Pathology and immunity after SARS-CoV-2 infection in male ferrets is affected by age and inoculation route

Improving COVID-19 intervention strategies partly relies on animal models to study SARS-CoV-2 disease and immunity. In our pursuit to establish a model for severe COVID-19, we inoculated young and adult male ferrets intranasally or intratracheally with SARS-CoV-2. Intranasal inoculation established an infection in all ferrets, with viral dissemination into the brain and gut. Upon intratracheal inoculation only adult ferrets became infected. However, neither inoculation route induced observable COVID-19 symptoms. Despite this, a persistent inflammation in the nose was prominent in especially young ferrets and follicular hyperplasia in the bronchi developed 21 days post infection. These effects -if sustained- might resemble long-COVID. Respiratory and systemic cellular responses and antibody responses were induced only in animals with an established infection. We conclude that intranasally-infected ferrets resemble asymptomatic COVID-19 and possibly aspects of long-COVID. Combined with the increasing portfolio to measure adaptive immunity, ferrets are a relevant model for SARS-CoV-2 vaccine research.

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Pathology and Immunity After SARS-CoV-2 Infection in Male Ferrets Is Affected by Age and Inoculation Route

Frontiers in Immunology ◽

10.3389/fimmu.2021.750229 ◽

2021 ◽

Vol 12 ◽

Author(s):

Koen van de Ven ◽

Harry van Dijken ◽

Lisa Wijsman ◽

Angéla Gomersbach ◽

Tanja Schouten ◽

...

Keyword(s):

Cellular Responses ◽

Intervention Strategies ◽

Antibody Responses ◽

Vaccine Research ◽

Relevant Model ◽

Follicular Hyperplasia ◽

Persistent Inflammation ◽

Inoculation Route ◽

The Brain ◽

Established Infection

Improving COVID-19 intervention strategies partly relies on animal models to study SARS-CoV-2 disease and immunity. In our pursuit to establish a model for severe COVID-19, we inoculated young and adult male ferrets intranasally or intratracheally with SARS-CoV-2. Intranasal inoculation established an infection in all ferrets, with viral dissemination into the brain and gut. Upon intratracheal inoculation only adult ferrets became infected. However, neither inoculation route induced observable COVID-19 symptoms. Despite this, a persistent inflammation in the nasal turbinates was prominent in especially young ferrets and follicular hyperplasia in the bronchi developed 21 days post infection. These effects -if sustained- might resemble long-COVID. Respiratory and systemic cellular responses and antibody responses were induced only in animals with an established infection. We conclude that intranasally-infected ferrets resemble asymptomatic COVID-19 and possibly aspects of long-COVID. Combined with the increasing portfolio to measure adaptive immunity, ferrets are a relevant model for SARS-CoV-2 vaccine research.

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Vaccination with Outer Membrane Complexes Elicits Rapid Protective Immunity to Multidrug-ResistantAcinetobacter baumannii

Infection and Immunity ◽

10.1128/iai.00741-10 ◽

2010 ◽

Vol 79 (1) ◽

pp. 518-526 ◽

Cited By ~ 76

Author(s):

Michael J. McConnell ◽

Juan Domínguez-Herrera ◽

Younes Smani ◽

Rafael López-Rojas ◽

Fernando Docobo-Pérez ◽

...

Keyword(s):

Outer Membrane ◽

Protective Immunity ◽

Cellular Responses ◽

Antibiotic Resistant ◽

Membrane Complex ◽

Sepsis Model ◽

Cytokine Levels ◽

Prophylactic Vaccination ◽

Resistant Strains ◽

Established Infection

ABSTRACTAcinetobacter baumanniicauses pneumonias, bacteremias, and skin and soft tissue infections, primarily in the hospitalized setting. The incidence of infections caused byA. baumanniihas increased dramatically over the last 30 years, while at the same time the treatment of these infections has been complicated by the emergence of antibiotic-resistant strains. Despite these trends, no vaccines or antibody-based therapies have been developed for the prevention ofA. baumanniiinfection. In this study, an outer membrane complex vaccine consisting of multiple surface antigens from the bacterial membrane ofA. baumanniiwas developed and tested in a murine sepsis model. Immunization elicited humoral and cellular responses that were able to reduce postinfection bacterial loads, reduce postinfection proinflammatory cytokine levels in serum, and protect mice from infection with human clinical isolates ofA. baumannii. A single administration of the vaccine was able to elicit protective immunity in as few as 6 days postimmunization. In addition, vaccine antiserum was used successfully to therapeutically rescue naïve mice with established infection. These results indicate that prophylactic vaccination and antibody-based therapies based on an outer membrane complex vaccine may be viable approaches to preventing the morbidity and mortality caused by this pathogen.

