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We know from pop science that our psychological states have an effect on our immune systems ("worrying ourselves sick", etc.), but what are the actual mechanisms through which our nervous systems pass information to the immune system?
Cell mediators come to mind, but where in the body would a nerve cell release an interleukin or other factor? (Put another way, are neurons releasing these factors as a part of their normal cell metabolism and the side effect is a communicative effect with the immune system?)
It is not only the immune system that prevents us from getting ill. Worrying much in my opinion won't make you catch a cold; rather, you can get problems with your cardiovascular system (arrhythmias, hypertension, angina pectoris) or limbic system (panic attacks, sweating attacks etc.).
The connections are many; here are some possible ones:
There are many glands in our body that are either densely innervated (like the thyroid gland) or are a part of nervous system (like pituitary gland, epiphysis). They can release hormones directly to our blood and make our hormone profile unstable, hence also impacting the immune system.
Sympathetic/parasympathetic nervous system is under direct control of the CNS (N.vagus, carotide sinus sinus etc.) and can dramatically change the peripheral resistance of our vascular system by constricting (=> angina pectoris, hypertension) or dilating (swellings, bowel movements problems -> constipations etc.) the small vessel. This alone can start so many different mechanisms resulting not only in being ill, but also being dead.
Speaking about connection between the nervous and immune system we must consider that:
- Many neuromediators, like adrenaline, for example, have clear effects on immune cells.
- The mediators and humoral factors released by nerve endings can easily diffuse outside of the synaptic cleft and act locally, attenuating immune response.
Here's pretty much the first thing that popped up on pubmed:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144148/ So clearly there are direct neurotransmitter receptors on immune cells themselves. Pick a favorite neurotransmitters and search "xyz and the immune system".
However, I can't tell you how relevant that is in terms of actually affecting large scale shifts in immune function. I think the previous poster Alexander Galkin had it right in that the nervous system affects hormones which have the ability to coordinate large scale, complex immune system shifts. It's like the president calling the generals to organize some troop movement and how many troops to deploy, what their targets are, etc.
I just wanted to add that tidbit that our "soldiers" do in fact carry cell phones. If the president wanted to, he could call the troops personally.
Nerve-cancer interactions in the stromal biology of pancreatic cancer
Interaction of cancer cells with diverse cell types in the tumor stroma is today recognized to have a fate-determining role for the progression and outcome of human cancers. Despite the well-described interactions of cancer cells with several stromal components, i.e., inflammatory cells, cancer-associated fibroblasts, endothelial cells, and pericytes, the investigation of their peculiar relationship with neural cells is still at its first footsteps. Pancreatic cancer (PCa) with its abundant stroma represents one of the best-studied examples of a malignant tumor with a mutually trophic interaction between cancer cells and the intratumoral nerves embedded in the desmoplastic stroma. Nerves in PCa are a rich source of neurotrophic factors like nerve growth factor (NGF), glial-cell-derived neurotrophic factor (GDNF), artemin of neuronal chemokines like fractalkine and of autonomic neurotransmitters like norepinephrine which can all enhance the invasiveness of PCa cells via matrix-metalloproteinase (MMP) upregulation, trigger neural invasion (NI), and activate pro-survival signaling pathways. Similarly, PCa cells themselves provide intrapancreatic nerves with abundant trophic agents which entail a remarkable neuroplasticity, leading to emergence of more routes for NI and cancer spread, to augmented local neuro-surveillance, neural sensitization, and neuropathic pain. The strong correlation of NI with PCa-associated desmoplasia suggests the potential presence of a triangular relationship between nerves, PCa cells, and other stromal partners like myofibroblasts and pancreatic stellate cells which generate tumor desmoplasia. Hence, although not a classical hallmark of human cancers, nerve-cancer interactions can be considered as an indispensable sub-class of cancer-stroma interactions in PCa. The present article provides an overview of the so far known nerve-cancer interactions in PCa and illustrates their ominous role in the stromal biology of human PCa.
Examining How Genetics Can Influence Epilepsy in Children
Jennifer Kearney, PhD, associate professor of Pharmacology, works in conjunction with the clinicians at Northwestern Memorial Hospital and the Ann and Robert H. Lurie Children’s Hospital of Chicago to learn how an individual’s genetic background influences epilepsy.
