Biology subjects

Alves, D. A.

Publications and source records attributed to Alves, D. A..

9 recordsLinked to original sources

bioRxiv2026

Bone marrow B cell collapse promotes bone metastasis in breast cancer

Metastasis remains the primary cause of cancer-related deaths and is characterized by complex reprogramming of systemic processes. Emerging evidence indicates that extraosseous tumors can rewire bone marrow physiology and disrupt hematopoiesis, thereby compromising effective systemic immune responses. However, how tumor-induced immune alterations in bone marrow contribute to skeletal metastasis remains poorly defined. Here, using immunocompetent mouse models of mammary tumor bone metastasis, we show that mammary cancer cells precondition the bone marrow niche prior to metastatic colonization, driving early remodeling of the microenvironment and depleting bone marrow lymphoid populations. Specifically, cancer cells induce a dramatic B cell reduction, the most abundant lymphoid subset in bone marrow, resulting from dysregulated cell cycle gene expression in pre-B cells, along with impaired B-cell proliferation and differentiation. These findings are further validated in breast cancer bone metastasis patients, who exhibit significant bone marrow B-cell loss alongside disrupted molecular and developmental programs. A causal role for B cells in restraining skeletal metastasis is supported by the finding that experimental B-cell depletion significantly increases both incidence and severity of bone metastasis. Mechanistically, we find that B-cell loss is driven by systemic elevation of G-CSF. Accordingly, pharmacological neutralization of G-CSF significantly reduces both B-cell depletion and bone metastasis susceptibility. Collectively, our data reveal that breast cancer cells can distantly hijack B-cell developmental trajectories, promoting skeletal metastasis. This work identifies B cells and G-CSF as potential therapeutic targets in bone metastasis and highlights the importance of targeting early bone marrow immune dysregulation to prevent or limit skeletal metastasis. HIGHLIGHTSO_LIMammary tumor cells reshape the bone marrow niche inducing B cell loss C_LIO_LIBone marrow B cell development is impaired in mammary tumor metastasis C_LIO_LIExperimental depletion of B cells promotes bone metastasis C_LIO_LIG-CSF mediates B cell loss in mammary tumor metastasis C_LI

cancer biology↗

bioRxiv2025

Discovery of an Adaptive Neuroimmune Response Driving Itch and Fast Tick Removal with Implications for Preventing Pathogen Transmission

Acquired tick resistance (ATR) is well characterized in tick-exposed animals, compromising tick fitness through antibody-mediated activation of basophils. Yet, anti-tick vaccines inducing ATR have had limited success. Here, we describe a neuroimmune event preceding ATR that leads to rapid host-mediated tick removal. Tick-sensitized guinea pigs mechanically remove ticks within 3-6 hours via an acquired neuroimmune-induced itch response that correlates with increased dermal expression of itch-associated genes like OSM and skin infiltration by T cells and macrophages, independently of IgG and IgE antibodies. When we expose humans to ticks, a similar immune response is observed. Blocking T cells before tick sensitization prevents immune cell infiltration to bite sites and abrogates scratching and tick removal. This neuroimmune response is independent of Trpv1 as tick-sensitized guinea pigs treated with resiniferatoxin remove ticks effectively. Itch-induced tick removal or IITR offers a novel approach to tick-borne disease prevention through early tick detection and removal.

neuroscience↗

bioRxiv2025

High-Resolution Proteomics Unveils Salivary Gland Disruption and Saliva-Hemolymph Protein Exchange in Plasmodium-Infected Mosquitoes

Plasmodium sporozoites, the stage that initiates a malaria infection, must invade the mosquito salivary glands (SGs) before transmitting to a vertebrate host. However, the effects of sporozoite invasion on salivary gland physiology and saliva composition remain largely unexplored. We examined the impact of Plasmodium infection on Anopheles gambiae salivary glands using high-resolution proteomics, gene expression, and morphological analysis. The data revealed differential expression of various proteins, including the enrichment of humoral proteins in infected salivary glands originating from the hemolymph. These proteins diffused into the SGs due to structural damage caused by the sporozoites during invasion. Conversely, saliva proteins diffused out into the circulation of infected mosquitoes. Moreover, infection altered saliva protein composition, as shown by proteomes from saliva collected from mosquitoes infected by P. berghei or P. falciparum, revealing a significant reduction of immune proteins compared to uninfected mosquitoes. This reduction is likely due to the association of these proteins with the surface of sporozoites within the mosquito salivary secretory cavities. The saliva protein profiles from mosquitoes infected with both Plasmodium species were remarkably similar, suggesting a conserved interaction between sporozoites and salivary glands. Our results provide a foundation for understanding the molecular interactions between Plasmodium sporozoites and mosquito salivary glands.

