Cancer vaccines are the promising tools in the hands of the clinical oncologist. Many tumor-associated antigens are excellent targets for immune therapy and vaccine design. Optimally designed cancer ...vaccines should combine the best tumor antigens with the most effective immunotherapy agents and/or delivery strategies to achieve positive clinical results. Various vaccine delivery systems such as different routes of immunization and physical/chemical delivery methods have been used in cancer therapy with the goal to induce immunity against tumor-associated antigens. Two basic delivery approaches including physical delivery to achieve higher levels of antigen production and formulation with microparticles to target antigen-presenting cells (APCs) have demonstrated to be effective in animal models. New developments in vaccine delivery systems will improve the efficiency of clinical trials in the near future. Among them, nanoparticles (NPs) such as dendrimers, polymeric NPs, metallic NPs, magnetic NPs and quantum dots have emerged as effective vaccine adjuvants for infectious diseases and cancer therapy. Furthermore, cell-penetrating peptides (CPP) have been known as attractive carrier having applications in drug delivery, gene transfer and DNA vaccination. This review will focus on the utilization of different vaccine delivery systems for prevention or treatment of cancer. We will discuss their clinical applications and the future prospects for cancer vaccine development.
Leishmaniasis is a vector-borne disease caused by the protozoan parasite of
genus and is a complex disease affecting mostly tropical regions of the world. Unfortunately, despite the extensive effort ...made, there is no vaccine available for human use. Undoubtedly, a comprehensive understanding of the host-vector-parasite interaction is substantial for developing an effective prophylactic vaccine. Recently the role of sandfly saliva on disease progression has been uncovered which can make a substantial contribution in vaccine design. In this review we try to focus on the strategies that most probably meet the prerequisites of vaccine development (based on the current understandings) including live attenuated/non-pathogenic and subunit DNA vaccines. Innovative approaches such as reverse genetics, CRISP/R-Cas9 and antibiotic-free selection are now available to promisingly compensate for intrinsic drawbacks associated with these platforms. Our main goal is to call more attention toward the prerequisites of effective vaccine development while controlling the disease outspread is a substantial need.
Cutaneous leishmaniasisis a vector-borne disease transmitted by Leishmania infected sand flies. PpSP15 is an immunogenic salivary protein from the sand fly Phlebotomus papatasi. Immunization with ...PpSP15 was shown to protect against Leishmania major infection. Lactococcus lactis is a safe non-pathogenic delivery system that can be used to express antigens in situ. Here, the codon-optimized Ppsp15-egfp gene was cloned in pNZ8121 vector downstream of the PrtP signal peptide that is responsible for expression and secretion of the protein on the cell wall. Expression of PpSP15-EGFP recombinant protein was monitored by immunofluorescence, flow cytometry and Western blot. Also, expression of protein in cell wall compartment was verified using whole cell ELISA, Western blot and TEM microscopy. BALB/c mice were immunized three times with recombinant L. lactis-PpSP15-EGFPcwa, and the immune responses were followed up, at short-term (ST, 2 weeks) and long-term (LT, 6 months) periods. BALB/c mice were challenged with L. major plus P. papatasi Salivary Gland Homogenate. Evaluation of footpad thickness and parasite burden showed a delay in the development of the disease and significantly decreased parasite numbers in PpSP15 vaccinated animals as compared to control group. In addition, immunized mice showed Th1 type immune responses. Importantly, immunization with L. lactis-PpSP15-EGFPcwa stimulated the long-term memory in mice which lasted for at least 6 months.
Today the development of antibiotic resistance, especially in the treatment of bacterial infections associated with biofilms, has led to increasing the importance of antimicrobial peptides (AMPs). In ...this work, antimicrobial and synergistic activity of three truncated HNP-1 analogs (2Abz14S29, 2Abz23S29, and HNP1ΔC18A) with β-lactam (amoxicillin and cefixime) and fluoroquinolones (ciprofloxacin and norfloxacin) antibiotics against multidrug-resistant (MDR) uropathogenic E. coli clinical isolates were evaluated. The anti-biofilm potential of peptides at different stages was also investigated. All peptides exhibited additive activity just with β-lactam antibiotics in a checkerboard synergy assay. Inhibition and eradication of MDR uropathogenic E. coli biofilm were shown by all test peptides at different concentrations. Thus, truncated HNP-1 analogs (2Abz14S29, 2Abz23S29, and HNP1ΔC18A) may have the potential for the treatment of urinary tract infections (UTIs) caused by biofilm-forming MDR uropathogenic E. coli.