Neuronal Signaling at a Molecular and Cellular Level
Geoff Swanson, PhD, professor of Pharmacology, studies how brain cells communicate with each other during normal circumstances, during memory processes and how the processes go wrong in disease.
Developing Mechanistic Based Therapeutic Opportunities for Parkinson’s Disease
Loukia Parisiadou, PhD, assistant professor of Pharmacology, uses a multidisciplinary approach spanning cellular, molecular, network and behavioral levels to understand the molecular basis of Parkinson’s disease.
Pioneering Academic Drug Discovery
Daniel Martin Watterson, PhD, professor of pharmacology and John G. Searle Professor of Molecular Biology and Biochemistry, studies biological mechanisms important in how cells communicate with each other. The work is advancing basic and translational knowledge about critical biological processes and molecules that regulate physiological pathways, and how they are altered in diseases such as Alzheimer’s disease, brain injury and cancer. The goal is to develop novel drug treatments that can intervene in disease progression.
Investigating Why Mutations in Ion Channels Cause Disease
Paul DeCaen, PhD, assistant professor of Pharmacology, studies why a class of proteins called ion channels cause diseases. His goal is to intervene with these diseases and either keep them from happening, or perhaps, control them after they've already manifested.
Investigating the molecular and cellular physiology of calcium signaling
Murali Prakriya, PhD, Professor of Pharmacology, studies how cellular calcium signals are generated and how these calcium signals impact the functional behavior of neurons, astrocytes, and immune cells.
Understanding the Molecular Mechanisms Underlying Neurotransmitters
Antonio Sanz-Clemente, PhD, assistant professor of Pharmacology, studies the molecular mechanisms underlying synapse unsilencing and their contribution to neurological diseases.
The microbiota consists of a multispecies microbial community living within a particular niche in a mutual synergy with the host organism. Besides bacteria, the microbiota includes fungi, archaea, and protozoans (1, 2), to which viruses are added, which seem to be even more numerous than microbial cells (3). The gastrointestinal tract (GIT), with its epithelial barrier with a total area of 400 m 2 , is a complex, open, and integrated ecosystem with the highest exposure to the external environment. The GIT contains at least 10 14 microorganisms belonging to Ϣ,000 species and 12 different phyla, the associated microbiome containing 150- to 500-fold more genes than the human DNA (1, 4𠄷). The GIT microbiota exhibits a huge diversity, being individually shaped by numerous and incompletely elucidated factors, such as host genetics, gender, age, immune system, antropometric parameters, health/disease condition, geographic and socio-economical factors (urban or rural, sanitary conditions), treatments, diet, etc. (8, 9). Recent metagenomic data demonstrated that the majority of component species is not present in the same time and in the same person, but, however, few species are abundant in healthy individuals, while other species are less represented (4, 7). In addition to the distribution along the digestive tract segments, the GIT microbiota of the three distinct transversal microhabitats, i.e., floating cells in the intestinal lumen, cells adherent to the mucus layer and respectively to the surface of the epithelial cells, is also different (3).
Recent findings suggest that the microbial colonization of the GIT starts before birth, as revealed by the placental microbiome profile, being composed of members of Firmicutes, Proteobacteria, Tenericutes, Bacteroidetes, and Fusobacteria groups, which were found to share some similarities with the human oral microbiome (10). Also, the meconium of full term infants is not sterile, harboring 30 genera normally found in the amniotic fluid, vagina, and the oral cavity (8, 9, 11). We can assume that the bacteria reach these sites mainly from the vaginal tract, although selective translocation is also possible. Archaea were also detected in the vaginal microbiota of pregnant women, accounting for a mother-to-child transmission (12).
Vaginally born infants have a microbiota containing species derived from the vaginal microbiota of their mothers. Conversely, in the case of cesarean section delivered babies, the microbiota is similar to the skin microbiota and is rich in Propionibacterium spp. and Staphylococcus spp. (13).
It is generally accepted that the pregnancy period and the first 1,000 days after birth are the most critical timeframes for interventions and any modulation made at this point has the potential to improve child growth and development (14). Delivery mode seems to influence immunological maturation through microbiota development. Cesarean section delivered children were found to have a higher number of antibody-secreting cells (11).
