The Zika virus (ZIKV) was first isolated from a rhesus macaque in the Zika forest of Uganda in 1947. Isolated cases were reported until 2007, when the first major outbreaks of Zika infection were reported from the Island of Yap in... more
The Zika virus (ZIKV) was first isolated from a rhesus macaque in the Zika forest of Uganda in 1947. Isolated cases were reported until 2007, when the first major outbreaks of Zika infection were reported from the Island of Yap in Micronesia and from French Polynesia in 2013. In 2015, ZIKV started to circulate in Latin America, and in 2016, ZIKV was considered by WHO to be a Public Health Emergency of International Concern due to cases of Congenital Zika Syndrome (CZS), a ZIKV-associated complication never observed before. After a peak of cases in 2016, the infection incidence dropped dramatically but still causes concern because of the associated microcephaly cases, especially in regions where the dengue virus (DENV) is endemic and co-circulates with ZIKV. A vaccine could be an important tool to mitigate CZS in endemic countries. However, the immunological relationship between ZIKV and other flaviviruses, especially DENV, and the low numbers of ZIKV infections are potential challen...
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‡ These authors contributed equally to this work.
BackgroundEpidemiological and experimental studies have shown a protective effect of helminth infections in weight gain and against the development of metabolic dysfunctions in the host. However, the mechanisms induced by the parasite... more
BackgroundEpidemiological and experimental studies have shown a protective effect of helminth infections in weight gain and against the development of metabolic dysfunctions in the host. However, the mechanisms induced by the parasite that regulate the development of metabolic diseases in the host are unclear. The present study aimed to verify the influence of Heligmosomoides polygyrus infection in early stages of high fat diet-induced obesity.Principal FindingsThe presence of infection was able to prevent exacerbated weight gain in mice fed with high fat diet when compared to non-infected controls. In addition, infected animals displayed improved insulin sensitivity and decreased fat accumulation in the liver. Obesity-associated inflammation was reduced in the presence of infection, demonstrated by higher levels of IL10 and adiponectin, increased infiltration of Th2 and eosinophils in adipose tissue of infected animals. Of note, the parasite infection was associated with increased ...
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Doxorubicin (DOX), a chemotherapy drug successfully used in the therapy of various types of cancer, is currently associated with the mucositis development, an inflammation that can cause ulcerative lesions in the mucosa of the... more
Doxorubicin (DOX), a chemotherapy drug successfully used in the therapy of various types of cancer, is currently associated with the mucositis development, an inflammation that can cause ulcerative lesions in the mucosa of the gastrointestinal tract, abdominal pain and secondary infections. To increase the safety of the chemotherapy, we loaded DOX into nanostructured lipid carriers (NLCs). The NLC–DOX was characterized by HPLC, DLS, NTA, Zeta potential, FTIR, DSC, TEM and cryogenic-TEM. The ability of NLC–DOX to control the DOX release was evaluated through in vitro release studies. Moreover, the effect of NLC–DOX on intestinal mucosa was compared to a free DOX solution in C57BL/6 mice. The NLC–DOX showed spherical shape, high drug encapsulation efficiency (84.8 ± 4.6%), high drug loading (55.2 ± 3.4 mg/g) and low average diameter (66.0–78.8 nm). The DSC and FTIR analyses showed high interaction between the NLC components, resulting in controlled drug release. Treatment with NLC–DOX...
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Infectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the... more
Infectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi , parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80 + macrophages, and T. cruzi tetramer-specific CD8 + T lymphocytes capable of producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) but not interleukin-17 (IL-17). T. cruzi -specific IgG was detected in...
