Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
1.
Proc Natl Acad Sci U S A ; 119(15): e2119893119, 2022 Apr 12.
Article in English | MEDLINE | ID: covidwho-1778688

ABSTRACT

The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.


Subject(s)
COVID-19 , Pandemics , COVID-19/drug therapy , COVID-19 Vaccines , Drug Development , Humans , Pandemics/prevention & control , SARS-CoV-2
3.
Neurol Neuroimmunol Neuroinflamm ; 8(2)2021 03.
Article in English | MEDLINE | ID: covidwho-999775

ABSTRACT

OBJECTIVE: To discuss the pathogenic and diagnostic relevance of cellular and humoral immune responses against severe acute respiratory syndrome novel coronavirus (SARS-COV-2) and pertinent observations made in progressive multifocal leukoencephalopathy (PML). METHODS: Review of pertinent literature. RESULTS: There is at least 1 precedent for an antibody response against a viral pathogen that fails to provide host protection in the absence of immune-competent CD4+ T cells. PML is an infection of the CNS caused by JC virus (JCV), which commonly occurs during treatment with the therapeutic monoclonal antibody natalizumab. In this context, the humoral immune response fails to prevent JCV reactivation, and elevated anti-JCV serum indices are associated with a higher PML incidence. The more relevant immune-competent cells in host defense against JCV appear to be T cells. T cell-mediated responses are also detectable in convalescing patients with SARS-COV-2 irrespective of the humoral immune response. CONCLUSION: Based on pathogenic lessons learned from PML under natalizumab therapy, we suggest the incorporation of functional assays that determine neutralizing properties of SARS-CoV-2-specific antibodies. In addition, we outline the potential role of T-cell detection assays in determining herd immunity in a given population or in studying therapeutic responses to vaccines.


Subject(s)
Adaptive Immunity/immunology , Antibodies, Viral/immunology , Antibody Formation/immunology , Immunity, Humoral/immunology , Leukoencephalopathy, Progressive Multifocal/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Humans , Leukoencephalopathy, Progressive Multifocal/drug therapy
4.
Proc Natl Acad Sci U S A ; 117(40): 24620-24626, 2020 10 06.
Article in English | MEDLINE | ID: covidwho-744434

ABSTRACT

The reduced development of COVID-19 for children compared to adults provides some tantalizing clues on the pathogenesis and transmissibility of this pandemic virus. First, ACE2, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, is reduced in the respiratory tract in children. Second, coronavirus associated with common colds in children may offer some protection, due to cross-reactive humoral immunity and T cell immunity between common coronaviruses and SARS-CoV-2. Third, T helper 2 immune responses are protective in children. Fourth, surprisingly, eosinophilia, associated with T helper 2, may be protective. Fifth, children generally produce lower levels of inflammatory cytokines. Finally, the influence of the downturn in the global economy, the impact of living in quarters among families who are the most at risk, and factors including the openings of some schools, are considered. Those most disadvantaged socioeconomically may suffer disproportionately with COVID-19.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/immunology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Respiratory Mucosa/metabolism , Respiratory Tract Infections/immunology , Angiotensin-Converting Enzyme 2 , COVID-19 , Child , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Host-Pathogen Interactions/immunology , Humans , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Respiratory Tract Infections/virology , SARS-CoV-2 , Th2 Cells/physiology
5.
J Neurol Sci ; 415: 116935, 2020 08 15.
Article in English | MEDLINE | ID: covidwho-626763

ABSTRACT

Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish 'PANIC', thereby 'left-shifting' severe COVID-19 patients to the group majority of those infected with SARS-CoV-2, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this disease. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon SARS-CoV-2 triggered 'PANIC Attack'. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons which could be leveraged to more effectively prepare for the next challenge to global health.