Proliferation of Leishmania (L.) parasites depends on polyamine availability, which can be generated by the L-arginine catabolism and the enzymatic activity of arginase (ARG) of the parasites and of ...the mammalian hosts. In the present study, we characterized and compared the arginase (arg) genes from pathogenic L. major and L. tropica and from non-pathogenic L. tarentolae. We quantified the level of the ARG activity in promastigotes and macrophages infected with pathogenic L. major and L. tropica and non-pathogenic L. tarentolae amastigotes. The ARG's amino acid sequences of the pathogenic and non-pathogenic Leishmania demonstrated virtually 98.6% and 88% identities with the reference L. major Friedlin ARG. Higher ARG activity was observed in all pathogenic promastigotes as compared to non-pathogenic L. tarentolae. In vitro infection of human macrophage cell line (THP1) with pathogenic and non-pathogenic Leishmania spp. resulted in increased ARG activities in the infected macrophages. The ARG activities present in vivo were assessed in susceptible BALB/c and resistant C57BL/6 mice infected with L. major, L. tropica and L. tarentolae. We demonstrated that during the development of the infection, ARG is induced in both strains of mice infected with pathogenic Leishmania. However, in L. major infected BALB/c mice, the induction of ARG and parasite load increased simultaneously according to the time course of infection, whereas in C57BL/6 mice, the enzyme is upregulated solely during the period of footpad swelling. In L. tropica infected mice, the footpads' swellings were slow to develop and demonstrated minimal cutaneous pathology and ARG activity. In contrast, ARG activity was undetectable in mice inoculated with the non-pathogenic L. tarentolae. Our data suggest that infection by Leishmania parasites can increase ARG activity of the host and provides essential polyamines for parasite salvage and its replication. Moreover, the ARG of Leishmania is vital for parasite proliferation and required for infection in mice. ARG activity can be used as one of the main marker of the disease severity.
Leishmaniasis is a health-threatening vector-borne disease in almost 90 different countries. While a prophylactic human vaccine is not yet available, the fact that recovery from leishmaniasis ...establishes lifelong immunity against secondary infection suggests that a vaccine is attainable. In the past, deliberate infection with virulent parasites, termed Leishmanization, was used as a live-vaccine against cutaneous leishmaniasis and effectively protected against vector-transmitted disease in endemic areas. However, the practice was discontinued due to major complications including non-healing skin lesions, exacerbation of skin diseases, and the potential impact of immunosuppression. Instead, tremendous effort has been made to develop killed, live attenuated, and non-living subunit formulations. Many of these formulations produce promising experimental results but have failed in field trials or against experimental challenge with infected sand flies. Recently, experimental models of leishmanization have unraveled the critical role of parasite persistence in maintaining the circulating CD4
effector T cells responsible for mitigating the inflammatory response early after sand fly challenge and mediating protective immunity. Here, we put forward the notion that for effective vaccine design (especially non-living vaccines), the role of antigen persistence and pre-existing effector CD4
T cells should be taken into consideration. We propose that dendritic cell-based vaccination strategies warrant greater attention because of their potential to act as long-term antigen depots, thereby emulating this critical requirement of naturally acquired protective immunity against infected sand fly challenge.
