The Samir Lab studies crosstalk between stress, innate immune, and
programmed cell death signaling in response to pathogenic challenges. We
are using, or willing to use, any tool and the kitchen sink if it can
help.
The innate immune system is the first line of defense
against pathogenic challenges including microbial pathogens. Innate
immune activation can lead to programmed cell death. Uncontrolled
programmed cell death can cause severe disease, and even death.
Pathogenic challenges also activate stress signaling pathways which
can lead to assembly of a membraneless cytoplasmic component called
stress granules. Stress granules have been reported to inhibit
programmed cell death and in the context of viral
infections amplify the type I interferon signaling. Therefore,
stress granule assembly could be a mechanism to restrict uncontrolled
programmed cell while maintaining antiviral state. Interestingly,
Toll-like Receptor (TLR) mediated innate immune
signaling compromises stress granules through the inhibitor of kappa
b kinase complex (IKK complex). This suggests another layer of
interplay between the stress, innate immune and programmed cell
signaling pathways. Our goal is to elucidate molecular
mechanisms that govern this cross regulation and ultimately build
quantitative models that would allow us to design precision therapeutic
interventions.
The foundational project: Cellular stress, innate immune signaling, regulated cell death, and hyperinflammation: Excessive inflammatory response, termed hyperinflammation, underlies tissue damage and organ dysfunction in conditions ranging from septic shock and cytokine release syndromes to Alzheimer's disease and other neurodegenerative pathologies. A central feature of hyperinflammation is dysregulated innate immune signaling, which not only amplifies cytokine production, but can also induce regulated cell death. Regulated cell death pathways vary in their inflammatory potential, from largely immunologically silent apoptosis to highly inflammatory pyroptosis.
Dysregulated innate immune responses are central contributors to hyperinflammation. The innate immune system orchestrates inflammatory signaling through pattern recognition receptors (PRRs) that sense pathogen- and damage associated molecular patterns (PAMPs and DAMPs). A critical downstream consequence of innate immune activation is induction of regulated cell death. The regulated cell death pathways span an inflammatory spectrum ranging from largely immunologically silent apoptosis to pyroptosis, a highly pro-inflammatory mode of cell death. However, mechanisms that control the magnitude of inflammatory signaling and the mode of cell death remain poorly understood. Cellular stress signaling is increasingly recognized as key to these decisions.
Figure 1: Innate signaling is activated by pathogen- and damage associated molecular patterns (PAMPs and DAMPs) recognition by pattern recognition receptors (PRR), leading to inflammation. In response to stress, integrated stress response (ISR) assembles stress granules through phosphorylation of translation initiation factor eIF2α. Stress granules dampen inflammatory signaling. Conversely, innate immune signaling inhibits stress granules formed in response to endoplasmic reticulum stress.
The integrated stress response (ISR) is a major stress adaptation mechanism, which converges on the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α), inhibition of translation initiation, and assembly of cytosolic membraneless compartments known as stress granules. Stress granule constituents include the small ribosomal subunit, mRNA, translation initiation factors and signaling molecules. Notably, stress granules modulate innate immune signaling pathways, including those controlling inflammatory gene expression and regulated cell death. Moreover, stress granule dysregulation plays a key role in pathogenesis of several diseases where hyperinflammation also contributes, including neurodegenerative diseases and viral infections.
Cellular stress and innate immune signaling pathways are simultaneously activated following pathogenic challenges and modulate each other’s activities, yet how these pathways interact to determine inflammatory outcomes is poorly understood. Our long-term goal is to elucidate the regulatory network that controls interactions between cellular stress and innate immune signaling pathways to regulate inflammation.
Focused project 1: Multifactorial interactions driving accelerated aging and neurodegenerative diseases: With aging populations worldwide, and in the United States, age-related health conditions including dementia represent a growing public health challenge. Epidemiological studies have identified various risk factors for dementia, yet the molecular mechanisms underlying these associations remain poorly defined. Our long-term goal is to elucidate the molecular mechanisms by which multifactorial interactions between epidemiologically established risk factors promote dementia so that we can develop prevention and treatment strategies.
Figure 2: Definition (Netea et
al, Nature Reviews Immunology 2020): “The concept of trained immunity
describes the long-term functional reprogramming of innate immune cells, which
is evoked by exogenous or endogenous insults, and which leads to an altered
response towards a second challenge after the return to a non-activated state.”
Trained immunity can cause stronger systemic inflammation resulting in
neuroinflammation and neuropathology.
Inflammation
is strongly associated with accelerated aging and dementia. Notably, repeated
exposure to inflammation causing agents or trauma results in a greater risk for
dementia. One such process is trained immunity, an innate immune response in
which prior pathogenic exposure or inflammatory insults induces memory in innate
immune cells to mount stronger non-specific inflammatory responses to
subsequent challenges. While trained immunity evolved to provide protection
against repeated infections, stronger inflammatory signaling may paradoxically
promote neurodegeneration and cognitive decline. We are investigating how
trained immunity contributes to accelerated aging and dementia.
This
work is in collaboration with several groups across UTMB and includes Dr. Alan
Landay, Dr. Thomas Blackwell, Dr. Balaji Krishnan, Dr. Tapas Hazra, Dr.
Alejandro Villasante-Tezanos, Dr. Aditi, and the Moody Brain Health Institute.
Focused
project 2:
Developing broad-spectrum host-directed antiviral drugs that interfere with
functions of viral biomolecular condensates: Influenza A Virus (IAV) remains a significant
global health threat due to its rapid mutation rate, genomic reassortment, and
structural diversity, making the development of effective antivirals
particularly challenging. While seasonal vaccines provide some protection, they
often fail against emerging strains. These limitations necessitate innovative approaches beyond
traditional virus-targeting strategies.
Recent
studies show that many viruses, including IAV, induce the formation of
biomolecular condensates. Biomolecular condensates are membraneless
compartments formed via liquid-liquid phase separation. These condensates promote
immune evasion and function as viral replication factories, creating
microenvironments optimized for virion assembly. Importantly, condensate
formation depends critically on host cellular machinery, presenting a
vulnerability that viruses cannot easily circumvent through mutations.
The
long-term goal of this project is to elucidate mechanisms that control
viral biomolecular condensate dynamics for developing condensate-modulating
antiviral drugs.
Figure 3: Cytoplasmic IAV
condensates promotes viral replication. Our preliminary work is showing that
formation of these condensates require host cell factors. Drugs that interfere
with these condensates inhibit viral replication representing an opportunity
for developing host-direct antivirals that are likely to remain efficacious
despite rapid viral evolution.
This work is in
collaboration with Dr. Alexander Frieberg and Dr. Aditi.
Focused project 3: Regulation of innate immune signaling
by biological condensates:
Biomolecular condensates are dynamic,
membraneless compartments formed through liquid-liquid phase separation that
concentrate specific proteins and nucleic acids to enable localized biochemical
activity. These structures are increasingly recognized as key regulators of
cellular functions such as stress response, gene expression, and signal
transduction. We have recently discovered that stress granule component TIA1 negatively
regulates the non-canonical NLRP3 inflammasome, which is a key contributer to
sepsis patholog. We are investigating how TIA1 specifically suppresses the non-canonical
NRLP3 inflammasome.
Focused project 4: Analyzing epidemiological data to
guide mechanistic studies of human disease pathogenesis: In collaboration with Dr. Aditi, we are analyzing epidemiological data to guide our mechanistic studies. More
information on this project will become available once our studies are
published.