Therapeutics for Postexposure Treatment of Ebola Virus Infection

Jerebtsova, Marina; Nekhai, Sergeï

doi:10.2217/fvl.14.109

Cited by 6 publications

(5 citation statements)

References 83 publications

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“…Both host and bacterial factors contribute to severe tissue damage in pneumonia, thus offering critical targets for therapy development (41, 42). The therapeutic use of passive antibodies has been well established for several primary viral infections (43–45). Similarly, the passive immunization afforded by antibodies to the pathogenic virulence factor pneumolysin can enhance the survival rate of mice with primary bacterial pneumonia (13).…”

Section: Discussionmentioning

confidence: 99%

Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia

Foo

Kwok

et al. 2019

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Secondary bacterial lung infection by Streptococcus pneumoniae (S. pneumoniae) poses a serious health concern, especially in developing countries. We posit that the emergence of multiantibiotic-resistant strains will jeopardize current treatments in these regions. Deaths arising from secondary infections are more often associated with acute lung injury, a common consequence of hypercytokinemia, than with the infection per se. Given that secondary bacterial pneumonia often has a poor prognosis, newer approaches to improve treatment outcomes are urgently needed to reduce the high levels of morbidity and mortality. Using a sequential dual-infection mouse model of secondary bacterial lung infection, we show that host-directed therapy via immunoneutralization of the angiopoietin-like 4 c-isoform (cANGPTL4) reduced pulmonary edema and damage in infected mice. RNA sequencing analysis revealed that anti-cANGPTL4 treatment improved immune and coagulation functions and reduced internal bleeding and edema. Importantly, anti-cANGPTL4 antibody, when used concurrently with either conventional antibiotics or antipneumolysin antibody, prolonged the median survival of mice compared to monotherapy. Anti-cANGPTL4 treatment enhanced immune cell phagocytosis of bacteria while restricting excessive inflammation. This modification of immune responses improved the disease outcomes of secondary pneumococcal pneumonia. Taken together, our study emphasizes that host-directed therapeutic strategies are viable adjuncts to standard antimicrobial treatments. IMPORTANCE Despite extensive global efforts, secondary bacterial pneumonia still represents a major cause of death in developing countries and is an important cause of long-term functional disability arising from lung tissue damage. Newer approaches to improving treatment outcomes are needed to reduce the significant morbidity and mortality caused by infectious diseases. Our study, using an experimental mouse model of secondary S. pneumoniae infection, shows that a multimodal treatment that concurrently targets host and pathogen factors improved lung tissue integrity and extended the median survival time of infected mice. The immunoneutralization of host protein cANGPTL4 reduced the severity of pulmonary edema and damage. We show that host-directed therapeutic strategies as well as neutralizing antibodies against pathogen virulence factors are viable adjuncts to standard antimicrobial treatments such as antibiotics. In view of their different modes of action compared to antibiotics, concurrent immunotherapies using antibodies are potentially efficacious against secondary pneumococcal pneumonia caused by antibiotic-resistant pathogens.

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Section: Discussionmentioning

confidence: 99%

Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia

Foo

Kwok

et al. 2019

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“…The constant EBOV infection threat and highly contagious nature of the infection make the search for post-exposure therapeutics especially important. The need for EBOV therapeutics was further signified after the 2014 outbreak when WHO permitted the use of untested drugs to control the high death rate (reviewed in [ 186 ]). Currently, 80 drugs with anti-EBOV activity are consented by the FDA (reviewed in [ 187 ]).…”

Section: Ebov: Prevention and Controlmentioning

confidence: 99%

Immunological Perspective for Ebola Virus Infection and Various Treatment Measures Taken to Fight the Disease

2020

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Ebolaviruses, discovered in 1976, belongs to the Filoviridae family, which also includes Marburg and Lloviu viruses. They are negative-stranded RNA viruses with six known species identified to date. Ebola virus (EBOV) is a member of Zaire ebolavirus species and can cause the Ebola virus disease (EVD), an emerging zoonotic disease that results in homeostatic imbalance and multi-organ failure. There are three EBOV outbreaks documented in the last six years resulting in significant morbidity (> 32,000 cases) and mortality (> 13,500 deaths). The potential factors contributing to the high infectivity of this virus include multiple entry mechanisms, susceptibility of the host cells, employment of multiple immune evasion mechanisms and rapid person-to-person transmission. EBOV infection leads to cytokine storm, disseminated intravascular coagulation, host T cell apoptosis as well as cell mediated and humoral immune response. In this review, a concise recap of cell types targeted by EBOV and EVD symptoms followed by detailed run-through of host innate and adaptive immune responses, virus-driven regulation and their combined effects contributing to the disease pathogenesis has been presented. At last, the vaccine and drug development initiatives as well as challenges related to the management of infection have been discussed.

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“…Type I IFN-α2b has been evaluated for the treatment of EBOV; however, IFN-α2b was not successful, as only delayed death but could not prevent mortality in EBOV-exposed monkeys. IFN-γ reduced the mortality rate in mice when administered either before or after EBOV infection ( 147 ), suggesting its promise as a prophylactic and/or therapeutic drug for use in EBOV infections. As IFN-γ has already been used to treat certain chronic medical conditions and has been approved by the FDA, it can be readily adapted for use against EBOV infections.…”

Section: Advances In Developing Drugs and Therapies Against Ebovmentioning

confidence: 99%

Advances in Designing and Developing Vaccines, Drugs, and Therapies to Counter Ebola Virus

et al. 2018

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Ebola virus (EBOV), a member of the family Filoviridae, is responsible for causing Ebola virus disease (EVD) (formerly named Ebola hemorrhagic fever). This is a severe, often fatal illness with mortality rates varying from 50 to 90% in humans. Although the virus and associated disease has been recognized since 1976, it was only when the recent outbreak of EBOV in 2014–2016 highlighted the danger and global impact of this virus, necessitating the need for coming up with the effective vaccines and drugs to counter its pandemic threat. Albeit no commercial vaccine is available so far against EBOV, a few vaccine candidates are under evaluation and clinical trials to assess their prophylactic efficacy. These include recombinant viral vector (recombinant vesicular stomatitis virus vector, chimpanzee adenovirus type 3-vector, and modified vaccinia Ankara virus), Ebola virus-like particles, virus-like replicon particles, DNA, and plant-based vaccines. Due to improvement in the field of genomics and proteomics, epitope-targeted vaccines have gained top priority. Correspondingly, several therapies have also been developed, including immunoglobulins against specific viral structures small cell-penetrating antibody fragments that target intracellular EBOV proteins. Small interfering RNAs and oligomer-mediated inhibition have also been verified for EVD treatment. Other treatment options include viral entry inhibitors, transfusion of convalescent blood/serum, neutralizing antibodies, and gene expression inhibitors. Repurposed drugs, which have proven safety profiles, can be adapted after high-throughput screening for efficacy and potency for EVD treatment. Herbal and other natural products are also being explored for EVD treatment. Further studies to better understand the pathogenesis and antigenic structures of the virus can help in developing an effective vaccine and identifying appropriate antiviral targets. This review presents the recent advances in designing and developing vaccines, drugs, and therapies to counter the EBOV threat.

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Therapeutics for Postexposure Treatment of Ebola Virus Infection

Cited by 6 publications

References 83 publications

Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia

Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia

Immunological Perspective for Ebola Virus Infection and Various Treatment Measures Taken to Fight the Disease

Advances in Designing and Developing Vaccines, Drugs, and Therapies to Counter Ebola Virus

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