Furthermore, the human milk is involved in the GIT microbiota and immune system development. In addition to its nutritional components, this natural functional food contains numerous bioactive substances and immunological components that control the maturation of the newborn intestine and the composition of the microbial community. Numerous studies revealed that breast-feeding has a protective role in infants, conferred by a complex mixture of molecules, including lysozyme, sIgA, alpha-lactalbumin, lactoferrin, but also free oligosaccharides, complex lipids, and other glycoconjugates (14). The proteolytic processing of glycoprotein k-casein, with the release of glycomacropeptides, prevents colonization of the gut by pathogens, through competition with the receptors of the gut epithelial cells in breast-fed infants. Lactoferricin is a potent antimicrobial agent, explaining the decreased infant death rate caused by gastrointestinal and respiratory infections in breast-fed infants (14, 15). Moreover, breast milk contains 縐 9 bacterial cells/L (16) and prebiotic oligosaccharides (fructans) which stimulate the multiplication of Bifidobacterium spp. and Lactobacillus spp., while follow-on milk powder stimulates proliferation of enterococci and enterobacteria (17, 18). As the infant grows, solid foods are introduced, therefore the microbiota diversity increases, and the microbiota community evolves toward the adult-like state. Although some dominant enterotypes represented by Bacteroides, Prevotella, and Ruminococcus genera are recognized, however, the final composition of the adult microbiota is unique and the factors guiding this feature are still a matter of debate (19).
The very active microbial community has been shown to mutually interact with the host and to exert a lot of beneficial roles, explaining its tolerance by the host organism. The GIT microbiota is involved in energy harvest and storage, and, due to its particular metabolic pathways and enzymes, it extends the potential of the host metabolism. This property is believed to exhibit a potent evolutionary pressure toward the establishment of bacteria as human symbionts (11). The GIT microbiota influences the normal gut development, due to its ability to influence epithelial cell proliferation and apoptosis of host cells. Although the intimate interactions between microbiota and host cells are widely unknown, a major mechanism seems to involve short-chain fatty acids (SCFA), resulted from the fermentation of indigestible polysaccharides (fibers), such as butyrate, acetate, and propionate with an important anti-inflammatory role. SCFAs also support intestinal homeostasis in the normal colon, by aiding intestinal repair through the promotion of cellular proliferation and differentiation. However, SCFAs seem to inhibit the cancerous cells proliferation. Among the different SCFAs, butyrate has a paramount role in intestinal homeostasis due to its role as a primary energy source for colonocytes (20, 21). In addition, the GIT microbiota stimulates the nonspecific and specific immune system components development, just after birth and during the entire life and it acts as an antiinfectious barrier by inhibiting the pathogens’ adherence and subsequent cellular substratum colonization and by the production of bacteriocins and of other toxic metabolites. Moreover, the microbiota is predominantly composed of anaerobes which prevent the process of translocation of aerobic/facultatively anaerobic bacteria and the consecutive systemic infections in immunodeficient individuals. Importantly, some GIT microbiota representatives (Escherichia coli and Bacteroides fragilis) are involved in the synthesis of vitamins, such as B1, B2, B5, B6, B12, K, folic acid, and biotin. Also, the GIT microbiota has the ability to degrade xenobiotics, sterols and to perform biliary acids deconjugation (B. fragilis and Fusobacterium spp.) (19).
All these aforementioned effects are occurring when the microbiota community is characterized by an interspecies balance, known as eubiosis. Any perturbation of eubiosis, known as dysbiosis, could become a pivotal driver for various infectious and non-infectious diseases, each of them with specific microbiota signatures that can further trigger pathophysiologies in different organs (11).
Our aim was to review these physiological roles, focusing on one side the GIT microbiota contribution to the immune system development and education, and on the other side, to what is happening when eubiosis is replaced by the dysbiosis status in this case the immunostasy is altered, the host becomes more susceptible to infections, both exogenous and endogenous immunotolerance is affected and the immune system will react against the self-components (autoimmunity), or vary in intensity, being either over (allergic reactions and chronic inflammation) or less/inappropriately (immunodeficiency and cancer) activated.
