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1.  Orchestrated activation of mGluR5 and CB1 promotes neuroprotection 
Molecular Brain  2016;9:80.
The metabotropic glutamate receptor 5 (mGluR5) and the cannabinoid receptor 1 (CB1) exhibit a functional interaction, as CB1 regulates pre-synaptic glutamate release and mGluR5 activation increases endocannabinoid synthesis at the post-synaptic site. Since both mGluR5 and CB1 promote neuroprotection, we delineated experiments to investigate a possible link between CB1 and mGluR5 activation in the induction of neuroprotection using primary cultured corticostriatal neurons. We find that either the pharmacological blockade or the genetic ablation of either mGluR5 or CB1 can abrogate both CB1- and mGluR5-mediated neuroprotection against glutamate insult. Interestingly, decreased glutamate release and diminished intracellular Ca2+ do not appear to play a role in CB1 and mGluR5-mediated neuroprotection. Rather, these two receptors work cooperatively to trigger the activation of cell signaling pathways to promote neuronal survival, which involves MEK/ERK1/2 and PI3K/AKT activation. Interestingly, although mGluR5 activation protects postsynaptic terminals and CB1 the presynaptic site, intact signaling of both receptors is required to effectively promote neuronal survival. In conclusion, mGluR5 and CB1 act in concert to activate neuroprotective cell signaling pathways and promote neuronal survival.
Electronic supplementary material
The online version of this article (doi:10.1186/s13041-016-0259-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13041-016-0259-6
PMCID: PMC4992217  PMID: 27543109
mGluR5; CB1; Cell death; AKT; ERK1/2
2.  Mutant Brucella abortus Membrane Fusogenic Protein Induces Protection against Challenge Infection in Mice 
Infection and Immunity  2015;83(4):1458-1464.
Brucella species can cause brucellosis, a zoonotic disease that causes serious livestock economic losses and represents a public health threat. The mechanism of virulence of Brucella spp. is not yet fully understood. Therefore, it is crucial to identify new molecules that serve as virulence factors to better understand this host-pathogen interplay. Here, we evaluated the role of the Brucella membrane fusogenic protein (Mfp) and outer membrane protein 19 (Omp19) in bacterial pathogenesis. In this study, we showed that B. abortus Δmfp::kan and Δomp19::kan deletion mutant strains have reduced persistence in vivo in C57BL/6 and interferon regulatory factor 1 (IRF-1) knockout (KO) mice. Additionally, 24 h after macrophage infection with a Δmfp::kan or Δomp19::kan strain expressing green fluorescent protein (GFP) approximately 80% or 65% of Brucella-containing vacuoles (BCVs) retained the late endosomal/lysosomal marker LAMP-1, respectively, whereas around 60% of BCVs containing wild-type S2308 were found in LAMP-1-negative compartments. B. abortus Δomp19::kan was attenuated in vivo but had a residual virulence in C57BL/6 and IRF-1 KO mice, whereas the Δmfp::kan strain had a lower virulence in these same mouse models. Furthermore, Δmfp::kan and Δomp19::kan strains were used as live vaccines. Challenge experiments revealed that in C57BL/6 and IRF-1 KO mice, the Δmfp::kan strain induced greater protection than the vaccine RB51 and protection similar that of vaccine S19. However, a Δomp19::kan strain induced protection similar to that of RB51. Thus, these results demonstrate that Brucella Mfp and Omp19 are critical for full bacterial virulence and that the Δmfp::kan mutant may serve as a potential vaccine candidate in future studies.
doi:10.1128/IAI.02790-14
PMCID: PMC4363440  PMID: 25644010
3.  Trypanosomes Modify the Behavior of Their Insect Hosts: Effects on Locomotion and on the Expression of a Related Gene 
PLoS Neglected Tropical Diseases  2015;9(8):e0003973.
Background
As a result of evolution, the biology of triatomines must have been significantly adapted to accommodate trypanosome infection in a complex network of vector-vertebrate-parasite interactions. Arthropod-borne parasites have probably developed mechanisms, largely still unknown, to exploit the vector-vertebrate host interactions to ensure their transmission to suitable hosts. Triatomines exhibit a strong negative phototaxis and nocturnal activity, believed to be important for insect survival against its predators.