microbiology↗

bioRxiv2024

A sustainable and bee-pollinated coffee to start your day

The integration of managed pollinators into agricultural systems represents a practical strategy for boosting crop production, optimising sustainable farming practices, and improving rural livelihoods. However, the use of managed bees to supplement the contribution of wild pollinators still faces challenges, such as over-reliance on pesticides in intensively managed agroecosystems. Here, we placed managed bee colonies on conventional farms to assess their impact on arabica coffee yield, quality and market value, while also to evaluate colony health in coffee fields treated with field rates of thiamethoxam-based products. We show that supplementing farms with managed bees increased farmer income by enhancing coffee yield and beverage quality, which is rewarded by specialty coffee markets. Moreover, our field-based study reveals that, even when exposed to field-realistic levels of the neonicotinoid thiamethoxam, managed bee colonies exhibited no significant adverse effects on their health within coffee fields. Our results underline that pollination is a key input on intensively managed coffee farms, and that agricultural production and environmental conservation interact synergically to maximize profitability, which is fundamental to encourage farmers to be good stewards of their croplands by adopting nature-positive practices.

ecology↗

bioRxiv2024

Cxcl10 is required for survival during SARS-CoV-2 infection in mice

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, remains endemic worldwide [~]5 years since the first documented case. Severe COVID-19 is widely considered to be caused by a dysregulated immune response to SARS-CoV-2 within the respiratory tract. Circulating levels of the chemokine CXCL10 are strongly positively associated with poor outcome; however, its precise role in pathogenesis and its suitability as a therapeutic target have remained undefined. Here, we challenged 4-6 month old C57BL/6 mice genetically deficient in Cxcl10 with a mouse-adapted strain of SARS-CoV-2. Infected male, but not female, Cxcl10-/- mice displayed increased mortality compared to wild type controls. Histopathological damage, inflammatory gene induction and virus load in the lungs of male mice 4 days post infection and before death were not broadly influenced by Cxcl10 deficiency. However, accumulation of B cells and both CD4+ and CD8+ T cells in the lung parenchyma of infected mice was reduced in the absence of Cxcl10. Thus, during acute SARS-CoV-2 infection, Cxcl10 regulates lymphocyte infiltration in the lung and confers protection against mortality. Our preclinical model results do not support targeting CXCL10 therapeutically in severe COVID-19.

immunology↗

bioRxiv2024

Structure-guided assembly of an influenza spike nanobicelle vaccine provides pan H1 intranasal protection

Development of intranasal vaccines for respiratory viruses has gained popularity. However, currently only a live-attenuated influenza vaccine is FDA-approved for intranasal administration. Here, we focused on influenza virus as it circulates seasonally, has pandemic potential, and has vaccine formulations that present hemagglutinin (HA) in different structural arrangements. These display differences have not been correlated with induction of pan-H1 antibodies or shown to provide intranasal protection. Using electron microscopy, biochemistry and animal studies, we identified HA complexes arranged as lipid discs with multiple trimeric HAs displayed along the perimeter, termed spike nanobicelles (SNB). We utilized a structure-guided approach to synthesize in vitro assembled spiked nanobicelles (IA-SNB) from a classical 1934 H1N1 influenza virus. IA-SNBs elicited pan-H1 antibodies and provided protection against antigenically divergent H1N1 viruses via intranasal immunizations. Viral glycoprotein spikes displayed as SNBs could aid in combating antigenic variation and provide innovative intranasal vaccines to aid universal influenza vaccine development.