Military Strategies for Sustainment of Nutrition and Immune Function in the Field (1999)
19Inflammatory Stress and the Immune System
During the last several years, it has become apparent that important ''bidirectional'' communication occurs between the neuroendocrine and immune systems. More precisely this cross-talk occurs among the immune, endocrine, and central nervous systems and relates to perturbations in any of these systems (Besedovsky and del Ray, 1996). Communication is mediated by a variety of molecules, including neuropeptides, neurotransmitters, hormones, and cytokines which are contained within these systems along with their respective receptors. Learning about these interactions has particularly been made possible bassed on the discovery and characterization of cytokines (Besedovsky and del Ray, 1996). Cytokines are glycoproteins/proteins produced by many cell types, including macrophages and monocytes, B- and T-lymphocytes, endothelial cells, fibroblasts, neurons, glia (microglia and astrocytes), and some epithelial cells. Cytokines act on many cell types, exert redundant actions, induce the
Leonard P. Kapcala, Department of Medicine and Department of Physiology, Division of Endocrinology, University of Maryland School of Medicine and Baltimore Veterans Administration Medical Center, Baltimore, MD 21201. Currently affiliated with the Department of Physiology, University of Maryland School of Medicine.
production and secretion of other cytokines (e.g., stimulate a cascade of many cytokines), and often synergize with other cytokines to potentiate their actions.
One immune-neuroendocrine interaction that has been extensively investigated pertains to cytokine regulation of the hypothalamic-pituitaryadrenal axis (HPAA) (Bateman et al., 1989 Besedovsky and del Ray, 1996 Chrousos, 1995 Gaillard, 1994 Harbuz and Lightman, 1992 Koenig, 1991 Lilly and Gann, 1992 Reichlin, 1993 Rivier, 1995 Tilders et al., 1994). Although many cytokines appear to modulate HPAA activation, the most important cytokines involved in this regulation are interleukin (IL)-1, IL-6, and tumor necrosis factor-&alpha (TNF-&alpha). Major biochemical components in this neuroendocrine axis (Figure 19-1) include hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), anterior pituitary adrenocorticotropin (ACTH), and adrenal glucocorticoids (cortisol in humans corticosterone [CORT] in rodents) (Chrousos, 1995). In response to stress, HPAA activation occurs primarily by increased release of hypothalamic CRH and AVP (Harbuz and Lightman, 1992). Whereas AVP, a relatively weak secretagogue for ACTH secretion, markedly potentiates CRH stimulation and may be a critical factor in facilitating responses to recurrent stress (Harbuz and
Schematic model of potential regulatory relationships between cytokines (using interleukin [IL]-1 as prototype) and the hypothalamic-pituitary-adrenal axis (HPAA) in the rat. AP, area postrema AVP, arginine vasopressin CRH, corticotropin-releasing hormone E, epinephrine ME, median eminence NE, norepinephrine NTS, nucleus tractus solitarius OVLT, organum vasculosum of lamina terminalis PG, prostaglandin PVN, paraventricular nucleus. SOURCE: Adapted from Kapcala et al. (1995).
Lightman, 1992), CRH is the major stimulator of ACTH release. Stimulated ACTH secretion subsequently stimulates adrenocorticosteroid (CS, particularly glucocorticoid) secretion. Glucocorticoids in turn modulate and inhibit HPAA activation via negative feedback effects at suprahypothalamic, hypothalamic, and pituitary levels (Harbuz and Lightman, 1992).
Why does the HPAA become activated during various immune, inflammatory, and infectious insults? According to a hypothesis proposed by Munck and colleagues (1984) several years ago, such activation of the HPAA occurs so that glucocorticoids can suppress immune and inflammatory responses initiated by cytokines and thereby can modulate and dampen immune system activation. This dampening of immune system activation prevents more severe and excessive catabolic effects, including the ultimate deleterious effect, death. Consequently, immune system activation of the HPAA appears to occur to modulate excessive, deleterious effects of cytokines after they have produced their initial, beneficial effects (Urbaschek and Urbaschek, 1987 Vogel and Hogan, 1990) in facilitating an inflammatory response. A fine balance occurs relative to the level of cytokine activity. In general, relatively low levels of specific cytokines promote beneficial protective effects in helping the host respond to a perturbing immune, inflammatory, or infectious challenge. In contrast, uncontrolled production of specific cytokines resulting in relatively high circulating levels often results in severe pathological consequences, such as hypotension and lethal shock. Although responses to specific inflammatory, immune, or infectious insults are not necessarily identical, they provoke a similar central neuroendocrine response via the generation of similar cytokines and thus can all be viewed as "inflammatory stress." For purposes of discussion, these environmental perturbations can be viewed similarly not only because they induce a similar counterregulatory response (i.e., HPAA activation) but also because the consequences of this response expose the organism to similar immunosuppressive and anti-inflammatory actions following the initial induction of immune potentiating and inflammatory effects (Besedovsky and del Ray, 1996). These actions are aimed at controlling the disruption of homeostasis produced by the offending agent or stimulus.