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Alpinetin Attenuates Persistent Inflammation, Immune Suppression, and Catabolism Syndrome in a Septic Mouse Model

Journal of Immunology Research ◽

10.1155/2021/9998517 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Yukun Liu ◽

Kang Wang ◽

Qaunrui Feng ◽

Yongsheng Zhang ◽

Chuntao Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Mouse Model ◽

Immune Suppression ◽

Antioxidant Activities ◽

Cecal Ligation ◽

Sham Operation ◽

Relevant Model ◽

Septic Mouse ◽

Persistent Inflammation ◽

Group 2

Patients who survive the acute phase of sepsis can progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which usually results in extended recovery periods and multiple complications. Alpinetin is a flavonoid isolated from Alpinia katsumadai Hayata that has been demonstrated to have anti-inflammatory, antibacterial, and antioxidant activities. The aim of this study was to investigate whether the administration of alpinetin could attenuate PICS in a septic mouse model. Mice were randomly divided into four groups: the (1) sham-operated group, (2) sham+alpinetin (1 mg/kg intravenously infused for once per day after sham operation), (3) cecal ligation and puncture (CLP), and (4) CLP+alpinetin (50 mg/kg intravenously infused for once per day after CLP). Eight days after sham operation or CLP surgery, mice were euthanized for subsequent examination. Alpinetin significantly improved the survival of septic mice. Also, it attenuated the CLP-induced persistent inflammation, immunosuppression, and catabolism syndrome. The level of plasma proinflammatory cytokines and apoptosis of T lymphocytes were obviously decreased by alpinetin as well. Moreover, oxidative stress in the organs was compelling lower in the alpinetin-treated CLP mice. In this clinically relevant model of sepsis, alpinetin ameliorates CLP-induced organ dysfunction and improves the likelihood of survival, possibly through suppressing the inflammatory response, oxidative stress, and apoptosis. These findings suggested that alpinetin could be a potential novel therapeutic approach to prevent sepsis-induced PICS.

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Pneumococcal colonization impairs nasal and lung mucosal immune responses to Live Attenuated Influenza Vaccination in adults

10.1101/2020.02.24.20025098 ◽

2020 ◽

Cited By ~ 1

Author(s):

Beatriz F. Carniel ◽

Fernando Marcon ◽

Jamie Rylance ◽

Seher Zaidi ◽

Jesus Reine ◽

...

Keyword(s):

Influenza Virus ◽

Immune Responses ◽

Influenza Vaccination ◽

Cellular Responses ◽

Antibody Responses ◽

Virus Infections ◽

Mucosal Antibody ◽

Pneumococcal Colonization ◽

Differential Immunity ◽

Nasal Microbiota

ABSTRACTInfluenza virus infections affect millions of people annually. Current available vaccines provide varying rates of protection. There is a knowledge gap on how the nasal microbiota, particularly established pneumococcal colonization, shapes the response to influenza vaccination. In this study, we inoculated healthy adults with live S. pneumoniae and vaccinated them three days later with either TIV or LAIV. Vaccine-induced immune responses were assessed in nose, blood and lung. Nasal pneumococcal colonization had no impact upon TIV-induced antibody responses to influenza, which manifested in all compartments. However, pre-existing pneumococcal colonization dampened LAIV-mediated mucosal antibody responses, primarily IgA in the nose and IgG in the lung. Pulmonary influenza-specific cellular responses were more apparent in the LAIV group compared to either TIV or an unvaccinated group. These results indicate that TIV and LAIV elicit differential immunity to adults and that LAIV immunogenicity is diminished by the nasal presence of S. pneumoniae. This important confounder should be considered when assessing LAIV efficacy.

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Differential Immunogenicity of BNT162b2 or ChAdOx1 Vaccines After Extended-Interval Homologous Dual Vaccination in Older People

10.21203/rs.3.rs-727799/v1 ◽

2021 ◽

Author(s):

Helen Parry ◽

Rachel Bruton ◽

Christine Stephens ◽

Kevin Brown ◽

Gayatri Amirthalingam ◽

...