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Immunological cross-reactivity between environmental allergens and helminth proteins has been demonstrated, although the clinically related implications of this cross-reactivity have not been addressed. To investigate the impact of... more
Immunological cross-reactivity between environmental allergens and helminth proteins has been demonstrated, although the clinically related implications of this cross-reactivity have not been addressed. To investigate the impact of molecular similarity among allergens and cross-reactive homologous helminth proteins in IgE-based serologic assessment of allergic disorders in a helminth-infected population, we performed ImmunoCAP tests in filarial-infected and noninfected individuals for IgE measurements to allergen extracts that contained proteins with high levels of homology with helminth proteins as well as IgE against representative recombinant allergens with and without helminth homologs. The impact of helminth infection on the levels and function of the IgE to these specific homologous and nonhomologous allergens was corroborated in an animal model. We found that having a tissue-invasive filarial infection increased the serological prevalence of ImmunoCAP-identified IgE directed ...
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Live attenuated Leishmania donovani parasites such as LdCen(-/-) have been shown elicit protective immunity against leishmanial infection in mice and hamster models. Previously, we have reported on the induction of strong immunogenicity... more
Live attenuated Leishmania donovani parasites such as LdCen(-/-) have been shown elicit protective immunity against leishmanial infection in mice and hamster models. Previously, we have reported on the induction of strong immunogenicity in dogs upon vaccination with LdCen(-/-) including an increase in immunoglobulin isotypes, higher lymphoproliferative response, higher frequencies of activated CD4(+) and CD8(+) T cells, IFN-γ production by CD8(+) T cells, increased secretion of TNF-α and IL-12/IL-23p40 and, finally, decreased secretion of IL-4. To further explore the potential of LdCen(-/-) parasites as vaccine candidates, we performed a 24-month follow up of LdCen(-/-) immunized dogs after challenge with virulent Leishmania infantum, aiming determination of parasite burden by qPCR, antibody production (ELISA) and cellular responses (T cell activation and cytokine production) by flow cytometry and sandwich ELISA. Our data demonstrated that vaccination with a single dose of LdCen(-/-...
Research Interests: Biology, Virology, Brazil, Leishmania, Medicine, and 15 moreBiological Sciences, Dogs, Leishmaniasis, Animals, Visceral Leishmaniasis, Follow-up studies, Vaccine, Vaccination, Tumor necrosis factor-alpha, Leishmania infantum, Enzyme Linked Immunosorbent Assay, Interleukin, Interferon gamma, real time polymerase chain reaction, and Medical and Health Sciences
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Research Interests: Immunology, Biology, Cytokines, Immunology of the Gut, Medicine, and 14 moreSignal Transduction, Toll like receptor signaling, Humans, Mice, Animals, The, Chagas disease, Trypanosoma Cruzi, Tumor necrosis factor-alpha, Antigen presenting cells, Interleukin, Innate Immune System, Interferon gamma, and Inflammation Mediators
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Background. Asthma is a chronic pulmonary disease that affects about 300 million people worldwide. Previous studies have associated antimicrobial use with allergies, but the real impact of antibiotics on asthma is still elusive. We... more
Background. Asthma is a chronic pulmonary disease that affects about 300 million people worldwide. Previous studies have associated antimicrobial use with allergies, but the real impact of antibiotics on asthma is still elusive. We investigated the potential impact of amoxicillin (Amox), trimethoprim/sulfamethoxazole (TMP/SMX), and metronidazole (Metro) in a murine model of OVA-induced allergic airway inflammation. Methods. BALB/c mice received three cycles of 7 days of antibiotics in drinking water followed by 7 days washout and were sensitized i.p. with OVA/Alum at days 0 and 14. After the end of the last antibiotic washout, the mice were challenged with aerosolized OVA. Pulmonary parameters were evaluated, and serum, BAL, and feces were collected for analysis. Results. Amox- and TMP/SMX-treated animals displayed more severe allergic airway inflammation parameters with increased airway hyperresponsiveness, reduced lung alveolar volume, and increased levels in BAL of IL-4 and IL-6....
