Biology subjects

Brayton, C.

Publications and source records attributed to Brayton, C..

5 recordsLinked to original sources

bioRxiv2025

A conserved region T-cell vaccine for Sarbecoviruses

The rapid development of vaccines was a critical part of the global response to the COVID-19 pandemic. SARS-CoV-2 (a Sarbecovirus and member of the Betacoronavirus genus responsible for the pandemic) virus was first detected in Wuhan, China in late 2019. Effective mRNA vaccines based on the viral Spike protein were designed from the earliest isolates and available by December of 2020. SARS-CoV-2 has continued to evolve in the human population, accruing neutralizing antibody resistance mutations that have necessitated updating the vaccine periodically to better match contemporary variants. Neutralizing antibody cross-reactivity is generally very limited among the diverse members of the betacoronavirus genus that are of clinical importance in people. Here, we present an alternative vaccine strategy based on eliciting T-cell responses targeting four highly conserved regions shared across the betacoronavirus proteomes. We hypothesized that cross-reactive responses to these regions could temper disease severity. Focusing immune responses on highly conserved epitopes could be beneficial as SARS-CoV-2 continues to evolve, or if a novel betacoronavirus should enter the human population. Vaccination with these highly conserved regions induced robust T-cell responses in mice and rhesus macaques. Vaccinated hamsters were significantly protected against weight loss and lung inflammation after challenge with the SARS-CoV-2 Omicron variant. After a SARS-CoV-2 Delta challenge in rhesus macaques, 3 out of 4 animals in the control group had infectious virus in their bronchoalveolar lavage samples, while the 4 animals in the vaccinated group did not.

immunology↗

bioRxiv2025

Multi-System Dysregulation in Placental Malaria Contributes to Adverse Perinatal Outcomes in Mice

Sequestration of Plasmodium parasites in the placental vasculature causes increased morbidity and mortality in pregnant compared to non-pregnant patients in malaria- endemic regions. In this study, outbred pregnant CD1 mice with semi allogeneic fetuses were infected with transgenic Plasmodium berghei or mock-inoculated by mosquito bite at either embryonic day (E) 6 (first trimester-equivalent) or 10 (second trimester- equivalent) and compared with non-pregnant females. P. berghei-infected mosquitoes had greater biting avidity for E10 dams than uninfected mosquitoes, which was not apparent for E6 dams nor non-pregnant females. Infected E10 dams had greater numbers of parasites than E6 dams in the uterus and spleen, but not in the blood or liver. While parasites were found in placentas, no parasites were present in fetuses. Maternal infection at E6 caused greater maternal morbidity, with greater rates of fetal reabsorption and stillbirths than at E10. Infection at E10 caused adverse offspring outcomes, including growth restriction. To identify possible mechanisms of adverse offspring outcomes, E10 dams were euthanized during peak parasitemia (8 days post infection), and outcomes were compared with mock-infected dams. P. berghei caused significant systemic maternal immune activation with elevated circulating lymphocytes, eosinophils, and neutrophils and splenic cytokine concentrations. P. berghei infection at E10 increased corticosterone and decreased progesterone concentrations, which could contribute to adverse perinatal outcomes through immunomodulation. There were limited changes in the maternal fecal microbiome after P. berghei infection. Mosquito bite infection of outbred dams with P. berghei causes placental malaria and provides a novel, tractable model to investigate therapeutic treatments.

microbiology↗

bioRxiv2021

Progression and Resolution of SARS-1 CoV-2 Infection in Golden Syrian Hamsters

To catalyze SARS-CoV-2 research including development of novel interventive and preventive strategies, we characterized progression of disease in depth in a robust COVID-19 animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at day 2, 4, 7, 14, and 28 days post-inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal timepoints, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 post-inoculation, corresponding with widespread necrosis and inflammation. At day 7, when infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 post-inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.

pathology↗

bioRxiv2019

A Drug Combination Approach Targeting Both Growing Bacteria and Dormant Persisters Eradicate Persistent Staphylococcus aureus Biofilm Infection

