The inevitable emergence of novel infectious viruses and their unpredictable pathogenicity,
transmissibility, and pandemic potentials are a major threat to human health. In particular,
highly pathogenic influenza A viruses (IAVs), severe acute respiratory syndrome- and
Middle East respiratory syndrome-coronavirus (SARS-CoV; MERS-CoV), Ebola virus (EBOV),
and mosquito-borne Zika virus (ZIKV; Flavivirus) have attracted the world's attention
due to their high pathogenicity, transmission and high mortality. While these viruses
are mostly found in animals they can cause diseases and death in humans (zoonosis)
when transmitted via close contact. Transmission of these pathogens is likely worsened
by globalization and close quarter living in densely populated areas, all of which
promotes rapid virus evolution and pandemic potential in humans. Significant research
has resulted in deeper understanding of the virology, virus-host interactions, and
disease pathology. These investigations have led to the development of vaccines and
antiviral drugs, particularly for IAVs, and experimental vaccines for EBOV. Nevertheless,
rapid and frequent virus mutations/reassortment often render current therapeutics
ineffective, highlighting the limitations of our current therapeutic design strategies.
Development of novel prevention and treatment options against these continuously mutating
viruses must be explored before the next pandemic occurs.
In this Research Topic, a series of articles provides comprehensive insights on the
current view of the virology, innate immune responses, and novel therapeutics to IAVs,
MERS-CoV, EBOV, and flavivirus in experimental settings as well as in clinical trials.
In original research articles, Westenius et al. demonstrate that the highly pathogenic
avian IAV H5N1 but not H3N2 and H7N9 virus replicate efficiently in primary human
dendritic cells (DCs) and macrophages despite the robust induction of antiviral cytokines.
This indicates an unusual level of resistance to host antiviral responses by the IAV
H5N1 subtype. Prescott et al. show that MERS-CoV infection leads to much higher viral
replication in the immuno-compromised rhesus macaque model, although this is accompanied
by milder pathology in airways compared with non-immunocompromised control animals.
This indicates that MERS-CoV infection in healthy individuals causes severe pathological
changes with increased inflammatory response and cellular infiltrates in the airways.
This is consistent with the finding that MERS-CoV-infected human patients have increased
numbers of neutrophils and macrophages in their bronchial lavage fluid (Prescott et
al.). Strandin et al. also show that the levels of neutrophils and the pro-inflammatory
cytokine IL-8 are substantially higher in the blood of patients with hantavirus infection-mediated
haemorrhagic fever with renal syndrome (HFRS). Neutrophil extracellular trap (NET)
activation is evident and is the result of hantavirus-infected microvascular endothelial
cells, indicating the importance of neutrophils in the disease pathology driven by
both MERS-CoV and hantavirus infections.
This Research Topic also features a number of Review Articles on IAVs, flaviviruses,
and EBOV, innate immune responses to infections, and novel therapeutic strategies
that are currently in experimental phase or human clinical trials. Dou et al. provide
a detailed review on IAV entry, viral replication, viral assembly and budding process,
while Horman et al. review the IAV fitness, clinical manifestation of the disease,
pathogenesis of highly pathogenic IAV infections. Hsu reviews the essential mutations
and IAV virulence factors that are important in IAV transmission, inflammatory cytokine
storm and efficient suppression of host antiviral response. Immune cells, such as
macrophages and DCs are important in the immediate control of viral replication in
the airways and also in establishing appropriate adaptive immune response for efficient
clearance of the virus. Vangeti et al. discuss how these immune cells contribute to
increased inflammation and severe disease caused by IAV. The prolonged inflammation
and severe pathologies in the airways are not only observed with IAV, but also with
MERS-CoV and hantavirus infections. Micro-RNAs (miRNAs; miRs) are a novel class of
immuno-regulators that have been shown to be involved in innate immune responses.
Nguyen et al. review several miRNAs that are highly induced by IAVs and directly promotes
nuclear-factor-kappa-B (NF-κB)-mediated inflammatory response.
