Biology subjects

Jackson, D. C.

Publications and source records attributed to Jackson, D. C..

4 recordsLinked to original sources

bioRxiv2020

Prophylactic intranasal administration of a TLR2 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model

Respiratory viruses such as coronaviruses represent major ongoing global threats, causing epidemics and pandemics with huge economic burden. Rapid spread of virus through populations poses an enormous challenge for outbreak control. Like all respiratory viruses, the most recent novel human coronavirus SARS-CoV-2, initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission. We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT to reduce SARS-CoV-2 transmission and provide protection against COVID-19.

immunology↗

bioRxiv2020

High antibody titres induced by protein subunit vaccines against Buruli ulcer using Mycobacterium ulcerans antigens Hsp18 and MUL_3720

BackgroundMycobacterium ulcerans is the causative agent of a debilitating skin and soft tissue infection known as Buruli ulcer (BU). There is no vaccine against BU. The purpose of this study was to investigate the vaccine potential of two previously described immunogenic M. ulcerans proteins, MUL_3720 and Hsp18, using a mouse tail infection model of BU. MethodsRecombinant versions of the two proteins were each electrostatically coupled with a previously described lipopeptide adjuvant. Seven C57BL/6 and seven BALB/c mice were vaccinated and boosted with each of the formulations. Vaccinated mice were then challenged with M. ulcerans via subcutaneous tail inoculation. Vaccine performance was assessed by time-to-ulceration compared to unvaccinated mice. ResultsThe MUL_3720 and Hsp18 vaccines induced high titres of antigen-specific antibodies that were predominately subtype IgG1. However, all mice developed ulcers by day-40 post-M. ulcerans challenge. No significant difference was observed in the time-to-onset of ulceration between the experimental vaccine groups and unvaccinated animals. ConclusionsThese data align with previous vaccine experiments using Hsp18 and MUL_3720 that indicated these proteins may not be appropriate vaccine antigens. This work highlights the need to explore alternative vaccine targets and different approaches to understand the role antibodies might play in controlling BU.

microbiology↗

bioRxiv2019

Vaccine-specific immune responses against Mycobacterium ulcerans infection in a low-dose murine challenge model

The neglected tropical disease Buruli ulcer (BU) is an infection of subcutaneous tissue with Mycobacterium ulcerans. There is no effective BU vaccine. Here, we assessed an experimental prime-boost vaccine in a low-dose murine tail infection model. We used the enoyl-reductase (ER) domain of the M. ulcerans mycolactone polyketide synthases electrostatically coupled with a previously described TLR-2 agonist-based lipopeptide adjuvant, R4Pam2Cys. Mice were vaccinated and then challenged via tail inoculation with 14-20 colony forming units (CFU) of an engineered bioluminescent strain of M. ulcerans. Mice receiving either the experimental ER vaccine or Mycobacterium bovis Bacille Calmette-Guerin (BCG) were equally well protected, with both groups faring significantly better than non-vaccinated animals (p<0.05). A suite of 29 immune parameters were assessed in the mice at the end of the experimental period. Multivariate statistical approaches were then used to interrogate the immune response data to develop disease-prognostic models. High levels of IL-2 and low IFN-{gamma} produced in the spleen best predicted control of infection across all vaccine groups. Univariate logistic regression then revealed vaccine-specific profiles of protection. High titres of ER-specific IgG serum antibodies together with IL-2 and IL-4 in the draining lymph node (DLN) were associated with protection induced by the experimental ER vaccine. In contrast, high titres of IL-6, TNF-, IFN-{gamma} and IL-10 in the DLN and low IFN{gamma} titres in the spleen were associated with protection following BCG vaccination. This study suggests an effective BU vaccine must induce localized, tissue-specific immune profiles with controlled inflammatory responses at the site of infection.

immunology↗

bioRxiv2018

Bioluminscent Mycobacterium ulcerans, a tool to study host-pathogen interactions in a murine tail model of Buruli ulcer

Buruli ulcer is a neglected tropical disease caused by infection with Mycobacterium ulcerans. In this study we used a previously reported strain of M. ulcerans, genetically engineered to constitutively produce bioluminescence, to follow the progression of Buruli ulcer in mice using an in-vivo imaging (IVIS(R)) system. We aimed to characterize a mouse tail infection model for pathogenesis, as well as for pre-clinical vaccine and drug development research for Buruli ulcer. Immune parameters, such as antibody titers and cytokine levels, were determined throughout the course of the infection and histology specimens were examined for comparison with human pathology. Nine out of ten (90%) BALB/c mice infected subcutaneously with 105 M. ulcerans JKD8049 (containing pMV306 hsp16+luxG13) exhibited light emission from the site of infection over the course of the experiment indicating M. ulcerans growth in-vivo. Five out of ten (50%) animals developed clinical signs of disease. Antibody titers were overall low and their onset was late, as measured by responses to both heterogenous (bacterial whole cell lysate) and single antigen (Hsp18) targets. IFN-{gamma}, and IL-10 are reported to play a vital role in host control of Buruli ulcer and these cytokines were elevated in animals with pathology. For mice with advanced pathology, histology revealed clusters of acid-fast bacilli within subcutaneous tissue 300-400 m beneath the epidermis of the tail, with macrophage infiltration and granuloma-formation resembling human Buruli ulcer. This study has shown the utility of using bioluminescent M. ulcerans and IVIS(R) in a mouse tail infection model to study Buruli ulcer infection.\n\nAuthor summaryBuruli ulcer is one of the so called neglected tropical diseases. It is an infectious disease, mainly occurring in West Africa but also in Australia. It manifests as skin lesion and ulcer. Up to date, the way of transmission is inadequately understood. Also, there is no vaccine to protect against the disease. Buruli ulcer is treatable with a course of antibiotics that need to be given for the duration of two months. More laboratory research is needed to elucidate the mechanism of transmission, develop a vaccine and improve and shorten antibiotic therapy. For this, animal (mouse) models of disease are used. The aim of this study was to refine and improve the mouse tail infection model of Buruli ulcer. For this, we used a genetically modified Mycobacterium ulcerans strain that emits light. After infection of animals, light emitted from the bacteria was read out with an in-vivo imaging (IVIS) camera. This allowed us to monitor the location of bacteria in the living animal over time without the need to kill the animal. We also measured parameters of the immune system such as antibodies and cytokines as a baseline for future studies into immunology, vaccine development and pathology of Buruli ulcer. We successfully improved and characterized the mouse tail infection model in Buruli ulcer with the use of modern technology using light emitting bacteria and the IVIS camera.

microbiology↗