Keyword(s):

Immune Responses ◽

Older People ◽

Natural Infection ◽

Cellular Responses ◽

Antibody Responses ◽

Vaccine Responses ◽

Cell Responses ◽

Boost Vaccine ◽

The Uk ◽

Cellular Immune

Abstract BackgroundSeveral SARS-CoV-2 vaccines have shown clinical efficacy against Covid-19 infection but there remains uncertainty about the immune responses elicited by different regimens. This is a particularly important question for older people who are at increased clinical risk following infection and in whom immune senescence may limit vaccine responses. The BNT162b2 mRNA and ChAdOx1 adenovirus vaccines were the first two vaccines deployed in the UK programme using an 8-12 week ‘extended interval’.ObjectivesWe undertook analysis of the spike-specific antibody and cellular immune response in 131 participants aged 80+ years after the second dose of ‘extended interval’ dual vaccination with either BNT162b2 mRNA (n=54) or ChAdOx1 (n=77) adenovirus vaccine. Blood samples were taken 2-3 weeks after second vaccine and were paired with samples taken at 5-weeks after first vaccine which have been reported previously. Antibody responses were measured using the Elecsys® electrochemiluminescence immunoassay assay and cellular responses were assessed by IFN-g ELISpot. ResultsAntibody responses against spike protein became detectable in all donors following dual vaccination with either vaccine. 4 donors had evidence of previous natural infection which is known to boost vaccine responses. Within the 53 infection-naïve donors the median antibody titre was 4030 U/ml (IQR 1892-8530) following BNT162b2 dual vaccination and 1405 (IQR 469.5- 2543) in the 74 patients after the ChAdOx1 vaccine (p=<0.0001). Spike-specific T cell responses were observed in 30% and 49% of mRNA and ChAdOx1 recipients respectively and median responses were 1.4-times higher in ChAdOx1 vaccinees at 14 vs 20 spots/million respectively (p=0.022).ConclusionDual vaccination with BNT162b2 or ChAdOx1 induces strong humoral immunity in older people following an extended interval protocol. Antibody responses are 2.9-times higher following the mRNA regimen whilst cellular responses are 1.7-times higher with the adenovirus-based vaccine. Differential patterns of immunogenicity are therefore elicited from the two vaccine platforms. It will be of interest to assess the relative stability of immune responses after these homologous vaccine regimens in order to assess the potential need for vaccine boosting. Furthermore, these findings indicate that heterologous vaccine platforms may offer the opportunity to further optimize vaccine responses.

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Cellular resolution imaging of vestibular processing across the larval zebrafish brain

10.1101/302752 ◽

2018 ◽

Cited By ~ 1

Author(s):

Itia A. Favre-Bulle ◽

Gilles Vanwalleghem ◽

Michael A. Taylor ◽

Halina Rubinsztein-Dunlop ◽

Ethan K. Scott

Keyword(s):

Vestibular System ◽

Cellular Responses ◽

Vestibular Stimulation ◽

Brain Regions ◽

Larval Zebrafish ◽

Cellular Resolution ◽

Separate Control ◽

Resolution Imaging ◽

Apply Physical ◽

The Brain

SummaryThe vestibular system, which reports on motion and gravity, is essential to postural control, balance, and egocentric representations of movement and space. The motion needed to stimulate the vestibular system complicates studying its circuitry, so we previously developed a method for fictive vestibular stimulation in zebrafish, using optical trapping to apply physical forces to the otoliths. Here, we combine this fictive stimulation with whole-brain calcium imaging at cellular resolution, delivering a comprehensive map of the brain regions and cellular responses involved in basic vestibular processing. We find these responses to be broadly distributed across the brain, with unique profiles of cellular responses and topography in each brain region. The most widespread and abundant responses involve excitation that is rate coded to the stimulus strength. Other responses, localized to the telencephalon and habenulae, show excitation that is only weakly rate coded and that is sensitive to weak stimuli. Finally, numerous brain regions contain neurons that are inhibited by vestibular stimuli, and these inhibited neurons are often tightly localised spatially within their regions. By exerting separate control over the left and right otoliths, we explore the laterality of brain-wide vestibular processing, distinguishing between neurons with unilateral and bilateral vestibular sensitivity, and revealing patterns by which conflicting vestibular signals from the two ears can be mutually cancelling. Our results show a broader and more extensive network of vestibular responsive neurons than has previously been described in larval zebrafish, and provides a framework for more targeted studies of the underlying functional circuits.

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A Rhombencephalitis Revealing HIV Virorachia

10.21203/rs.3.rs-465507/v1 ◽

2021 ◽

Author(s):

Annick Melanie MAGNEROU ◽

Martine NIDA ◽

Daniel MASSI GAMS ◽

Hugues Martial ZANGA ◽

Fidelie Scolastique NGOUNGOURE HALIMA ◽

...

Keyword(s):

Viral Suppression ◽

Treated Patient ◽

Brain Mri ◽

Undetectable Viral Load ◽

Brain Parenchyma ◽

Hiv Replication ◽

Csf Analysis ◽

Persistent Inflammation ◽

The Central Nervous System ◽

The Brain

Abstract One of the possible causes of persistent inflammation of the brain parenchyma in the age of antiretrovirals is residual HIV replication, despite effective viral suppression in the bloodstream with Antiretroviral treatment (ART). The central nervous system (CNS) is infected early during primary HIV infection and is one of the reservoirs of this virus during chronic infection. Inadequate penetration of certain ART into the CNS could promote some degree of intrathecal HIV replication.We describe the case of an HIV-infected patient compliant to ART with an undetectable viral load in the blood but present in the cerebrospinal fluid (CSF). The patient presented with subacute rhombencephalitis due to HIV which was fatal to him.An HIV-infected and treated patient, well controlled on ART, with new neurological disorders, should be promptly investigated by brain MRI and CSF analysis for exhaustive detection of viruses including that of HIV itself.