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Background. Currently, the number of obese people in the world has reached alarming proportions. During the expansion of adipose tissue, a number of functions such as activation and release of cytokines and hormones may be affected. This... more
Background. Currently, the number of obese people in the world has reached alarming proportions. During the expansion of adipose tissue, a number of functions such as activation and release of cytokines and hormones may be affected. This causes the body to take a pro-inflammatory pattern, which may affect the proper functioning of many tissues. Thus, studying the mechanisms by which obesity induces physiological disorders is necessary, and may be facilitated by the use of animal models, in particular rodents. We sought to investigate whether the gerbil (Meriones unguiculatus) would be a good experimental model for the study of obesity and metabolic changes resulting from a diet rich in fats and sugars. Methods. 14 gerbils were divided according to weight into two experimental groups and received a a standard diet with 4,15kcal/g (CT; n = 7) or a diet rich in simple carbohydrates and fats with 5,86kcal/g (OB, n = 7) for 11 weeks. The animals had free access to water and food. The wei...
Several antigens from , the causative agent of Chagas disease (CD), contain amino acid repeats identified as targets of the host immune response. Ribosomal proteins containing an Ala, Lys, Pro-rich repeat domain are among the antigens... more
Several antigens from , the causative agent of Chagas disease (CD), contain amino acid repeats identified as targets of the host immune response. Ribosomal proteins containing an Ala, Lys, Pro-rich repeat domain are among the antigens that are strongly recognized by antibodies from CD patients. Here we investigated the role of amino acid repeats present in the ribosomal protein L7a, by immunizing mice with recombinant versions of the full-length protein (TcRpL7a), as well as with truncated versions containing only the repetitive (TcRpL7aRep) or the non-repetitive domains (TcRpL7aΔRep). Mice immunized with full-length TcRpL7a produced high levels of IgG antibodies against the complete protein as well as against the repeat domain, whereas mice immunized with TcRpL7aΔRep or TcRpL7aRep produced very low levels or did not produce IgG antibodies against this antigen. Also in contrast to mice immunized with the full-length TcRpL7a, which produced high levels of IFN-γ, only low levels of IF...
Excess intake of sodium is often associated with high risk for cardiovascular disease. More recently, some studies on the effects of high-salt diets (HSDs) have also demonstrated that they are able to activate Th17 cells and increase... more
Excess intake of sodium is often associated with high risk for cardiovascular disease. More recently, some studies on the effects of high-salt diets (HSDs) have also demonstrated that they are able to activate Th17 cells and increase severity of autoimmune diseases. The purpose of the present study was to evaluate the effects of a diet supplemented with NaCl in the colonic mucosa at steady state and during inflammation. We showed that consumption of HSD by mice triggered a gut inflammatory reaction associated with IL-23 production, recruitment of neutrophils, and increased frequency of the IL-17-producing type 3 innate lymphoid cells (ILC3) in the colon. Moreover, gut inflammation was not observed in IL-17-/- mice but it was present, although at lower grade, in RAG mice suggesting that the inflammatory effects of HSD was dependent on IL-17 but only partially on Th17 cells. Expression of SGK1, a kinase involved in sodium homeostasis, increased 90 min after ingestion of 50% NaCl solut...
Implied under the rubric of the hygiene hypothesis is that helminth infection can protect against allergic disease. It is well known that helminths induce processes associated with type 2 immune responses, but they also induce important... more
Implied under the rubric of the hygiene hypothesis is that helminth infection can protect against allergic disease. It is well known that helminths induce processes associated with type 2 immune responses, but they also induce important regulatory responses that can modulate these type 2-associated responses-modulation that influences responses to bystander antigens including allergens. Indeed, most epidemiological studies demonstrate a beneficial effect of helminth infection on atopy, but there are also convincing data to demonstrate that helminth infection can precipitate or worsen allergic inflammation/disease. Reasons for these disparate findings are much debated, but there is a school of thought that suggests that helminth-triggered type 2-associated responses, including IgE to cross-reactive aeroallergens, can offset the regulatory effects imposed by the same organisms. The cross-reactivity among helminths and allergenic tropomyosins dominated the antigen/allergen cross-reacti...