microbiology↗

bioRxiv2023

Durable immunity to SARS-CoV-2 in both lower and upper airways achieved with a gorilla adenovirus (GRAd) S-2P vaccine in non-human primates

SARS-CoV-2 continues to pose a global threat, and current vaccines, while effective against severe illness, fall short in preventing transmission. To address this challenge, theres a need for vaccines that induce mucosal immunity and can rapidly control the virus. In this study, we demonstrate that a single immunization with a novel gorilla adenovirus-based vaccine (GRAd) carrying the pre-fusion stabilized Spike protein (S-2P) in non-human primates provided protective immunity for over one year against the BA.5 variant of SARS-CoV-2. A prime-boost regimen using GRAd followed by adjuvanted S-2P (GRAd+S-2P) accelerated viral clearance in both the lower and upper airways. GRAd delivered via aerosol (GRAd(AE)+S-2P) modestly improved protection compared to its matched intramuscular regimen, but showed dramatically superior boosting by mRNA and, importantly, total virus clearance in the upper airway by day 4 post infection. GrAd vaccination regimens elicited robust and durable systemic and mucosal antibody responses to multiple SARS-CoV-2 variants, but only GRAd(AE)+S-2P generated long-lasting T cell responses in the lung. This research underscores the flexibility of the GRAd vaccine platform to provide durable immunity against SARS-CoV-2 in both the lower and upper airways.

immunology↗

bioRxiv2023

Atypical Chemokine Receptor 1 (Ackr1)-deficient Mice Resist Lethal SARS-CoV-2 Challenge

High pro-inflammatory chemokine levels have been reported in blood and lung in patients with COVID-19. To investigate specific roles in pathogenesis, we studied the regulation of chemokine ligands and receptors in the lungs of 4-6-month-old wild type C57BL/6 mice infected with the MA10 mouse-adapted strain of SARS-CoV-2. We found that atypical chemokine receptor 1 (Ackr1, also known as Duffy antigen receptor for chemokines/DARC) was the most highly upregulated chemokine receptor in infected lung, where it localized to endothelial cells of veins and arterioles. In a screen of 7 leukocyte chemoattractant or chemoattractant receptor knockout mouse lines, Ackr1-/- mice were unique in having lower mortality after SARS-CoV-2 infection, particularly in males. ACKR1 is a non-signaling chemokine receptor that in addition to endothelium is also expressed on erythrocytes and Purkinje cells of the cerebellum. It binds promiscuously to both inflammatory CC and CXC chemokines and has been reported to control chemokine availability which may influence the shape of chemotactic gradients and the ability of leukocytes to extravasate and produce immunopathology. Of note, erythrocyte ACKR1 deficiency is fixed in sub-Saharan African populations where COVID-19 has been reported to result in low mortality compared to worldwide data. Our data suggest the possibility of a causal contribution of ACKR1 deficiency to low sub-Saharan COVID-19 mortality and identify ACKR1 as a possible drug target in the disease.

immunology↗

bioRxiv2023

Anopheles salivary apyrase regulates blood meal hemostasis and drives malaria parasite transmission

Mosquito salivary proteins play a crucial role in regulating hemostatic responses at the bite site during blood feeding. In this study, we investigate the function of Anopheles gambiae salivary apyrase (AgApyrase) in Plasmodium transmission. Our results demonstrate that salivary apyrase interacts with and activates tissue plasminogen activator, facilitating the conversion of plasminogen to plasmin, a human protein previously shown to be required for Plasmodium transmission. Microscopy imaging shows that mosquitoes ingest a substantial amount of apyrase during blood feeding which reduces coagulation in the blood meal by enhancing fibrin degradation and inhibiting platelet aggregation. Supplementation of Plasmodium infected blood with apyrase significantly enhanced Plasmodium infection in the mosquito midgut. In contrast, AgApyrase immunization inhibited Plasmodium mosquito infection and sporozoite transmission. This study highlights a pivotal role for mosquito salivary apyrase for regulation of hemostasis in the mosquito blood meal and for Plasmodium transmission to mosquitoes and to the mammal host, underscoring the potential for new strategies to prevent malaria transmission.

microbiology↗