Biology subjects

Ostroff, G. R.

Publications and source records attributed to Ostroff, G. R..

4 recordsLinked to original sources

bioRxiv2026

Identification of Cryptococcus neoformans capsule-associated protein antigens that mediate B cell-dependent vaccine protection in mice and elicit antibody responses in humans with cryptococcosis

Infection with the encapsulated fungal pathogen Cryptococcus neoformans causes substantial global disease burden in persons with compromised T cell function. Previously, we demonstrated that vaccines containing adjuvanted recombinant cryptococcal proteins protected mice against lethal infection by mechanisms dependent on CD4+ T cells. For the present study, we hypothesized that vaccines containing protein antigens naturally located on the surface of the cryptococcal capsule would contribute protective B cell responses. We found that B cell-deficient mice exhibited reduced survival following vaccination with any of four capsule-associated antigens: Blp4, Cpd1, Lhc1, or Krp1. To further elucidate the role of antibodies in protection, we tested serum from mice vaccinated with a live-attenuated strain (cda123) and then challenged with a virulent C. neoformans strain for IgG responses to a panel of 26 cryptococcal recombinant proteins. Strong reactivity was detected against Blp4, which we focused on because it is capsule-associated and protects mice when administered in adjuvanted subunit vaccines, by mechanisms partly dependent on B cells. Blp4 antibodies were consistently present in surviving mice, including those vaccinated with unrelated proteins or those challenged with diverse clinical isolates. Additionally, serum from Blp4-vaccinated mice promoted macrophage opsonophagocytosis of C. neoformans. Finally, IgG antibodies against Blp4 were detected in 20 of 21 serum samples from patients who survived cryptococcosis, compared with only 4 of 14 samples from healthy controls. Together, these data identify Blp4 as an antigen that elicits protective B cell responses and is a strong candidate for inclusion in subunit cryptococcal vaccines.

immunology↗

bioRxiv2026

Endothelin-1 from Tongue Glands Gates 1 Sodium Taste and Intake

Sodium is an essential nutrient. To survive sodium deficiency, animals dramatically increase their appetite for salt. However, whether and how sodium depletion impacts the taste of salt to drive sodium intake is unknown. Here we show that tongue gland-derived endothelin-1 (EDN1) regulates the amiloride-sensitive, sodium-selective salt taste. Edn1 is specifically expressed in the glands embedded within the tongue. Under normal conditions, EDN1 suppresses salt taste by acting on its receptor EDNRB on the projections of salt-sensing taste neurons innervating taste buds. When internal sodium levels drop, EDN1 expression decreases, lifting this inhibition and enhancing responses to salt. Applying EDN1 directly to the tongue, using a nonionic eutectic-based organogel (Neogel) delivery technology that we establish here, dampens the activity of the salt-sensing taste neurons and reduces salt intake and preference. Conversely, genetic deletion of Ednrb in taste neurons mimics the effects of sodium deficiency, enhancing salt-sensing neuron activity and increasing salt consumption. These findings reveal a peripheral mechanism that regulates salt taste and intake in response to internal sodium levels, highlighting a direct role of the taste pathway in maintaining nutrient homeostasis.

neuroscience↗

bioRxiv2025

Hookworm genes encoding intestinal excreted-secreted proteins are transcriptionally upregulated in response to the host's immune system

Hookworms are intestinal parasitic nematodes that chronically infect [~]500 million people, with reinfection common even after clearance by drugs. How infecting hookworms successfully overcome host protective mechanisms is unclear, but it may involve hookworm proteins that digest host tissues, or counteract the hosts immune system, or both. To find such proteins in the zoonotic hookworm Ancylostoma ceylanicum, we identified hookworm genes encoding excreted-secreted (ES) proteins, hookworm genes preferentially expressed in the hookworm intestine, and hookworm genes whose transcription is stimulated by the host immune system. We collected ES proteins from adult hookworms harvested from hamsters; mass spectrometry identified 565 A. ceylanicum genes encoding ES proteins. We also used RNA-seq to identify A. ceylanicum genes expressed both in young adults (12 days post-infection) and in intestinal and non-intestinal tissues dissected from mature adults (19 days post-infection), with hamster hosts that either had normal immune systems or were immunosuppressed by dexamethasone. In adult A. ceylanicum, we observed 1,670 and 1,196 genes with intestine- and non-intestine-biased expression, respectively. Comparing hookworm gene activity in normal versus immunosuppressed hosts, we observed almost no changes of gene activity in 12-day young adults or non-intestinal 19-day adult tissues. However, in intestinal 19-day adult tissues, we observed 1,951 positively immunoregulated genes (upregulated at least two-fold in normal hosts versus immunosuppressed hosts), and 137 genes that were negatively immunoregulated. Thus, immunoregulation was observed primarily in mature adult hookworm intestine directly exposed to host blood; it may include hookworm genes activated in response to the host immune system in order to neutralize the host immune system. We observed 153 ES genes showing positive immunoregulation in 19-day adult intestine; of these genes, 69 had ES gene homologs in the closely related hookworm Ancylostoma caninum, 24 in the human hookworm Necator americanus, and 24 in the more distantly related strongylid parasite Haemonchus contortus. Such a mixture of rapidly evolving and conserved genes could comprise virulence factors enabling infection, provide new targets for drugs or vaccines against hookworm, and aid in developing therapies for autoimmune diseases.

genomics↗

bioRxiv2020

Recombinant Paraprobiotics as a New Paradigm for Treating Gastrointestinal Nematode Parasites of Humans

Gastrointestinal nematodes (GINs) of humans, e.g., hookworms, negatively impact childhood growth, cognition, nutrition, educational attainment, income, productivity, and pregnancy. Hundreds of millions of people are targeted with mass drug administration (MDA) of donated benzimidazole (BZ) anthelmintics. However, BZ efficacy against GINs is suboptimal, and reduced/low efficacy has been seen. Developing an anthelmintic for human MDA is daunting: it must be safe, effective, inexpensive, stable without a cold chain, and massively scalable. Bacillus thuringiensis (Bt) crystal protein 5B (Cry5B) has anthelmintic properties that could fill this void. Here we develop an API (Active Pharmaceutical Ingredient) form of Bt Cry5B compatible with MDA. We expressed Cry5B in asporogenous Bt during vegetative phase, forming cytosolic crystals. These Bacteria with Cytosolic Crystals (BaCC) were rendered inviable (inactivated BaCC or IBaCC) with food-grade essential oils. IBaCC potency was validated in vitro against nematodes. IBaCC was also potent in vivo against human hookworm infections in hamsters. IBaCC production was successfully scaled to 350 liters at a contract manufacturing facility. A simple fit-for-purpose formulation to protect against stomach digestion and powdered IBaCC were successfully made and used against GINS in hamsters and mice. A pilot histopathology study and blood chemistry workup showed that five daily consecutive doses of 200 mg/kg Cry5B IBaCC (the curative single dose is 40 mg/kg) was non-toxic and completely safe. IBaCC is a safe, inexpensive, highly effective, easy-to-manufacture, and scalable anthelmintic that is practical for MDA and represents a new paradigm for treating human GINs.

microbiology↗