Biology subjects

Goncalves, R.

Publications and source records attributed to Goncalves, R..

7 recordsLinked to original sources

bioRxiv2026

Host cell traversal by Plasmodium parasites is essential for sterilizing hepatic cellular immunity.

An effective vaccine capable of inducing sterile protection against Plasmodium, the causative agent of malaria, is critical to aid global eradication. Whole-organism vaccines using liver-infective sporozoites provide high levels of sterile protection against pre-erythrocytic infection. Yet, determinants of sporozoite immunogenicity remain poorly characterized. Using rodent models of vaccination, we demonstrate that the ability of Plasmodium sporozoites to actively migrate through multiple host cells prior to infecting hepatocytes is required for sterilizing immunity, regardless of the time of intrahepatic development of immunizing parasites. We further establish that host cell traversal is sufficient to trigger robust protection against Plasmodium hepatic infection. Impaired cell traversal precludes protective liver-resident memory CD8 T cell responses following vaccination, but not the production of anti-plasmodial antibodies. Our findings challenge the prevailing notion that intrahepatic parasite development is the sole determinant of whole-sporozoite vaccination-induced protection, and highlight parasite behavior traits as critical immunogenic events shaping sterilizing cellular immunity against Plasmodium liver stages.

immunology↗

bioRxiv2025

Activation of nuclear receptors correlates with tuberculosis severity and is a target for host-directed therapy

The immune response to Mycobacterium tuberculosis is accompanied by metabolic adaptations that fuel host immunity, but that are exploited by the pathogen to ensure persistence and growth. Nuclear receptors, such as liver-X-receptors (LXR), orchestrate macrophage immunometabolic adaptations to infection and globally associate with tuberculosis (TB) protection. Here, we show that the "signalling by nuclear receptors" (SNR) pathway is detected in the whole blood of TB patients and that its expression correlates with disease severity. Accordingly, we also show that the activation of the LXR pathway progressively increases in the lungs of M. tuberculosis-infected C57BL/6 and C3HeB/FeJ mice. Pharmacologic activation of LXR, specifically at the chronic stage of infection, improved infection outcomes and significantly prolonged the survival of the highly susceptible C3HeB/FeJ mice. Common to both mouse models and to in vitro macrophage infections, LXR activation enhanced bacterial control together with an increase in extracellular cholesterol levels. We propose that progressive LXR activation is required to fine-tune host cholesterol availability during M. tuberculosis infections and restrict access to this nutrient during chronic stages of infections. Collectively, we identify the SNR pathway as a potential biomarker of TB severity and timely LXR activation as a candidate host-directed therapy.

immunology↗

bioRxiv2024

Essential sterols from engineered yeast prevent honeybee colony population decline

Honeybees, the worlds most important crop pollinators, are increasingly facing pollen starvation arising from agricultural intensification and climate change. Frequent flowering dearth periods and high-density rearing conditions weaken colonies, often leading to their demise. Beekeepers provide colonies with pollen substitutes, but these feeds cannot sustain brood production because they lack essential sterols found in pollen. Here, we describe a technological breakthrough in honeybee nutrition with wide-reaching impacts on global food security. We first measured the quantity and proportion of sterols found in honeybee tissues. Using this information, we genetically engineered a strain of the oleaginous yeast, Yarrowia lipolytica, to produce a mixture of essential sterols for bees and incorporated it into an otherwise nutritionally complete diet. Colonies fed exclusively with this diet reared brood for significantly longer than those fed diets without suitable sterols. Incorporating sterol supplements into pollen substitutes using this method will enable beekeepers to rear healthier, longer-lived colonies to meet the growing demands for global crop pollination. It could also reduce competition between bee species for access to natural floral resources, stemming the decline of wild bee populations.

synthetic biology↗

bioRxiv2024

Semantic computing for human phenotypes

In many fields, research progress may be hindered by indefiniteness of language used to describe experimental conditions and outcomes. Harmonization of data resources generated by independent groups is important for integrative analysis. Adoption of formal ontologies and vocabularies for experiment annotation should help with harmonization tasks, but the use of ontologies also suffers from a lack of definiteness. In this study we explore how natural language characterization of human diseases coupled with ontologic mapping of study outcome terminology can be used to integrate information from multiple studies of genetic origins of disease risk. Open source tools and workflows are presented. This work exposes areas for improvement in tooling for data harmonization, which is a fundamental requirement for efficient research progress.

systems biology↗

bioRxiv2024

Dynamic representation of appetitive and aversive stimuli in nucleus accumbens shell D1- and D2-medium spiny neurons

The nucleus accumbens (NAc) is a key brain region for motivated behaviors, yet how distinct neuronal populations encode appetitive or aversive stimuli remains undetermined. Using microendoscopic calcium imaging, we tracked NAc shell D1- or D2-medium spiny neurons (MSNs) activity during exposure to stimuli of opposing valence and associative learning. Despite drift in individual neurons coding, both D1- and D2-population activity was sufficient to discriminate opposing valence unconditioned stimuli, but not predictive cues. Notably, D1- and D2-MSNs were similarly co-recruited during appetitive and aversive conditioning, supporting a concurrent role in associative learning. Conversely, when contingencies changed, there was an asymmetric response in the NAc, with more pronounced changes in the activity of D2-MSNs. Optogenetic manipulation of D2-MSNs provided causal evidence of the necessity of this population in the extinction of aversive associations. Our results reveal how NAc shell neurons encode valence, Pavlovian associations and their extinction, and unveil new mechanisms underlying motivated behaviors.