Methodology/Principal Findings
In this study we quantified phototaxis and locomotion in starved fifth instar nymphs of Rhodnius prolixus infected with Trypanosoma cruzi or Trypanosoma rangeli. T. cruzi infection did not alter insect phototaxis, but induced an overall 20% decrease in the number of bug locomotory events. Furthermore, the significant differences induced by this parasite were concentrated at the beginning of the scotophase. Conversely, T. rangeli modified both behaviors, as it significantly decreased bug negative phototaxis, while it induced a 23% increase in the number of locomotory events in infected bugs. In this case, the significant effects were observed during the photophase. We also investigated the expression of Rpfor, the triatomine ortholog of the foraging gene known to modulate locomotion in other insects, and found a 4.8 fold increase for T. rangeli infected insects.
Conclusions/Significance
We demonstrated for the first time that trypanosome infection modulates the locomotory activity of the invertebrate host. T. rangeli infection seems to be more broadly effective, as besides affecting the intensity of locomotion this parasite also diminished negative phototaxis and the expression of a behavior-associated gene in the triatomine vector.
Author Summary
The control of Chagas disease, an infection that affects ca. 8 million people in Latin America, is mostly based on vector control activities. Understanding vector biology and how these insects interact with their environment, hosts and pathogens is crucial to improve vector control strategies. The behavior of triatomines has been largely studied, yet few reports have focused on the behavioral effects of the interaction that these insects endure with their natural parasites. Trypanosoma cruzi and Trypanosoma rangeli are two protozoan parasites found naturally infecting Rhodnius species. In this study, we showed for the first time that the locomotory activity of Rhodnius prolixus, a relevant vector of Chagas disease, is affected by trypanosome infection. T. cruzi was found to decrease bug locomotory activity during night hours, while T. rangeli promoted a generally increased insect locomotion. In addition, we searched for the R. prolixus orthologue (Rpfor) of a gene associated with the modulation of insect activity (foraging gene) and found that Rpfor expression was also affected by trypanosome infection.
doi:10.1371/journal.pntd.0003973
PMCID: PMC4546274  PMID: 26291723
4.  Sm10.3, a Member of the Micro-Exon Gene 4 (MEG-4) Family, Induces Erythrocyte Agglutination In Vitro and Partially Protects Vaccinated Mice against Schistosoma mansoni Infection 
Background
The parasitic flatworm Schistosoma mansoni is a blood fluke that causes schistosomiasis. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy to control disease is a combination of drug treatment and immunization with an anti-schistosome vaccine. Numerous antigens that are expressed at the interface between the parasite and the mammalian host have been assessed. Among the most promising molecules are the proteins present in the tegument and digestive tract of the parasite.
Methodology/Principal Findings
In this study, we evaluated the potential of Sm10.3, a member of the micro-exon gene 4 (MEG-4) family, for use as part of a recombinant vaccine. We confirmed by real-time PCR that Sm10.3 was expressed at all stages of the parasite life cycle. The localization of Sm10.3 on the surface and lumen of the esophageal and intestinal tract in adult worms and lung-stage schistosomula was confirmed by confocal microscopy. We also show preliminary evidence that rSm10.3 induces erythrocyte agglutination in vitro. Immunization of mice with rSm10.3 induced a mixed Th1/Th2-type response, as IFN-γ, TNF-α, and low levels of IL-5 were detected in the supernatant of cultured splenocytes. The protective effect conferred by vaccination with rSm10.3 was demonstrated by 25.5–32% reduction in the worm burden, 32.9–43.6% reduction in the number of eggs per gram of hepatic tissue, a 23.8% reduction in the number of granulomas, an 11.8% reduction in the area of the granulomas and a 39.8% reduction in granuloma fibrosis.
Conclusions/Significance
Our data suggest that Sm10.3 is a potential candidate for use in developing a multi-antigen vaccine to control schistosomiasis and provide the first evidence for a possible role for Sm10.3 in the blood feeding process.