Leishmaniasis is a neglected vector-borne disease caused by
Leishmania
parasites transmitted through the infected sand flies bite. Current treatments are limited, partly due to their high cost and ...significant adverse effects, and no human vaccine is yet available. Sand flies saliva has been examined for their potential application as an anti-
Leishmania
vaccine. The salivary protein, PpSP15, was the first protective vaccine candidate against
L. major
. Additionally, PsSP9 was already introduced as a highly immunogenic salivary protein against
L. tropica
. Herein, we aimed to develop an effective multivalent live vaccine to control Cutaneous Leishmaniasis induced by two main species,
L. major
and
L. tropica
. Hence, the two above-mentioned salivary proteins using T2A linker were incorporated inside the
L. tarentolae
genome as a safe live vector. Then, the immunogenicity and protective effects of recombinant
L. tarentolae
co-expressing PpSP15 and PsSP9 were evaluated in pre-treated BALB/c mice with CpG against
L. major
and
L. tropica
. Following the cytokine assays, parasite burden and antibody assessment at different time-points at pre and post-infection, promising protective Th1 immunity was obtained in vaccinated mice with recombinant
L. tarentolae
co-expressing PpSP15 and PsSP9. This is the first study demonstrating the potency of a safe live vaccine based on the combination of different salivary proteins against the infectious challenge with two different species of
Leishmania
.
Leishmania parasites are deposited in the host through sand fly bites along with sand fly saliva. Therefore, salivary proteins are promising vaccine candidates for controlling leishmaniasis. Herein, ...two immunogenic salivary proteins, PpSP15 from Phlebotomus papatasi and PsSP9 from Phlebotomus sergenti, were selected as vaccine candidates to be delivered by live Leishmania tarentolae as vector. The stepwise in silico protocol advantaged in this study for multi-protein design in L. tarentolae is then described in detail. All possible combinations of two salivary proteins, PpSP15 and PsSP9, with or without T2A peptide were designed at the mRNA and protein levels. Then, the best combination for the vaccine candidate was selected based on mRNA and protein stability along with peptide analysis. At the mRNA level, the most favored secondary structure was PpSP15-T2A-PsSP9. At the protein level, the refined three-dimensional models of all combinations were structurally valid; however, local quality estimation showed that the PpSp15-T2A-PsSP9 fusion had higher stability for each amino acid position, with low root-mean-square deviation (RMSD), compared with the original proteins. In silico evaluation confirmed the PpSP15-T2A-PsSP9 combination as a good Th1-polarizing candidate in terms of high IFN-gamma production and low IL-10/TGF-beta ratio in response to three consecutive immunizations. Potential protein expression was then confirmed by Western blotting. The approach presented herein is among the first studies to have privileged protein homology modeling along with mRNA analysis for logical live vaccine design-coding multi-proteins.
Biomarkers of Cutaneous Leishmaniasis Bahrami, Fariborz; Harandi, Ali M; Rafati, Sima
Frontiers in cellular and infection microbiology,
06/2018, Letnik:
8
Journal Article
Recenzirano
Odprti dostop
Cutaneous leishmaniasis (CL) is an immune-mediated skin pathology caused mainly by
(
.)
, and
. The burden of CL in terms of morbidity and social stigmas are concentrated on certain developing ...countries in Asia, Africa, and South America. People with asymptomatic CL represent a large proportion of the infected individuals in the endemic areas who exhibit no lesion and can control the infection by as yet not fully understood mechanisms. Currently, there is no approved prophylactic control measure for CL. Discovery of biomarkers of CL infection and immunity can inform the development of more precise diagnostics tools as well as curative or preventive strategies to control CL. Herein, we provide a brief overview of the state-of-the-art for the biomarkers of CL with a special emphasis on the asymptomatic CL biomarkers. Among the identified CL biomarkers so far, direct biomarkers which indicate the actual presence of the infection as well as indirect biomarkers which reflect the host's reaction to the infection, such as alterations in delayed type hypersensitivity, T-cell subpopulations and cytokines, adenosine deaminase, and antibodies against the sand fly saliva proteins are discussed in detail. The future avenues such as the use of systems analysis to identify and characterize novel CL biomarkers are also discussed.
Although there have been significant advances in the treatment of visceral leishmaniasis (VL) and several novel compounds are currently in pre-clinical and clinical development for this manifestation ...of leishmaniasis, there have been limited advances in drug research and development (R & D) for cutaneous leishmaniasis (CL). Here we review the need for new treatments for CL, describe in vitro and in vivo assays, models and approaches taken over the past decade to establish a pathway for the discovery, and pre-clinical development of new drugs for CL. These recent advances include novel mouse models of infection using bioluminescent Leishmania, the introduction of PK/PD approaches to skin infection, and defined pre-clinical candidate profiles.
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