Flavivirus, such as Dengue virus (DENV) and recently emerged ZIKV are mosquito-borne
infectious pathogens. Laureti et al. critically review important Flavivirus species,
including DENV, Japanese encephalitis virus (JEV), ZIKV, and yellow fever virus (YFV),
their binding receptor diversity and virus entry mechanisms. Blom et al. review the
innate immune responses and immuno-pathologies induced by these pathogens.
In terms of therapeutics, virus-targeted strategies remain a popular approach. Valkenburg
et al. review the criteria, strategies, and obstacles in the development of universal
influenza vaccines, and the requirement to increase the strength and duration of vaccine-induced
immune responses. In addition to vaccines, Davidson reviews the potentials of several
IAV haemagglutinin (HA)-targeted monoclonal antibodies and viral polymerase inhibitory
compounds that show promising therapeutic effects in pre-clinical or clinical trials.
Lee et al. review DNA vaccines carrying various chimeric fusion proteins of conserved
regions of IAV structural proteins and their effectiveness in inducing cross-reactive
antibody response to different subtypes of IAVs. While universal IAV vaccines are
still in experimental/clinical phase, vaccines targeting one flavivirus species have
been shown to induce cross-reactive response against another viral species. Blom et
al. review T cell cross-reactivity induced by JEV- and YFV-vaccine to DENV and ZIKA,
respectively, indicating the potential use of JEV or YFV vaccine as protective therapeutics
against ZIKA.
Viruses, such as IAVs undergo rapid virus mutations that often render vaccines and
antiviral drugs less effective. Alternative host-targeted approaches are also extensively
reviewed in this Research Topic as strategies to improve anti-viral therapy. HA cleavage
and activation by host proteases is a critical step to rendering newly made IAV particles
infectious. Yip et al. review a number of clinically used protease inhibitors currently
used for diseases, such as liver fibrosis and cancer that also inhibit HA activation
in in vitro and/or in vivo models. This highlights the potential of repurposing these
compounds as antivirals drugs against IAVs. Hsu also reviews a number of peptide-based
small molecules that inhibit HA-mediated viral internalization and reduce infection,
and many of which are currently in the experimental phase of testing and in human
clinical trials.
As disease pathologies are mostly driven by exaggerated immune responses, immuno-modulatory
molecules have also been discussed as potential therapeutics to reduce tissue damage.
Nguyen et al. review various miRNA inhibitors shown to directly suppress IAV replication,
as well as those that reduce IAV-induced inflammatory cytokine storm in in vivo models.
As an exaggerated inflammatory response appears to be a common phenomenon driven by
most of the infectious viruses described here, they may also be applicable to other
viral infections, such as MERS-CoV as treatments. Antiviral responses are critical
in the immediate control of viral replication and are induced by the binding of host
pattern recognition receptors to viral RNAs. Viruses, such as IAVs and EBOV produce
virulence factors that inhibit the production of antiviral cytokines (Hsu, Dhama).
Yong et al. review the use of synthetic virus RNA analogs and small molecule modulators
as pan-antiviral drugs and vaccine adjuvants that boost antiviral responses against
RNA viruses, such as IAVs or flavivirus.
The recent Ebola epidemics in Africa during 2014–2016 and in 2018 have raised serious
concerns of EBOV infection as a global health threat due to its high mortality rate.
Dhama et al. not only review the general virology of EBOV and disease progression,
but also discuss current progress in the development of virus-, DNA-, and plant-based
vaccines and treatment-based therapeutics that are urgently needed to prevent or reduce
EBOV-mediated disease and mortality.
Collectively, this Research Topic highlights the ease in which viruses are able to
cause severe disease, and the complexities of virus-host interactions that impact
both disease pathology and outcome. The knowledge acquired from the articles contained
within this special issue may lead to the development of more specific peptide-based
antiviral agents, monoclonal antibodies and novel vaccines that protect against infections
in the future. Synthetic- and host-RNA-based immuno-modulatory compounds may act as
potential treatment that reduce symptoms and disease. As these are host-targeted they
may be suited for multiple viral-induced diseases. This area of research is absolutely
essential and is urgently required in preparation of future pandemics.
We wish to convey our appreciation to all the authors who have participated in this
Research Topic and the reviewers for their insightful comments.
Author contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.