Immune Regulation of the HPAA by Cytokines
IL-1, TNF-&alpha, and IL-6 are the most important cytokines for stimulating the HPAA (Chrousos, 1995 Gaillard, 1994 Reichlin, 1993). Because IL-1 is the most potent (on a molar basis) cytokine that activates the HPAA, and the most frequently studied relative to the HPAA, stimulation of the HPAA by IL-1 is often viewed as a prototypical model for immune activation of the HPAA. Additional complexity is added by the fact that IL-1 exists in two forms (&alpha, which is primarily membrane-associated, and &beta, which is primarily secreted) that there are at least two IL-1 receptors and that IL-1 actions can be counterregulated by an endogenous receptor antagonist (IL-1ra) (Dinarello,
1992 Pruitt et al., 1995 Schöbitz et al., 1994). IL-1 effects may also be diminished by soluble receptors or a "decoy" receptor that is not coupled to a signal transduction message. Furthermore, IL-1 can exert a positive auto-feedback whereby it stimulates its own expression in the periphery (Dinarello et al., 1987) and brain (Gao et al., 1996 He et al., 1996) and stimulates hypothalamic transcription of its type 1 receptor (Gao et al., 1996, based on inhibition of an IL-1 stimulated increase in mRNA by a pharmacological inhibitor of transcription). Under acute circumstances, cytokines are thought to act centrally to stimulate hypothalamic CRH and perhaps AVP release (Bateman et al., 1989 Chrousos, 1995 Gaillard, 1994 Harbuz and Lightman, 1992 Lilly and Gann, 1992 Reichlin, 1993 Rivier, 1995), and subsequently ACTH and glucocorticoid secretion are stimulated.
Other studies suggest the possibility that direct stimulation of IL-1 at the pituitary level may also occur, but that stimulation at this level develops primarily during more prolonged cytokine activation (Chrousos, 1995 Gaillard, 1994 Koenig, 1991 Kehrer et al., 1988). However, it is not clear whether such stimulation is related to circulating cytokines or induction of IL-1, other cytokines, or other events within the pituitary via paracrine effects (Koenig et al., 1990). In addition, direct stimulation of IL-1 at the level of the adrenal has been suggested based on in vitro and in vivo studies (Andreis et al., 1991 Bateman et al., 1989 Chrousos, 1995 Gaillard, 1994 Gwosdow et al., 1992). This stimulation also appears to require prolonged exposure to IL-1. If such cytokine stimulation at these other levels of the axis are of physiological import, these mechanisms could be particularly significant during prolonged immune/cytokine system stimulation.
The major mechanism (Figure 19-1) mediating acute stimulation of ACTH secretion by IL-1 appears to involve CRH release (Bateman et al., 1989 Chrousos, 1995 Matta et al., 1990 Rivier, 1995 Sapolsky et al., 1987) and possibly AVP release (Nakatsuru et al., 1991 Watanobe and Takebe, 1994 Whitnall et al., 1992) from terminals at the median eminence. Based on many studies, it appears that the potency of the immune stimulus is directly related to the magnitude and duration of HPAA activation. This phenomenon of prolonged activation is manifested by higher levels of circulating ACTH or glucocorticoid for longer periods. IL-1 administered peripherally in relatively high doses or centrally also increases CRH mRNA (Brady et al., 1994 Ericsson et al., 1994 Harbuz et al., 1992b Rivier, 1995 Suda et al., 1990) and immunocytochemical CRH (Ju et al., 1991 Rivest et al., 1992) in some parvocellular paraventricular nuclear (PVN) neurons, which are involved in stimulating the HPAA. Furthermore, IL-1 stimulates expression of mRNA and protein of an immediate-early gene (c-fos) in PVN and several other brain sites (Brady et al., 1994 Chang et al., 1993 Ericsson et al., 1994 Ju et al., 1991 Rivest et al., 1992 Veening et al., 1993). Together, these studies illustrate activation of the CRH perikaryon (i.e., cell body) however, the relationship between IL-1-induced c-fos production and activation of CRH gene expression
is not clear. Nevertheless, it appears that stimulation of perikarya producing CRH in PVN results in enhanced CRH synthesis when a sufficiently strong immune stimulus above a certain threshold induces significant cytokine production and secretion. Augmented CRH synthesis could maintain increased CRH release and therefore facilitate prolonged HPAA activation. In addition, centrally administered IL-1 increased AVP mRNA in PVN (Lee and Rivier, 1994), and it was found that endotoxin/lipopolysaccharide (LPS), which induces the production of cytokines, increased AVP mRNA in PVN when administered peripherally in a high dose (Kapcala et al., 1995). Increased release of AVP into the pituitary portal circulation has also been found in an animal model of inflammatory arthritis (Harbuz et al., 1992a), raising the possibility that different mechanisms may be involved in facilitating chronic activation of the HPAA in response to a chronic inflammatory stimulus.