Subject(s)
Betacoronavirus/drug effects , Clinical Trial Protocols as Topic , Coronavirus Infections/drug therapy , Leucovorin/therapeutic use , Methotrexate/therapeutic use , Pneumonia, Viral/drug therapy , COVID-19 , Disease Management , Humans , Immunosuppressive Agents/therapeutic use , Immunotherapy/methods , Pandemics , SARS-CoV-2
6.
J Neurochem ; 154(5): 465-467, 2020 09.
Article in English | MEDLINE | ID: covidwho-616158

ABSTRACT

In a rare neurologic disease known as IgM monoclonal gammopathy the immune system targets a sulfated trisaccharide known as the Human Natural Killer-1 (HNK-1) epitope that comprises a constituent of the myelin sheath known as MAG (myelin-associated glycoprotein). This Editorial highlights a study by Aliu and colleagues in the current issue of the Journal of Neurochemistry, in which the investigators constructed a biodegradable poly-l-lysine backbone with multiple copies of this sulfated HNK-1 trisaccharide. This decoy, poly(phenyl disodium 3-O-sulfo-ß-d-glucopyranuronate)-(1→3)-ß-d-galactopyranoside, known as PPSGG, removed anti-MAG IgM autoantibodies from the blood, while not activating the immune system. These findings provide a path for the selective removal of a pathogenic set of antibodies that target the myelin sheath resulting in neuropathy. These findings are applicable to a parallel strategy for the generation of polysaccharides similar to those present in the receptor-binding domain of CoViD-19, which might inhibit viral adhesion to its receptor, the angiotensin-converting enzyme-2 (ACE2) protein, thereby impairing cellular uptake of the virus itself. The deployment of complex polysaccharides that mimic actual COVID19 polysaccharides on the spike protein may also provide a feasible structural basis for a vaccine. Carbohydrate mimics, if conjugated to a carrier or backbone, might provoke an immune response to the spike protein. A vaccine that targets critical carbohydrates on COVID19, and then neutralizes the virus would recapitulate a successful strategy employed in other microbial vaccines, like the pneumococcal vaccines and the meningococcal vaccines. These vaccines direct an immune response to complex carbohydrates and successfully prevent life-threatening disease. This paper provides lessons from a rare neurologic disease that may teach us strategies applicable to a global pandemic.


Subject(s)
Coronavirus Infections , Myelin-Associated Glycoprotein , Pandemics , Pneumonia, Viral , Vaccines , Autoantibodies , Betacoronavirus , COVID-19 , Humans , Immunoglobulin M , Myelin Sheath , Polysaccharides , SARS-CoV-2
7.
J Neurol Sci ; 415: 116936, 2020 08 15.
Article in English | MEDLINE | ID: covidwho-599251

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has produced a world-wide collapse of social and economic infrastructure, as well as constrained our freedom of movement. This respiratory tract infection is nefarious in how it targets the most distal and highly vulnerable aspect of the human bronchopulmonary tree, specifically, the delicate yet irreplaceable alveoli that are responsible for the loading of oxygen upon red cell hemoglobin for use by all of the body's tissues. In most symptomatic individuals, the disease is a mild immune-mediated syndrome, with limited damage to the lung tissues. About 20% of those affected experience a disease course characterized by a cataclysmic set of immune activation responses that can culminate in the diffuse and irreversible obliteration of the distal alveoli, leading to a virtual collapse of the gas-exchange apparatus. Here, in Part I of a duology on the characterization and potential treatment for COVID-19, we define severe COVID-19 as a consequence of the ability of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to trigger what we now designate for the first time as a 'Prolific Activation of a Network-Immune-Inflammatory Crisis', or 'PANIC' Attack, in the alveolar tree. In Part II we describe an immunotherapeutic hypothesis worthy of the organization of a randomized clinical trial in order to ascertain whether a repurposed, generic, inexpensive, and widely available agent is capable of abolishing 'PANIC'; thereby preventing or mitigating severe COVID-19, with monumental ramifications for world health, and the global pandemic that continues to threaten it.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Models, Immunological , Pneumonia, Viral/immunology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/physiopathology , Humans , Pandemics , Pneumonia, Viral/physiopathology , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL