Although viruses and bacteria have been known as agents of diseases since 1546, 250 years went by until the first vaccines against these pathogens were developed (1796 and 1800s). In contrast, ...Malaria, which is a protozoan-neglected disease, has been known since the 5th century BCE and, despite 2,500 years having passed since then, no human vaccine has yet been licensed for Malaria. Additionally, no modern human vaccine is currently licensed against Visceral or Cutaneous leishmaniasis. Vaccination against Malaria evolved from the inoculation of irradiated sporozoites through the bite of Anopheles mosquitoes in 1930's, which failed to give protection, to the use of controlled human Malaria infection (CHMI) provoked by live sporozoites of
and curtailed with specific chemotherapy since 1940's. Although the use of CHMI for vaccination was relatively efficacious, it has some ethical limitations and was substituted by the use of injected recombinant vaccines expressing the main antigens of the parasite cycle, starting in 1980. Pre-erythrocytic (PEV), Blood stage (BSV), transmission-blocking (TBV), antitoxic (AT), and pregnancy-associated Malaria vaccines are under development. Currently, the RTS,S-PEV vaccine, based on the circumsporozoite protein, is the only one that has arrived at the Phase III trial stage. The "R" stands for the central repeat region of
circumsporozoite protein (CSP); the "T" for the T-cell epitopes of the CSP; and the "
" for hepatitis B surface antigen (HBsAg). In Africa, this latter vaccine achieved only 36.7% vaccine efficacy (VE) in 5-7 years old children and was associated with an increase in clinical cases in one assay. Therefore, in spite of 35 years of research, there is no currently licensed vaccine against Malaria. In contrast, more progress has been achieved regarding prevention of leishmaniasis by vaccine, which also started with the use of live vaccines. For ethical reasons, these were substituted by second-generation subunit or recombinant DNA and protein vaccines. Currently, there is one live vaccine for humans licensed in Uzbekistan, and four licensed veterinary vaccines against visceral leishmaniasis: Leishmune® (76-80% VE) and CaniLeish® (68.4% VE), which give protection against strong endpoints (severe disease and deaths under natural conditions), and, under less severe endpoints (parasitologically and PCR-positive cases), Leishtec® developed 71.4% VE in a low infective pressure area but only 35.7% VE and transient protection in a high infective pressure area, while Letifend® promoted 72% VE. A human recombinant vaccine based on the Nucleoside hydrolase NH36 of
, the main antigen of the Leishmune® vaccine, and the sterol 24-c-methyltransferase (SMT) from
has reached the Phase I clinical trial phase but has not yet been licensed against the disease. This review describes the history of vaccine development and is focused on licensed formulations that have been used in preventive medicine. Special attention has been given to the delay in the development and licensing of human vaccines against Protozoan infections, which show high incidence worldwide and still remain severe threats to Public Health.
Leishmania amazonensis is the etiological agent of tegumentary leishmaniasis, a disease characterized by the emergence of cutaneous and mucocutaneous ulcerated lesions that can evolve into severe ...destruction of skin tissue. Treatment of the disease is often accompanied by high toxicity and variable efficacy. Essential oils stand out for having diverse pharmacological properties. Here, we screened a panel of fourteen essential oils for their anti‐L. amazonensis activity, cytotoxicity, and chemical profile. Lippia sidoides (LSEO) and Piper callosum (PCEO) oils displayed the best anti‐promastigote and anti‐amastigote activities with IC50 of 31 and 21 μg/ml, respectively. PCEO was the safest oil with a desirable selectivity index >10. In addition, PCEO showed no cytotoxicity against the VERO line and erythrocytes. PCEO‐treated amastigotes displayed mitochondrial membrane depolarization and high levels of intracellular ROS. Safrole (54.72 %) was the main component of PCEO. The results described here highlight the use of essential oils to combat tegumentary leishmaniasis.
Humoral response in Leishmaniasis Conde, Luciana; Maciel, Gabriela; de Assis, Gustavo Meira ...
Frontiers in cellular and infection microbiology,
12/2022, Volume:
12
Journal Article
Peer reviewed
Open access
Leishmaniasis presents different types of clinical manifestations that can be divided into cutaneous leishmaniasis and visceral leishmaniasis. The host's immune system, associated with genetic and ...nutritional factors, is strongly involved in the evolution of the disease or parasite escape. Humoral immunity is characterized by the production of antibodies capable of promoting neutralization, opsonization, and activation of the complement system. In this scenario, B lymphocytes produce antibodies that play an important role in Leishmania infection although neglected for a long time. Thus, relevant aspects in the establishment of Leishmania infection will be addressed, highlighting the importance of humoral immunity during the entire process of Leishmania infection.
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is the etiological agent of Cutaneous (CL) and Mucocutaneous leishmaniasis (ML) in the New World. CL can be more benign but ML can be severe and disfiguring. Immunity to these diseases include ...hypersensitivity, an enhanced inflammatory response with strong IFN-γ and TNF-α secretion. Additionally, the production of IL-10 which down modulates the immune response is reduced. The Nucleoside hydrolase (NH36) of
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is the main antigen of the Leishmune veterinary vaccine and its F3 domain induces a CD4
T cell-mediated protection against
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infection. Prevention of
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.)
infection requires in contrast an additional CD8
T cell mediated response induced by the F1 domain. Consequently, the F1F3 recombinant chimera, which contains both domains cloned in tandem, optimized the vaccine efficacy against
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mouse infection. We compared the efficacies of NH36, F1, F3, and the FIF3 chimera against
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mouse infection. The F1F3 chimera increased the NH36 specific IgA and response before and after infection and the IgG and IgG3 levels after challenge. It also induced a 49% stronger intradermal response to leishmanial antigen (IDR) than NH36 that was positively correlated to the levels of IFN-γ and TNF-α, IgG, IgG2a, IgG2b, and IgG3 anti-NH36 antibodies. However, stronger Th1 responses with elevated IFN-γ
IL-10 and TNF-α
IL-10 ratios were promoted by the F3 and F1 vaccines and detected in infected controls while the F1F3 chimera promoted the highest IL-10 secretion, which reduced the pathological Th1 response, and characterized the induction of a mixed and/or T-cell regulatory response. We identified the epitopes responsible for these immune responses. The F3 vaccine induced the earliest immunity and after challenge, the F1F3 chimera promoted the highest CD4
and CD8
cytokine-secreting T cell responses, and the predominant frequencies of multifunctional CD4
and CD8
IL-2
TNF-α
IFN-γ
T cells. Also as observed against
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.)
infection, the F1F3 chimera showed the strongest reduction of the ear lesions sizes induced by
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.)
. Our results confirm the potential use of the F1F3 chimera in a multi-species cross-protective vaccine against
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.
Leishmania infantum is responsible for visceral leishmaniasis, the most severe form of the disease. The treatments currently used are pentavalent antimonials and amphotericin B, but they present ...serious side effects and resistant species that already exist. Therefore, it is necessary to find new compounds to avoid those acute problems. In vitro, this study evaluated the effects of fifteen digoxin derivative compounds on promastigotes and two of these compounds on amastigotes of L. infantum. We also assess the impact of these compounds on mitochondrial metabolism. The results showed that two of the fifteen compounds tested showed a high anti-Leishmania effect. Compounds 3 and 15 showed no toxicity across the cell lines RAW 264.7. Compound 15 inhibited macrophage infection and reduced the number of amastigotes. The two compounds showed a reduction in oxygen consumption by promastigotes. In this way, compounds 3 and 15 appear to be promising anti-leishmanial. Therefore, we checked both compounds in vivo also evaluating the toxicity by measuring ALT, AST, urea, and creatinine. Our results may contribute in the future to the development and application of new anti-Leishmania drugs.
The
nucleoside hydrolase NH36 is the main antigen of the Leishmune
vaccine and one of the promising candidates for vaccination against visceral leishmaniasis. The antigenicity of the N-terminal (F1), ...the central (F2), or the C-terminal recombinant domain (F3) of NH36 was evaluated using peripheral blood mononuclear cells (PBMC) from individuals infected with
from an endemic area of visceral leishmaniasis of Spain. Both NH36 and F1 domains significantly increased the PBMC proliferation stimulation index of cured patients and infected asymptomatic individuals compared to healthy controls. Moreover, F1 induced a 19% higher proliferative response than NH36 in asymptomatic exposed subjects. In addition, in patients cured from visceral leishmaniasis, proliferation in response to NH36 and F1 was accompanied by a significant increase of IFN-γ and TNF-α secretion, which was 42-43% higher, in response to F1 than to NH36. The interleukin 17 (IL-17) secretion was stronger in asymptomatic subjects, in response to F1, as well as in cured cutaneous leishmaniasis after NH36 stimulation. While no IL-10 secretion was determined by F1, a granzyme B increase was detected in supernatants from cured patients after stimulation with either NH36 or F1. These data demonstrate that F1 is the domain of NH36 that induces a recall cellular response in individuals with acquired resistance to the infection by
. In addition, F1 and NH36 discriminated the IgG3 humoral response in patients with active visceral leishmaniasis due to
(Ethiopia) and
(Spain) from that of endemic and non-endemic area controls. NH36 showed higher reactivity with sera from
-infected individuals, indicating species specificity. We conclude that the F1 domain, previously characterized as an inducer of the Th1 and Th17 responses in cured/exposed patients infected with
, may also be involved in the generation of a protective response against
and represents a potential vaccine candidate for the control of human leishmaniasis alone, or in combination with other HLA epitopes/antigens.