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Nowadays, the number of obese people in the world has reached alarming proportions. During the expansion of adipose tissue, a number of functions such as activation and release of cytokines and hormones may be affected. This leads the... more
Nowadays, the number of obese people in the world has reached alarming proportions. During the expansion of adipose tissue, a number of functions such as activation and release of cytokines and hormones may be affected. This leads the body to a pro-inflammatory pattern, which may affect the proper functioning of many tissues. Thus, studying the mechanisms by which obesity induces physiological disorders is necessary, and may be facilitated by the use of animal models, in particular rodents. We sought to characterize the metabolic and adipose tissue changes resulting from a diet rich in fats and simple sugars in gerbils. We divided 14 gerbils into two experimental groups that received a diet rich in simple carbohydrates and fats with 5,86 kcal/g (OB, n = 7) or a standard diet with 4.15 kcal/g (CT; n = 7) for 11 weeks. The animals had free access to water and food. The animal weight and food consumption were measured weekly. Blood, adipose tissue and liver of each animal were collecte...
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Live attenuated Leishmania donovani parasites such as LdCen(-/-) have been shown elicit protective immunity against leishmanial infection in mice and hamster models. Previously, we have reported on the induction of strong immunogenicity... more
Live attenuated Leishmania donovani parasites such as LdCen(-/-) have been shown elicit protective immunity against leishmanial infection in mice and hamster models. Previously, we have reported on the induction of strong immunogenicity in dogs upon vaccination with LdCen(-/-) including an increase in immunoglobulin isotypes, higher lymphoproliferative response, higher frequencies of activated CD4(+) and CD8(+) T cells, IFN-γ production by CD8(+) T cells, increased secretion of TNF-α and IL-12/IL-23p40 and, finally, decreased secretion of IL-4. To further explore the potential of LdCen(-/-) parasites as vaccine candidates, we performed a 24-month follow up of LdCen(-/-) immunized dogs after challenge with virulent Leishmania infantum, aiming determination of parasite burden by qPCR, antibody production (ELISA) and cellular responses (T cell activation and cytokine production) by flow cytometry and sandwich ELISA. Our data demonstrated that vaccination with a single dose of LdCen(-/-...
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The efficacy of the association of paromomycin sulfate (PA) with recombinant (r) interleukin (IL)-12 was investigated by topical treatment of BALB/c mice infected with Leishmania major that displayed fully developed cutaneous lesions.... more
The efficacy of the association of paromomycin sulfate (PA) with recombinant (r) interleukin (IL)-12 was investigated by topical treatment of BALB/c mice infected with Leishmania major that displayed fully developed cutaneous lesions. Although healing was observed in PA-treated groups, lesions recurred in 100% of these animals 70 days after treatment. In contrast, lesions were absent in a high proportion of PA- and rIL-12-treated mice 120 days after treatment. The PA/rIL-12-treated mice had a switch in cytokine response, from high IL-4 and low interferon (IFN)-gamma levels to low IL-4 and high IFN-gamma levels, and reductions in parasite load, dissemination of parasites, and inflammation. Thus, the association of rIL-12 to topical chemotherapy for leishmaniasis may be an important strategy for increasing cure rates and decreasing the incidence of relapse.
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The hygiene hypothesis suggests that parasitic infection modulates host immune responses and decreases atopy. Other data suggest parasitic infections may induce allergic responsiveness. To assess the structural and immunologic... more
The hygiene hypothesis suggests that parasitic infection modulates host immune responses and decreases atopy. Other data suggest parasitic infections may induce allergic responsiveness. To assess the structural and immunologic relationships between the known Dermatophagoides pteronyssinus (Der p 10) tropomyosin allergen and filarial tropomyosin of Onchocerca volvulus (OvTrop). The molecular, structural, and immunologic relationships between OvTrop and Der p 10 were compared. Levels of OvTrop-specific and Der p 10-specific IgE, IgG, and IgG₄ in sera of filaria-infected and filarial-uninfected D pteronyssinus-atopic individuals were compared, as were the responses in nonhuman primates infected with the filarial parasite Loa loa. Cross-reactivity was compared by antigen-mediated depletion assays and functionality by passive basophil sensitization. Filarial and mite tropomyosins were very similar, with 72% identity at the amino acid level, and overlapping predicted 3-dimensional structures. The prevalence of IgE and IgG to Der p 10 was increased in filaria-infected individuals compared with uninfected subjects. There was a strong correlation between serum levels of Ov- and Der p 10-tropomyosin-specific IgE, IgG, and IgG₄ (P < .0001; r > 0.79). Preincubation of sera from anti-Der p 10-positive subjects with OvTrop completely depleted IgE, IgG, and IgG₄ anti-Der p 10. Basophils sensitized with sera from individuals allergic to Der p 10 released histamine similarly when triggered with OvTrop or Der p 10. Primates experimentally infected with L loa developed IgE that cross-reacted with Der p 10. Filarial infection induces strong cross-reactive antitropomyosin antibody responses that may affect sensitization and regulation of allergic reactivity.
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Research Interests: Cytokines, Drug interactions, Macrophages, Flavonoids, Antioxidants, and 14 moreIn Vitro, Reactive Oxygen Species, Mice, Nitric oxide, Animals, Male, Phosphodiesterase Inhibitors, European, Cyclic nucleotides, Anti Inflammatory Activity, Mechanism of action, Polyphenol, Respiratory Burst, and Butylated hydroxytoluene
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Hookworms digest hemoglobin from erythrocytes via a proteolytic cascade that begins with the aspartic protease, APR-1. Ac-APR-1 from the dog hookworm, Ancylostoma caninum, protects dogs against hookworm infection via antibodies that... more
Hookworms digest hemoglobin from erythrocytes via a proteolytic cascade that begins with the aspartic protease, APR-1. Ac-APR-1 from the dog hookworm, Ancylostoma caninum, protects dogs against hookworm infection via antibodies that neutralize enzymatic activity and interrupt blood-feeding. Toward developing a human hookworm vaccine, we expressed both wild-type (Na-APR-1(wt)) and mutant (Na-APR-1(mut)-mutagenesis of the catalytic aspartic acids) forms of Na-APR-1 from the human hookworm, Necator americanus. Refolded Na-APR-1(wt) was catalytically active, and Na-APR-1(mut) was catalytically inactive but still bound substrates. Vaccination of canines with Na-APR-1(mut) and heterologous challenge with A. caninum resulted in significantly reduced parasite egg burdens (P=0.034) and weight loss (P=0.022). Vaccinated dogs also had less gut pathology, fewer adult worms, and reduced blood loss compared to controls but these did not reach statistical significance. Vaccination with Na-APR-1(mut) induced antibodies that bound the native enzyme in the parasite gut and neutralized enzymatic activity of Na-APR-1(wt) and APR-1 orthologues from three other hookworm species that infect humans. IgG1 against Na-APR-1(mut) was the most prominently detected antibody in sera from people resident in high-transmission areas for N. americanus, indicating that natural boosting may occur in exposed humans. Na-APR-1(mut) is now a lead antigen for the development of an antihematophagy vaccine for human hookworm disease.
Research Interests: Physiology, Vaccines, Treatment Outcome, Dogs, Humans, and 14 moreWeight Loss, Animals, Statistical Significance, Vaccination, Medical Physiology, Enzyme, Intestines, Cysteine endopeptidases, Enzymatic Activity, Blood Loss, Necator Americanus, Catalytic Activity, Biochemistry and cell biology, and Neutralizing antibodies
Research Interests: Immune response, Dendritic Cells, Biological Sciences, Cell Differentiation, Humans, and 13 moreAdaptive Immunity, Chronic Disease, Animals, Antigen Presentation, Dendritic cell, Middle Aged, Eosinophils, Adult, Cell Proliferation, Cell Surface Markers, Necator Americanus, Differential expression, and Activation Function
Necator americanus Ancylostoma Secreted Protein-2 (Na-ASP-2) is a leading larval-stage hookworm vaccine candidate. Recombinant Na-ASP-2 was expressed in Pichia pastoris and formulated with Alhydrogel. In a phase 1 trial, 36 healthy adults... more
Necator americanus Ancylostoma Secreted Protein-2 (Na-ASP-2) is a leading larval-stage hookworm vaccine candidate. Recombinant Na-ASP-2 was expressed in Pichia pastoris and formulated with Alhydrogel. In a phase 1 trial, 36 healthy adults without history of hookworm infection were enrolled into 1 of 3 dose cohorts (n=12 per cohort) and randomized to receive intramuscular injections of either Na-ASP-2 or saline placebo. Nine participants in the first, second and third cohorts were assigned to receive 10, 50 and 100 microg of Na-ASP-2, respectively, on study days 0, 56 and 112, while 3 participants in each cohort received placebo. The most frequent adverse events were mild-to-moderate injection site reactions; in 8 participants these were delayed and occurred up to 10 days after immunization. No serious adverse events occurred. Anti-Na-ASP-2 IgG endpoint titers as determined by ELISA increased from baseline in all vaccine groups and peaked 14 days after the third injection, with geometric mean titers of 1:7066, 1:7611 and 1:11,593 for the 10, 50 and 100 microg doses, respectively, compared to <1:100 for saline controls (p<0.001). Antibody titers remained significantly elevated in all vaccine groups until the end of the study, approximately 8 months after the third vaccination. In vitro stimulation of PBMCs collected from participants with Na-ASP-2 resulted in robust proliferative responses in those who received vaccine, which increased with successive immunizations and remained high in the 50 and 100 microg dose groups through the end of the study. This first trial of a human hookworm vaccine demonstrates that the Na-ASP-2 vaccine is well-tolerated and induces a prolonged immune response in adults not exposed to hookworm, justifying further testing of this vaccine in an endemic area.
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Research Interests: Immune response, Dendritic Cells, Biological Sciences, Cell Differentiation, Humans, and 13 moreAdaptive Immunity, Chronic Disease, Animals, Antigen Presentation, Dendritic cell, Middle Aged, Eosinophils, Adult, Cell Proliferation, Cell Surface Markers, Necator Americanus, Differential expression, and Activation Function
Intracellular replication of Toxoplasma gondii requires cholesterol uptake by host cell low-density lipoprotein receptor (LDLr), a critical element in atherosclerosis. We evaluated host parasitism, inflammatory responses and development... more
Intracellular replication of Toxoplasma gondii requires cholesterol uptake by host cell low-density lipoprotein receptor (LDLr), a critical element in atherosclerosis. We evaluated host parasitism, inflammatory responses and development of atherosclerosis in LDLr knockout (LDLr(-/-)) and their controls C57BL/6 mice infected with T. gondii. Our results show that T. gondii cysts were reduced in LDLr(-/-) mice when compared to C57BL/6 mice. However, in presence of hypercholesterolemic diet, parasite growth in LDLr(-/-) mice was similar to that seen in infected C57BL/6 mice. In presence of a hypercholesterolemic diet, T. gondii infection leads to a 60% reduction of serum triacylglycerol, total and atherogenic lipoprotein cholesterol. When aortic valve lesion was analyzed, infected mice showed a reduction of atherosclerotic lesion area as well as CD36 expression. MCP-1, SRA-I, SRA-II, ICAM-1 and VCAM-1 mRNA expression was kept similar between infected and control groups. Thus, despite the intense inflammatory process, the drastic reduction in serum lipids seems to limit the development of atherosclerosis in LDLr(-/-) mice infected with T. gondii. In conclusion, our results indicate that T. gondii employs host LDLr to acquire cholesterol and favor its growth. However, in the presence of hypercholesterolemia, T. gondii parasites are able to acquire cholesterol-rich lipoproteins through an alternative host receptor, and overcome LDLr deficiency, favoring host parasitism and impairing lipid loading of foam cells.