neuroscience↗

bioRxiv2022

Social cues of safety can override differences in threat level

Animals in groups integrate social information with that directly-gathered about the environment to guide decisions regarding reproduction, foraging and defense against predatory threats. In the context of predation, usage of social information has acute fitness benefits, aiding the detection of predators, the mounting of concerted defensive responses, or allowing the inference of safety, permitting other beneficial behaviors such as foraging for food. Individual and group defense responses to predatory threats can vary in modality and vigor depending on the perceived threat level. Moreover, predation level has been shown to modulate the use of social cues about foraging sites. Whether and how different threat levels affect the use of social cues to guide defense responses, is currently unknown. We previously showed that Drosophila melanogaster display a graded decrease in freezing behavior, triggered by an inescapable visual threat, with increasing group sizes. Crucially, we identified the movement of others as a cue of safety and its cessation a cue of threat and found the group responses to be primarily guided by the safety cues, resulting in a net social buffering effect. Here, we investigated how threat level impacts the use of social cues by exposing flies individually and in groups to two threat imminences using looms of different speeds. We show that freezing responses are stronger to the faster looms regardless of social condition. However, social buffering was stronger for groups exposed to the fast looms, such that the increase in freezing caused by the higher threat was less prominent in flies tested in groups than those tested individually. Through artificial control of behavior, we created different group compositions, titrating the motion cues that were maintained across threat levels. We, found that the same level of safety motion cues had a bigger weight on the flies decisions when these were exposed to the higher threat, thus overriding differences in perceived threat levels. These findings shed light on the safety in numbers effect, revealing the modulation of the saliency of social safety cues across threat intensities, a possible mechanism to regulate costly defensive responses.

neuroscience↗

bioRxiv2019

Sand fly synthetic sex-aggregation pheromone co-located with insecticide reduces canine Leishmania infantum infection incidence: a stratified cluster randomised trial

ObjectiveTo evaluate the efficacy of a synthetic sex-aggregation pheromone of the sand fly vector Lu. longipalpis, co-located with residual insecticide, to reduce the infection incidence of Leishmania infantum in the canine reservoir, and to reduce sand fly vector abundance. To compare the outcomes to those resulting from fitting deltamethrin-impregnated collars to the canine reservoir.\n\nMethodsA stratified cluster-randomised trial was designed to detect a 50% reduction in canine incident infection after 24 months in 42 recruited clusters, randomly assigned to one of three intervention arms (14 cluster each): pheromone + insecticide, insecticide-impregnated dog collars, or placebo control. Infection incidence was measured by seroconversion to anti-Leishmania antibody, Leishmania parasite detection and canine tissue parasite loads. Changes in relative Lu. longipalpis abundance within households were measured by setting three CDC light traps per household.\n\nResultsA total 1,454 seronegative dogs were follow-up for a median 15.2 (95% C.I.s: 14.6, 16.2) months per cluster. The pheromone + insecticide intervention provided 13% (95% C.I. 0%, 44.0%) protection against anti-Leishmania antibody seroconversion, 52% (95% C.I. 6.2%, 74{middle dot}9%) against parasite infection, reduced tissue parasite loads by 53% (95% C.I. 5.4%, 76.7%), and reduced household female sand fly abundance by 49% (95% C.I. 8.2%, 71.3%). Variation in the efficacy against seroconversion varied between trial strata. Equivalent protection attributed to the impregnated-collars were 36% (95% C.I. 14.4%, 51.8%), 23% (95% C.I. 0%, 57{middle dot}5%), 48% (95% C.I. 0%, 73.4%) and 43% (95% C.I. 0%, 67.9%), respectively. Comparison of the outcomes of the two interventions showed no statistically consistent differences in their efficacies; however, the errors were broad for all outcomes. Reductions in sand fly numbers were predominant where insecticide was located (chicken and dog sleeping sites), with no evidence of insecticide-induced repellency onto humans or dogs.\n\nConclusionThe synthetic pheromone lure-and-kill approach provides protection particularly against L. infantum parasite transmission and sand fly vector abundance. The effect estimates are not dissimilar to those of the insecticide-impregnated collars, which are documented to reduce canine infection incidence, and human infection and clinical VL disease incidence, in different global regions. As a low-cost alternative or complimentary vector control tool, optimisation of best community deployment of the pheromone + insecticide are now underway.\n\nAuthor summaryThe sand fly vector of the intracellular parasite Leishmania infantum causing human and canine visceral leishmaniasis in the Americas is Lutzomyia longipalpis. Dogs are the proven reservoir. Vector control tools to reduce transmission suited to this predominantly exophilic vector are lacking. Insecticide-impregnated dog collars protect dogs against infectious bites from sand fly vectors, resulting in reductions of new infections in both dogs and humans. However, collars are costly particularly for endemic communities, and alternative approaches are needed. Recent bulk synthesis of a sex-aggregation pheromone produced by male Lu. longipalpis was shown to attract large numbers of conspecific females to lethal pyrethroid insecticides. This study, conducted in Brazil, evaluated the efficacy of this novel lure-and-kill approach to reduce seroconversion and infection incidence with L. infantum in the canine reservoir, in addition to measuring its impact on household abundance of Lu. longipalpis. Deployed in 14 stratified clusters, the outcomes were compared to those resulting attributed to the collars fitted to dogs in another 14 clusters; each intervention was compared to the 14 clusters that received placebo treatments. The beneficial effects of the lure-and-kill method were most noticeable on confirmed infection incidence and clinical parasite loads, and in reducing sand fly abundance. The overall effect of the two interventions were not statistically dissimilar, though the confidence intervals were broad. We conclude that the novel low-cost lure-and-kill approach should be added to the vector control toolbox against visceral leishmaniasis in the Americas.

microbiology↗