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Brain Vasculature and Cognition

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.118.311906 ◽

2019 ◽

Vol 39 (4) ◽

pp. 593-602 ◽

Cited By ~ 6

Author(s):

Abdelrahman Y. Fouda ◽

Susan C. Fagan ◽

Adviye Ergul

Keyword(s):

Cognitive Impairment ◽

Intervention Strategies ◽

Proper Function ◽

Cerebral Vasculature ◽

Brain Vasculature ◽

Cerebrovascular Function ◽

Cerebrovascular Dysfunction ◽

Function Preservation ◽

Almost All ◽

The Brain

There is a complex interaction between the brain and the cerebral vasculature to meet the metabolic demands of the brain for proper function. Preservation of cerebrovascular function and integrity has a central role in this sophisticated communication within the brain, and any derangements can have deleterious acute and chronic consequences. In almost all forms of cognitive impairment, from mild to Alzheimer disease, there are changes in cerebrovascular function and structure leading to decreased cerebral blood flow, which may initiate or worsen cognitive impairment. In this focused review, we discuss the contribution of 2 major vasoactive pathways to cerebrovascular dysfunction and cognitive impairment in an effort to identify early intervention strategies.

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COVID-19 Vaccines: “Warp Speed” Needs Mind Melds, Not Warped Minds

Journal of Virology ◽

10.1128/jvi.01083-20 ◽

2020 ◽

Vol 94 (17) ◽

Cited By ~ 18

Author(s):

John P. Moore ◽

P. J. Klasse

Keyword(s):

Antibody Response ◽

Antibody Responses ◽

Vaccine Uptake ◽

Vaccine Research ◽

Vaccine Candidates ◽

Virus Challenge ◽

Additional Information ◽

Initial Wave ◽

Adverse Influence ◽

Induced Immunity

ABSTRACT In this review, we address issues that relate to the rapid “Warp Speed” development of vaccines to counter the COVID-19 pandemic. We review the antibody response that is triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of humans and how it may inform vaccine research. The isolation and properties of neutralizing monoclonal antibodies from COVID-19 patients provide additional information on what vaccines should try to elicit. The nature and longevity of the antibody response to coronaviruses are relevant to the potency and duration of vaccine-induced immunity. We summarize the immunogenicity of leading vaccine candidates tested to date in animals and humans and discuss the outcome and interpretation of virus challenge experiments in animals. By far the most immunogenic vaccine candidates for antibody responses are recombinant proteins, which were not included in the initial wave of Warp Speed immunogens. A substantial concern for SARS-CoV-2 vaccines is adverse events, which we review by considering what was seen in studies of SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) vaccines. We conclude by outlining the possible outcomes of the Warp Speed vaccine program, which range from the hoped-for rapid success to a catastrophic adverse influence on vaccine uptake generally.

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How Stress Physically Re-shapes the Brain: Impact on Brain Cell Shapes, Numbers and Connections in Psychiatric Disorders

10.31234/osf.io/f3nj8 ◽

2019 ◽

Author(s):

Dominic Kaul ◽

Sibylle Schwab ◽

Naguib Mechawar ◽

Natalie Matosin

Keyword(s):

Psychiatric Disorders ◽

Molecular Mechanisms ◽

Brain Regions ◽

Brain Cell ◽

Intervention Strategies ◽

Traumatic Experiences ◽

Brain Pathology ◽

Cell Shapes ◽

Brain Circuitry ◽

The Brain

Exposure to stressful or traumatic experiences is one of the most robust risk factors for severe psychiatric disorders and has been shown to reshape entire brain regions, especially those involved in processing the stress response. This is likely underpinned by alterations to brain cell shapes, numbers and their connections, thus changing brain circuitry to enable coping with the current and future stress. In this review, we present a model for how stress re-shapes the brain, consolidating evidence of morphometric changes and the cellular and molecular mechanisms that underlie them. We illustrate how the temporal effects of stress can cause persistent remodelling of brain cells, highlighting that an individual's stress history is important for understanding psychiatric disorder risk and development. Understanding how stress re-shapes the brain is a critical step for understanding stress as a risk factor for brain pathology, and to develop appropriate biomarkers, treatments and intervention strategies.

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