Staphylococcus aureus can cause a variety of infections, many of which involve biofilm infections. Inside biofilms, growing and non-growing bacteria such as persisters co-exist, making it challenging to completely eradicate a persistent and recurrent infection with current treatments. Despite the clinical relevance, most of the current antibiotic treatments mainly kill the growing bacteria and have poor activity against non-growing persister bacteria and thus have limited effect on treating persistent infections including biofilm infections. We previously proposed a Yin-Yang model using a drug combination approach targeting both growing bacteria and persister bacteria for more effective clearance of persistent infections. Here, as a proof of principle, we showed that combining drugs that have high activity against growing forms, such as vancomycin or meropenem, with drugs that have robust anti-persister activity, such as clinafloxacin and oritavancin, could completely eradicate S. aureus biofilm bacteria in vitro. In contrast, single or two drugs including the current treatment for persistent S. aureus infection doxycycline plus rifampin failed to kill all biofilm bacteria in vitro. We then developed a chronic persistent skin infection mouse model with biofilm-seeded bacterial inocula demonstrating that biofilm bacteria caused more severe and persistent skin lesions than log phase S. aureus bacteria. More importantly, we found that the drug combination which eradicated biofilm bacteria in vitro is more efficacious than current treatments and completely eradicated S. aureus biofilm infection in mice. The complete eradication of biofilm bacteria is attributed to the unique high anti-persister activity of clinafloxacin, which could not be replaced by other fluoroquinolones such as moxifloxacin, levofloxacin or ciprofloxacin. Our study is the first to demonstrate that the combination of meropenem, daptomycin, plus clinafloxacin completely cleared the persistent infection, healed the lesions, and had less inflammation, while mice treated with doxycycline plus rifampin, the current clinically recommended treatment for chronic tissue infection, failed to do so. We also compared our persister drug combination with other approaches for treating persistent infections including gentamicin+fructose and ADEP4+rifampin in the S. aureus biofilm infection mouse model. Neither gentamicin+fructose nor ADEP4+rifampin could eradicate or cure the persistent biofilm infection in mice. In contrast, our drug combination regimen with persister drug clinafloxacin plus meropenem and daptomycin completely eradicated and cured the persistent biofilm infection in 7 days. An unexpected observation is that ADEP4 treatment group developed worsened skin lesions and caused more extensive pathology than the untreated control mice. Our study demonstrates an important treatment principle for persistent infections by targeting both growing and non-growing heterogeneous bacterial populations utilizing persister drugs for more effective eradication of persistent and biofilm infections. Our findings may have implications for improved treatment of many other persistent infections in general.

microbiology↗

bioRxiv2018

Infection with Persister Forms of Staphylococcus aureus Causes a Chronic Persistent Skin Infection with More Severe Lesion that Takes Longer to Heal and is not Eradicated by the Current Recommended Treatment in Mice

Staphylococcus aureus is an opportunistic pathogen that can cause persistent infections clinically. Treatment for chronic S. aureus infections ranges from at least one week to several months and such infections are prone to relapse likely due to the presence of persistent forms of bacteria such as persister cells. Persister cells, which are bacterial cells that become dormant under stress conditions, can be isolated in vitro but their clinical significance in in vivo infections are largely unclear. Here, we evaluated S. aureus persistent forms using stationary phase cultures and biofilm bacteria (enriched in persisters) in comparison with log phase cultures in terms of their ability to cause disease in a mouse skin infection model. Surprisingly, we found that infection of mice with stationary phase cultures and biofilm bacteria produced a more severe chronic skin infection with more pronounced lesions which took longer to heal than log phase (actively growing) cultures. After two week infection, the bacterial load and skin tissue pathology, as determined by hyperplasia, immune cell infiltration, and crust/lesion formation, of mice infected with the more persistent forms (e.g. stationary phase bacteria and biofilm bacteria) were greater than mice infected with log phase bacteria. Using our persistent infection mouse model, we showed that the clinically recommended treatment for recurrent S. aureus skin infection, doxycycline + rifampin, was not effective in eradicating the bacteria in the treatment study, despite reducing lesion sizes and pathology in infected mice. Analogous findings were also observed in a Caenorhabditis elegans model, where S.aureus stationary phase cultures caused a greater mortality than log phase culture as early as two days post-infection. Thus, we established a new model for chronic persistent infections using persister bacteria that could serve as a relevant model to evaluate therapeutic options for persistent infections in general. Our findings connect persisters with persistent infections, have implications for understanding disease pathogenesis, and are likely to be broadly valid for other pathogens.

microbiology↗