- Pathogenesis of emerging and re-emerging RNA viruses
- Innate antiviral signaling pathways against viral infections
- Immune evasion of RNA viruses
- Cytokines and inflammation
- Antivirals and vaccine strategies against RNA virusses of host innate immunity
My
primary research is focused on understanding how RNA viruses trigger
the host immune responses and how animals defend against emerging and
re-emerging viruses. Specifically, we study the molecular and cellular
interplays whereby the innate immune responses
are initiated and regulated and how an unregulated innate immunity
leads to diseases and mortality. We are particularly interested in
dissecting the antiviral signaling pathways by which pathologically
relevant host cells mount innate immune responses
to invading viruses. We are also interested in how viruses evade the
host defense system. The ultimate goal of our studies is to understand
and identify novel molecules of the innate immune system as targets for
preventive and therapeutic intervention
against RNA viral infections.
RNA virus infection is detected
by the host cells through either toll-like receptor (TLR)-3 and -7/8,
which are located primarily on the endosomal membrane, or the cytosolic
RNA helicase proteins RIG-I (retinoic acid-inducible gene I) and MDA5
(melanoma
differentiation antigen 5), which transmitting activation signals to
the cytosolic adaptor TRIF, MyD88, and MAVS/IPS, respectively, that
ultimately leads the activation of an array of antiviral genes,
including type I interferons (IFNs), inflammatory
cytokines and chemokines, and many interferon-stimulated genes
(ISGs), via at least three overlapping antiviral pathways mediated by
transcription factors NFκB, interferon regulatory factor-3 (IRF-3), and
ATF2/cJUN intermediate signaling
molecules. Among various RNA viruses, we are currently focusing on
dissecting the antiviral signaling pathways induced by severe acute
respiratory syndrome coronavirus (SARS-CoV, a BSL-3 pathogen), Rift
Valley Fever virus (RVFV, a BSL-3+ pathogen),
Junin virus (JV, a BSL-4 pathogen), Dhori virus, a tick-born
Orthomyxovirus, which is a BSL-2 pathogen sharing a strikingly similar
pathogenetic mechanism with avian influenza H5N1 virus in mice. To
ensure the success of our studies, we adopt a two-stage
strategy for the proposed studies. Specifically, we first perform in
vitro studies using virally permissive and pathologically relevant
human cells, including lung epithelial cells (SARS, Dhori virus), human
umbilical vascular endothelial cells (HUVEC)
and hepatocytes (RVF, Dhori), along with two of the most implicated
classic innate immune cells, e.g., primary human macrophages and
dendritic cells (RVFV and JV). Once specific signaling pathway(s) and
cellular targets are identified, we will use
suitable animal models for the verification purpose. In this regard,
experimental infection of mice has been used successfully as animal
models. Particularly, we have been using transgenic mice expressing
hACE2 (human angiotensin-converting enzyme
2), the receptor for SARS-CoV, as the animal model for SARS-CoV. We
also use mouse-adapted SARS-CoV, designated MA-15, to infect wild type
and various strains of selected gene knockout (KO) mice, aiming at
dissecting the mechanism of host innate immunity
against SARS-CoV and/or immune-mediated diseases. Various
state-of-art approaches involving virology, immunology, biochemistry,
molecular biology, and genetics are used to establish and characterize
cell lines/clones with specific gene KO or knock
down (KD) (i.e., loss-of-function) or constitutive expression (i.e.,
gain-of-function) phenotypes, and identify the role(s) of selected
genes in the host antiviral defense. We are also interested in
evaluating the impact of the cellular interplays
on the pathogenesis of viruses in vitro, via using two- and/or
three-dimensional culture systems. Our research is currently supported
in part by grants and contracts from the National Institutes of Health,
and other Pharmaceutical industries.