Passing the Torch McFadden, Grant
PLoS pathogens,
01/2020, Letnik:
16, Številka:
1
Journal Article
Recenzirano
Odprti dostop
When the original founders of PLoS (Harold Varmus, Mike Eisen and Patrick Brown) proposed the new concept of the Creative Commons Attribution License back in 2004 that permitted the unrestricted use, ...distribution and reproduction of properly cited scientific work, the historical arc of scientific research publication was fundamentally inflected. The realities of shepherding a new biotech start-up company, OncoMyx, as well as trying to maintain funding for an independent, curiosity-based research lab in an era when the average PI needs to write 10 grant applications in order to get one funded, simply have come home to roost. ...I want to thank my PP EIC partner-in-crime, Kasturi Haldar, for helping to oversee the journal with me for these past years.
Cancer remains a leading cause of death worldwide. Despite many signs of progress, currently available cancer treatments often do not provide desired outcomes for too many cancers. Therefore, newer ...and more effective therapeutic approaches are needed. Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, which selectively targets and kills cancer cells while sparing normal ones. In the past several decades, many different OV candidates have been developed and tested in both laboratory settings as well as in cancer patient clinical trials. Many approaches have been taken to overcome the limitations of OVs, including engineering OVs to selectively activate anti-tumor immune responses. However, newer approaches like the combination of OVs with current immunotherapies to convert "immune-cold" tumors to "immune-hot" will almost certainly improve the potency of OVs. Here, we discuss strategies that are explored to further improve oncolytic virotherapy.
...when my longtime collaborator Peter Forsyth injected it into human gliomas transplanted into the brains of test immunodeficient mice, the virus grew selectively within the transplanted human ...brain tumors just like it does in the internal tissues of myxoma-infected rabbits! Since it is totally nonpathogenic for humans, this discovery has convinced us to develop myxoma virus as a new potential therapeutic for a variety of human cancers.
Oncolytic viruses (OVs) constitute a new and promising immunotherapeutic approach toward cancer treatment. This therapy takes advantage of the natural propensity of most tumor cells to be infected by ...specific OVs. Besides the direct killing potential (oncolysis), what makes OV administration attractive for the present cancer immunotherapeutic scenario is the capacity to induce two new overlapping, but distinct, immunities: anti-tumoral and anti-viral. OV infection and oncolysis naturally elicit both innate and adaptive immune responses (required for long-term anti-tumoral immunity); at the same time, the viral infection prompts an anti-viral response. In this review, we discuss the dynamic interaction between OVs and the triggered responses of the immune system. The anti-OV immunological events that lead to viral clearance and the strategies to deal with such potential loss of the therapeutic virus are discussed. Additionally, we review the immune stimulatory actions induced by OVs through different inherent strategies, such as modulation of the tumor microenvironment, the role of immunogenic cell death, and the consequences of genetically modifying OVs by arming them with therapeutic transgenes. An understanding of the balance between the OV-induced anti-tumoral versus anti-viral immunities will provide insight when choosing the appropriate virotherapy for any specific cancer.
...the history of the many consequences of smallpox on humankind reads like a long litany of human misery and calamitous events, but is juxtaposed with the more noble accomplishments that began ...with the discovery of vaccination by Jenner in 1798 and culminated with the World Health Organization (WHO) certifying the world free of smallpox in 1980 2. ...we find ourselves still wrestling with an issue that intermingles public health policy, philosophy, national security, and bioterrorism, and affects our perceptions of research ethics with extreme pathogens in general.
Multicellular organisms possess very sophisticated defense mechanisms that are designed to effectively counter the continual microbial insult of the environment within the vertebrate host. However, ...successful microbial pathogens have in turn evolved complex and efficient methods to overcome innate and adaptive immune mechanisms, which can result in disease or chronic infections. Although the various virulence strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms that are used to subvert and exploit immune systems that are shared between these diverse microbial pathogens. The success of each pathogen is directly dependant on its ability to mount an effective anti-immune response within the infected host, which can ultimately result in acute disease, chronic infection, or pathogen clearance. In this review, we highlight and compare some of the many molecular mechanisms that bacterial and viral pathogens use to evade host immune defenses.
The orchestration of the inflammatory responses to both infection and tissue damage is arguably the key physiological function of NF-κB, and thus interference with the activation of NF-κB represents ...an exceptional strategy for a successful pathogen to exploit to counter multiple host innate defense processes through the targeting of a single host regulatory pathway. Because of their large genomes, which typically encode ~200 proteins, and their unusual independence from the host nuclear transcriptional machinery, poxviruses are especially well suited to manipulate the cytoplasmic activation of NF-κB. Indeed, poxviruses are known to encode multiple proteins that regulate the activation of NF-κB in a variety of different ways and these can be considered potential paradigms for the development of novel anti-inflammatory therapies and more effective vaccines. Given the renewed interest in the pathogenesis of orthopoxviruses like smallpox and monkeypox, we review the current understanding of how the various classes of poxviral immunomodulatory proteins target and manipulate the NF-κB pathway.
Oncolytic viruses are one of the most promising novel therapeutics for malignant cancers. They selectively infect and kill cancer cells while sparing the normal counterparts, expose cancer- specific ...antigens and activate the host immune system against both viral and tumor determinants. Oncolytic viruses can be used as monotherapy or combined with existing cancer therapies to become more potent. Among the many types of oncolytic viruses that have been developed thus far, members of poxviruses are the most promising candidates against diverse cancer types. This review summarizes recent advances that are made with oncolytic myxoma virus (MYXV), a member of the Leporipoxvirus genus. Unlike other oncolytic viruses, MYXV infects only rabbits in nature and causes no harm to humans or any other non-leporid animals. However, MYXV can selectively infect and kill cancer cells originating from human, mouse and other host species. This selective cancer tropism and safety profile have led to the testing of MYXV in various types of preclinical cancer models. The next stage will be successful GMP manufacturing and clinical trials that will bring MYXV from bench to bedside for the treatment of currently intractable malignancies.
Neutrophils mediate bacterial clearance through various mechanisms, including the release of mesh-like DNA structures or neutrophil extracellular traps (NETs) that capture bacteria. Although ...neutrophils are also recruited to sites of viral infection, their role in antiviral innate immunity is less clear. We show that systemic administration of virus analogs or poxvirus infection induces neutrophil recruitment to the liver microvasculature and the release of NETs that protect host cells from virus infection. After systemic intravenous poxvirus challenge, mice exhibit thrombocytopenia and the recruitment of both neutrophils and platelets to the liver vasculature. Circulating platelets interact with, roll along, and adhere to the surface of adherent neutrophils, forming large, dynamic aggregates. These interactions facilitate the release of NETs within the liver vasculature that are able to protect host cells from poxvirus infection. These findings highlight the role of NETs and early tissue-wide responses in preventing viral infection.
► Systemic virus challenge induces neutrophil and platelet recruitment to the liver ► Platelets bind adherent neutrophils, generating large dynamic aggregates ► Viral infection induces the release of NETs within the liver microvasculature ► NETs can protect host cells from viral infection in vivo
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