Author Summary
Schistosomiasis mainly occurs in developing countries and is the most important human helminth infection in terms of global mortality. This parasitic disease affects more than 200 million people worldwide and causes more than 250,000 deaths per year. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy for controlling schistosomiasis is a combination of drug treatment and immunization with an anti-schistosome vaccine. Consequently, significant effort has been dedicated to developing and characterizing an anti-schistosome vaccine. Over the last five years, considerable data have been generated regarding the genomics, transcriptomics and proteomics of Schistosoma mansoni. In the present study, we characterize the Sm10.3 protein and evaluate its potential to protect against S. mansoni infection in a murine model. We demonstrate that Sm10.3 is primarily expressed during the stages of the parasite life cycle that involve infection and disease development in the human host. Sm10.3 is located on the surface of the digestive epithelia of adult female worms, an important host/parasite interface. Moreover, the vaccination of mice with rSm10.3 confers partial protection against S. mansoni. Taken together, our data suggest that Sm10.3 may be a useful component of a multi-antigen vaccine against schistosomiasis.
doi:10.1371/journal.pntd.0002750
PMCID: PMC3961193  PMID: 24651069
5.  An insight into the sialome of Glossina morsitans morsitans 
BMC Genomics  2010;11:213.
Background
Blood feeding evolved independently in worms, arthropods and mammals. Among the adaptations to this peculiar diet, these animals developed an armament of salivary molecules that disarm their host's anti-bleeding defenses (hemostasis), inflammatory and immune reactions. Recent sialotranscriptome analyses (from the Greek sialo = saliva) of blood feeding insects and ticks have revealed that the saliva contains hundreds of polypeptides, many unique to their genus or family. Adult tsetse flies feed exclusively on vertebrate blood and are important vectors of human and animal diseases. Thus far, only limited information exists regarding the Glossina sialome, or any other fly belonging to the Hippoboscidae.
Results
As part of the effort to sequence the genome of Glossina morsitans morsitans, several organ specific, high quality normalized cDNA libraries have been constructed, from which over 20,000 ESTs from an adult salivary gland library were sequenced. These ESTs have been assembled using previously described ESTs from the fat body and midgut libraries of the same fly, thus totaling 62,251 ESTs, which have been assembled into 16,743 clusters (8,506 of which had one or more EST from the salivary gland library). Coding sequences were obtained for 2,509 novel proteins, 1,792 of which had at least one EST expressed in the salivary glands. Despite library normalization, 59 transcripts were overrepresented in the salivary library indicating high levels of expression. This work presents a detailed analysis of the salivary protein families identified. Protein expression was confirmed by 2D gel electrophoresis, enzymatic digestion and mass spectrometry. Concurrently, an initial attempt to determine the immunogenic properties of selected salivary proteins was undertaken.
Conclusions
The sialome of G. m. morsitans contains over 250 proteins that are possibly associated with blood feeding. This set includes alleles of previously described gene products, reveals new evidence that several salivary proteins are multigenic and identifies at least seven new polypeptide families unique to Glossina. Most of these proteins have no known function and thus, provide a discovery platform for the identification of novel pharmacologically active compounds, innovative vector-based vaccine targets, and immunological markers of vector exposure.
doi:10.1186/1471-2164-11-213
PMCID: PMC2853526  PMID: 20353571
6.  Prominent Actin Fiber Arrays in Drosophila Tendon Cells Represent Architectural Elements Different from Stress Fibers 
Molecular Biology of the Cell  2008;19(10):4287-4297.
Tendon cells are specialized cells of the insect epidermis that connect basally attached muscle tips to the cuticle on their apical surface via prominent arrays of microtubules. Tendon cells of Drosophila have become a useful genetic model system to address questions with relevance to cell and developmental biology. Here, we use light, confocal, and electron microscopy to present a refined model of the subcellular organization of tendon cells. We show that prominent arrays of F-actin exist in tendon cells that fully overlap with the microtubule arrays, and that type II myosin accumulates in the same area. The F-actin arrays in tendon cells seem to represent a new kind of actin structure, clearly distinct from stress fibers. They are highly resistant to F-actin–destabilizing drugs, to the application of myosin blockers, and to loss of integrin, Rho1, or mechanical force. They seem to represent an important architectural element of tendon cells, because they maintain a connection between apical and basal surfaces even when microtubule arrays of tendon cells are dysfunctional. Features reported here and elsewhere for tendon cells are reminiscent of the structural and molecular features of support cells in the inner ear of vertebrates, and they might have potential translational value.
doi:10.1091/mbc.E08-02-0182
PMCID: PMC2555930  PMID: 18667532

Results 1-6 (6)