Human tegumentary leishmaniasis (HTL) is a serious tropical disease caused by 'Leishmania amazonensis'. Developing new leishmanicidal agents can help overcome current treatment challenges, such as ...drug resistance and toxicity. Essential oils are a source of lipophilic substances with diverse therapeutic properties. This study aimed to determine the anti-'L. amazonensis' activity, cytotoxicity, and chemical profile of 'Allium sativum' essential oil (ASEO). The effect of ASEO on parasite and mammalian cells viability was evaluated using resazurin and MTT assays, respectively. The oil's effect against intracellular amastigotes was also determined. Transmission electron microscopy was used to assess the ultrastructural changes induced by ASEO. In addition, the chemical constituents of ASEO were identified by gas chromatography-mass spectrometry (GC-MS). The cytotoxic potential was evaluated in vitro and in silico. The oil displayed IC50 of 1.76, 3.46, and 3.77 μg/mL against promastigotes, axenic, and intracellular amastigotes, respectively. Photomicrographs of treated parasites showed plasma membrane disruption, increased lipid bodies, and autophagic-like structures. ASEO chemical profiling revealed 1,2,4,6-tetrathiepane (24.84%) and diallyl disulfide (16.75%) as major components. Computational pharmacokinetics and toxicological analysis of ASEO's major components demonstrated good oral bioavailability and better toxicological endpoints than the reference drugs. Altogether, the results suggest that ASEO could be an alternative drug candidate against HTL.
The SARS-CoV-2 P.1 variant, responsible for an outbreak in Manaus, Brazil, is distinguished by 12 amino acid differences in the S protein, potentially increasing its ACE-2 affinity and immune evasion ...capability. We investigated the innate immune response of this variant compared to the original B.1 strain, particularly concerning cytokine production. Blood samples from three severe COVID-19 patients were analyzed post-infection with both strains. Results showed no significant difference in cytokine production of mononuclear cells and neutrophils for either variant. While B.1 had higher cytopathogenicity, neither showed viral replication in mononuclear cells. Structural analyses of the S protein highlighted physicochemical variations, which might be linked to the differences in infectivity between the strains. Our studies point to the increased infectivity of P.1 could stem from altered immunogenicity and receptor-binding affinity.
Physical contact between dendritic cells (DCs) and T cell lymphocytes is necessary to trigger the immune cell response. CCL19 and CCL21 chemokines bind to the CCR7 receptor of mature DCs, and of T ...cells and regulate DCs migration to the white pulp (wp) of the spleen, where they encounter lymphocytes. In visceral leishmaniasis (VL), cellular immunosuppression is mediated by impaired DC migration due to the decreased chemokine secretion by endothelium and to the reduced DCs CCR7 expression. The
nucleoside hydrolase NH36 and its C-terminal domain, the F3 peptide are prominent antigens in the generation of preventive immunity to VL. We assessed whether these vaccines could prevent the migrating defect of DCs by restoring the expression of CCR7 receptors. C57Bl6 mice were vaccinated with NH36 and F3 and challenged with
. The F3 vaccine induced a 100% of survival and a long-lasting immune protection with an earlier CD4
Th1 response, with secretion of higher IFN-γ and TNF-α/IL-10 ratios, and higher frequencies of CD4
T cells secreting IL-2
, TNF-α
, or IFN-γ
, or a combination of two or the three cytokines (IL-2
TNF-α
IFN-γ
). The CD8
T cell response was promoted earlier by the NH36-vaccine, and later by the F3-vaccine. Maximal number of F3-primed DCs migrated
in response to CCL19 and showed a high expression of CCR7 receptors (26.06%). Anti-CCR7 antibody treatment inhibited DCs migration
(90%) and increased parasite load
. When transferred into 28-day-infected mice, only 8% of DCs from infected, 59% of DCs from NH36-vaccinated, and 84% of DCs from F3-vaccinated mice migrated to the wp. Consequently, immunotherapy of infected mice with F3-primed DCs only, promoted increases in corporal weight and reductions of spleen and liver parasite loads and relative weights. Our findings indicate that vaccination with F3-vaccine preserves the maturation, migration properties and CCR7 expression of DCs, which are essential processes for the generation of cell-mediated immunity. The F3 vaccine is more potent in reversing the migration defect that occurs in VL and, therefore, more efficient in immunotherapy of VL.
Visceral leishmaniasis is a neglected disease caused by
protozoa parasites transmitted by infected sand fly vectors. This disease represents the second in mortality among tropical infections and is ...associated to a profound immunosuppression state of the host. The hallmark of this infection-induced host immunodeviation is the characteristic high levels of the regulatory interleukin-10 (IL-10) cytokine. In the present study, we investigated the role of B-1 cells in the maintenance of splenic IL-10 levels that could interfere with resistance to parasite infection. Using an experimental murine infection model with
we demonstrated an improved resistance of B-1 deficient BALB/XID mice to infection. BALB/XID mice developed a reduced splenomegaly with diminished splenic parasite burden and lower levels of IL-10 secretion of purified splenocytes at 30 days post-infection, as compared to BALB/c wild-type control mice. Interestingly, we found that resident peritoneal macrophages isolated from BALB/XID mice were more effective to control the parasite load in comparison to cells isolated from BALB/c wild-type mice. Our findings point to a role of B-1 cells in the host susceptibility to visceral leishmaniasis.
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