System ◽  
Neutralizing Capacity ◽  
Important Evidence ◽  
Transmission Blocking Vaccines

ABSTRACT Recent studies have shown that immune responses against the cell-traversal protein for Plasmodium ookinetes and sporozoites (CelTOS) can inhibit parasite infection. While these studies provide important evidence toward the development of vaccines targeting this protein, it remains unknown whether these responses could engage the Plasmodium falciparum CelTOS in vivo. Using a newly developed rodent malaria chimeric parasite expressing the P. falciparum CelTOS (PfCelTOS), we evaluated the protective effect of in vivo immune responses elicited by vaccination and assessed the neutralizing capacity of monoclonal antibodies specific against PfCelTOS. Mice immunized with recombinant P. falciparum CelTOS in combination with the glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE) or glucopyranosyl lipid adjuvant-liposome-QS21 (GLA-LSQ) adjuvant system significantly inhibited sporozoite hepatocyte infection. Notably, monoclonal antibodies against PfCelTOS strongly inhibited oocyst development of P. falciparum and Plasmodium berghei expressing PfCelTOS in Anopheles gambiae mosquitoes. Taken together, our results demonstrate that anti-CelTOS responses elicited by vaccination or passive immunization can inhibit sporozoite and ookinete infection and impair vector transmission.

scholarly journals SaeRS Is Responsive to Cellular Respiratory Status and Regulates Fermentative Biofilm Formation in Staphylococcus aureus

2017 ◽  
Vol 85 (8) ◽  
Author(s):  
Ameya A. Mashruwala ◽  
Casey M. Gries ◽  
Tyler D. Scherr ◽  
Tammy Kielian ◽  
Jeffrey M. Boyd
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Protein A ◽  
Regulatory System ◽  
Cellular Respiration ◽  
Signal Molecule ◽  
Terminal Electron Acceptor ◽  
Content Type ◽  
Respiratory Status

ABSTRACT Biofilms are multicellular communities of microorganisms living as a quorum rather than as individual cells. The bacterial human pathogen Staphylococcus aureus uses oxygen as a terminal electron acceptor during respiration. Infected human tissues are hypoxic or anoxic. We recently reported that impaired respiration elicits a programmed cell lysis (PCL) phenomenon in S. aureus leading to the release of cellular polymers that are utilized to form biofilms. PCL is dependent upon the AtlA murein hydrolase and is regulated, in part, by the SrrAB two-component regulatory system (TCRS). In the current study, we report that the SaeRS TCRS also governs fermentative biofilm formation by positively influencing AtlA activity. The SaeRS-modulated factor fibronectin-binding protein A (FnBPA) also contributed to the fermentative biofilm formation phenotype. SaeRS-dependent biofilm formation occurred in response to changes in cellular respiratory status. Genetic evidence presented suggests that a high cellular titer of phosphorylated SaeR is required for biofilm formation. Epistasis analyses found that SaeRS and SrrAB influence biofilm formation independently of one another. Analyses using a mouse model of orthopedic implant-associated biofilm formation found that both SaeRS and SrrAB govern host colonization. Of these two TCRSs, SrrAB was the dominant system driving biofilm formation in vivo. We propose a model wherein impaired cellular respiration stimulates SaeRS via an as yet undefined signal molecule(s), resulting in increasing expression of AtlA and FnBPA and biofilm formation.

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