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Neural Control of Immunity and Longevity

The nervous system is the master controller of multiple organ systems, known to regulate physiology, behavior and movement. Research in human and model organisms in recent past has indicated that the nervous system can regulate immune responses. The overarching goal of my laboratory is to determine if the nervous system has a broad role in regulation of longevity, and immune responses to infection. Using Caenorhabditis elegans as a model system, we plan to address how sensory perception of cues in the environment or body regulates life-span or susceptibility to an infection.

c elegans
Caenorhabditis elegans is a 1mm long, soil-dwelling nematode. The soma of adult hermaphrodite is transparent and consists of 959 cells. The nervous system is composed of 302 neurons and 56 glial cells. The nervous system responds to external and internal cues causing attraction/avoidance, physiological responses and movement.
C. elegans can be infected and killed by human microbial pathogens such as Gram negative bacteria (Pseudomonas aeruginosa, Salmonella enterica, Vibrio cholera, Yersinia pestis) Gram positive bacteria (Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae) and fungi (Candida albicans, Cryptococcus neoformans etc). Stress response pathways such as Heat shock responses, unfolded protein response and p38 MAPK are some of the important signaling mechanisms involved in innate immune responses to P. aeruginosa.


GPCR signaling and innate immune responses: Pattern recognition receptors have a limited presence in C. elegans genome. Only known toll like receptor homolog TOL-1 is expressed predominantly in the nervous system. It plays some role in the immune response to S. enterica but has no role in defense against many other microbial pathogens. Interestingly, we have found that sensory receptors in the nervous system are involved in immune responses to bacterial pathogens. Signaling in specific neurons or via G protein coupled receptors (GPCRs) can regulate stress response pathways involved in innate immune responses. A GPCR adaptor protein called beta arrestin (Arrestin-1) is expressed exclusively in the nervous system (Figure 2) and regulates immunity to bacterial pathogens. Specifically, Arrestin1-GPCR signaling in four distinct subsets of sensory neurons regulates innate immune responses to Gram negative bacterial pathogens (Figure 3). Three of these neurons are part of the most important sensory organ in C. elegans “Amphid”. Amphid consists of twelve bilaterally symmetrical pairs of sensory neurons. These neurons can be polymodal and known to express more than one GPCR. A major focus of the laboratory is to identify neurons and sensory receptors involved in differential responses to bacterial and fungal pathogens. We do this using a combination of mutagenesis and transgenesis approach to perturb neuronal function or the function of individual GPCRs expressed in the nervous system.

arrestin-1
Figure 2: Confocal image of an arrestin-1 (ok401) deletion strain of Caenorhabditis elegans expressing wild type copy of arresin-1 gene fused to GFP. Arrestin-1 is expressed in the nervous system. The amphid sensory channel of the nematode is denoted.


gpcr-arrestin-1

Figure 3. GPCR-Arrestin activity in four subsets of C. elegans sensory neurons regulates non-canonical unfolded protein response and Immune homeostasis (Singh & Aballay, 2012). Four of these neurons (ADF, AFD, ASH and ASI) are part of Amphid sensory organ which can senses cues in the environment of C. elegans (schematic courtesy of wormbook.org).

Current projects:
Differential regulation of innate immunity to pathogenic microbes (bacteria and fungi) by the nervous system.
Microbes produce structurally and functionally diverse pattern associated molecular patterns(PAMPs). In mammals, these PAMPs engage different toll like or nod like receptors. In C. elegans, our studies suggest that sensory neurons and receptors therein regulate immune responses. However neurons engaged in response to Gram negative pathogens have no roles in immune response to Gram positive bacteria. We also know that the nervous system causes differential gene expression response to Gram negative vs Gram positive bacteria. Using genetic approaches (mutation, RNAi and transgenesis) to perturb different components of the nervous system, we plan to address how differential response to pathogens is initiated in the nervous system and affects immune signaling in other tissues using a number of assays.

Do sensory neurons respond directly to bacterial pathogens?
This is a bioengineering project designed to investigate whether molecules from Gram negative bacteria can directly activate neural circuits in C. elegans. We utilize a combination of genetics and microfluidics (in collaboration with faculty at Center for NanoScience Engineering CeNSE) to study calcium transients in Amphid neurons.  As a follow up, we plan to identify specific pathogen molecules which activate neuronal signaling. 

Do GPCRs regulate life-span and lipid metabolism in C. elegans?
C. elegans has paved the direction of research in the field of aging and longevity. Some well-studied regulators of longevity include nutrient availability/starvation response, insulin signaling, lipid stores, mitochondrial activity, and sensory perception. GPCRs constitute the largest and most diverse family of sensory receptors. They also have the most diverse set of ligands ranging from peptides, neurotransmitters, hormones, oxygen and small molecules. We and others have shown that GPCR signaling components- trimeric G protein subunits and GPCR adaptor beta arrestin- also regulate life span. To test the hypothesis that GPCRs have a broad and important role in regulation of longevity, we are analyzing a large collection of GPCR mutants to study if they affect life-span, lipid stores and sensory perception using a combination of genetic approaches, lipid staining and attraction/avoidance assays.