Biology subjects

Hode, T.

Publications and source records attributed to Hode, T..

3 recordsLinked to original sources

bioRxiv2022

A novel biopolymer for mucosal adjuvant against respiratory pathogens

Mucosal vaccinations for respiratory pathogens provide effective protection as they stimulate localized cellular and humoral immunities at the site of infection. Currently, the major limitation of intranasal vaccination is using effective adjuvants capable of withstanding the harsh environment imposed by the mucosa. Herein, we describe the efficacy of using a novel biopolymer, N-dihydrogalactochitosan (GC), as a nasal mucosal vaccine adjuvant against respiratory infections. Specifically, using COVID as an example, we mixed GC with recombinant SARS-CoV-2 trimeric spike (S) and nucleocapsid (NC) proteins to intranasally vaccinate K18-hACE2 transgenic mice, in comparison with Addavax (AV), an MF-59 equivalent. In contrast to AV, intranasal application of GC induces a robust, systemic antigen-specific antibody response and increases the number of T cells in the cervical lymph nodes. Moreover, GC+S+NC-vaccinated animals were largely resistant to the lethal SARS-CoV-2 challenge and experienced drastically reduced morbidity and mortality, with animal weights and behavior returning to normal 22 days post-infection. In contrast, animals intranasally vaccinated with AV+S+NC experienced severe weight loss, mortality, and respiratory distress, with none surviving beyond 6 days post-infection. Our findings demonstrate that GC can serve as a potent mucosal vaccine adjuvant against SARS-CoV-2 and potentially other respiratory viruses.

bioengineering↗

bioRxiv2022

A novel biopolymer synergizes type I IFN and IL-1β production through STING

N-dihydrogalactochitosan (GC) is developed for inducing immune responses. Synthesized from chitosan and galactose, GC is a new chemical entity that significantly enhances the immune-stimulating properties of its parental material, chitosan, making it a promising therapeutic agent. When used in combination with antigenic material, GC stimulates innate and adaptive antitumor and antiviral immunities. However, the mechanism of GC has not been fully investigated. Herein we demonstrate that GC drives type I IFN production and IFN responses in antigen presenting cells (APCs) and has superior potency compared to its corresponding chitosan. More importantly, GC drives alternative activation of STING leading to inflammatory cell death that enhances dendritic cell (DC) activation, which triggers a variety of nucleic acid sensing pattern recognition receptors (PRRs) and IL-1{beta} production. In vivo, GC induced a potent response of type I IFN and upregulated genes associated with STING signaling within the tumor microenvironment (TME). Moreover, intratumoral delivery of GC reduced the numbers of M2-like macrophages residing within the TME, while subsequently increasing the number of DCs. Our findings demonstrate GCs unique ability to activate STING and stimulate a broad type I IFN response which holds therapeutic promise in generating antitumor and antiviral immunities.

cancer biology↗

bioRxiv2021

N-dihydrogalactochitosan reduces mortality in a lethal mouse model of SARS-CoV-2

The rapid emergence and global dissemination of SARS-CoV-2 that causes COVID-19 continues to cause an unprecedented global health burden resulting in nearly 7 million deaths. While multiple vaccine countermeasures have been approved for emergency use, additional treatments are still needed due to sluggish vaccine rollout, vaccine hesitancy, and inefficient vaccine-mediated protection. Immunoadjuvant compounds delivered intranasally can guide non-specific innate immune responses during the critical early stages of viral replication, reducing morbidity and mortality. N- dihydrogalactochitosan (GC) is a novel mucoadhesive immunostimulatory polymer of {beta}- 0-4-linked N-acetylglucosamine that is solubilized by the conjugation of galactose glycans with current applications as a cancer immunotherapeutic. We tested GC as a potential countermeasure for COVID-19. GC was well-tolerated and did not produce histopathologic lesions in the mouse lung. GC administered intranasally before and after SARS-CoV-2 exposure diminished morbidity and mortality in humanized ACE2 receptor expressing mice by up to 75% and reduced infectious virus levels in the upper airway. Fluorescent labeling of GC shows that it is confined to the lumen or superficial mucosa of the nasal cavity, without involvement of adjacent or deeper tissues. Our findings demonstrate a new application for soluble immunoadjuvants such as GC for preventing disease associated with SARS-CoV-2 and may be particularly attractive to persons who are needle-averse. IMPORTANCEThe ongoing COVID-19 pandemic necessitates new approaches to reduce disease caused by SARS-CoV-2. We tested the immunoadjuvant N-dihydrogalactochitosan (GC), used previously as an immunostimulant for tumor therapy and adjuvant for viral vaccines, as a potential COVID-19 countermeasure. When GC was administered before and after inoculation of a lethal dose of SARS-CoV-2 into the nose of humanized mice expressing an entry receptor for the virus, fewer mice showed weight loss and died compared to mice that received only the vehicle but no GC. GC-treated mice also had lower levels of infectious SARS-CoV-2 in their upper airway. These results suggest that GC may be a candidate to prevent or treat COVID-19. Single Sentence SummaryThe immunoadjuvant N-dihydrogalactochitosan diminishes SARS-CoV-2 disease in humanized ACE2 mice, representing a new countermeasure against COVID-19.

microbiology↗