Central Actions of IL-1
Although it is clear that peripherally generated cytokines activate the HPAA centrally, precise mechanisms by which this occurs have not been clearly established. Recognizing the presence of IL-1 receptors in many sites throughout the brain (Cunningham and DeSouza, 1994), including circumventricular organs, there are several putative mechanisms by which peripherally generated cytokines may communicate with the brain and more specifically regulate the HPAA (Figure 19-1). Although IL-1 transport into the brain has been described (Banks et al., 1991), stimulation via this mechanism is not widely held because IL-1 does not easily cross the blood-brain barrier (Coceani et al., 1988) under normal circumstances. However, with increased levels of circulating cytokines, the blood-brain barrier may be made more permeable to macromolecules such as cytokines (Burrought et al., 1992 Saija et al., 1995) and permit some cytokine entry into brain. Alternatively, a peripheral cytokine such as IL-1 might transduce brain signaling by stimulating endothelial IL-1 receptors (Cunningham and DeSouza, 1994 Dinarello, 1992 Tilders et al., 1994). Subsequently, a cytokine signal may spread throughout brain parenchyma (Breder et al., 1994 van Dam et al., 1995) by mechanisms that remain to be elucidated. Actions at circumventricular organs (e.g., the organum vasculosum of lamina terminalis [OVLT], median eminence, and area postrema&mdashbrain regions where a normal blood-brain barrier is not intact) could be important. This concept is consistent with stimulating CRH secretion from the median eminence (Matta et al., 1990) via IL-1 receptor stimulation of catecholamine release from axon terminals in this location. Additional evidence suggests peripheral IL-1 signaling of the brain and the HPAA particularly at the OVLT (Gaillard, 1994 Katsuura et al., 1990 Tilders et al., 1994). More specifically, it has been proposed (Katsuura et al., 1990) that IL-1 enters the OVLT and stimulates cells such as astrocytes to synthesize and release prostaglandins, which stimulate neuronal circuits that ultimately activate CRH
and AVP neurons in the PVN. Stimulation of presumably transcription of an immediate early gene such as c-fos in the nucleus tractus solitarius of the medulla, which sends noradrenergic projections to the median eminence and PVN, could reflect neuronal activation by IL-1 and would support peripheral IL-1 stimulation of the brain via the nearby area postrema. In consonance with this view, neuroanatomical cuts caudal to hypothalamus inhibit HPAA activation by intravenous (iv) IL-1&beta (Sawchenko et al., 1996).
Brain signaling by peripheral cytokines may also involve stimulation of afferent sensory circuits such as the vagus or peripheral nociceptive (pain-transmitting) neural pathways (Dantzer et al., 1994 Donnerer et al., 1992 Lilly and Gann, 1992 Wan et al., 1994). Subdiaphragmatic vagotomy inhibits the induction of many central effects produced by IL-1 or LPS particularly when administered intraperitoneally (Bluthe et al., 1994 Laye et al., 1995 Maier et al., 1993 Wan et al., 1994 Watkins et al., 1994a, b, 1995a). Of interest to the focus here, vagotomy inhibits stimulation of ACTH by intraperitoneal (ip) IL-1&beta (Kapcala et al., 1996) and LPS (Gaykema et al., 1995) and stimulation of CORT (Fleshner et al., 1995) secretion by ip IL-1&beta. Treatment with capsaicin (an alkaloid derivative of red pepper that inhibits the function of peripheral sensory afferents, including those mediating nociception) inhibits stimulation of plasma ACTH and CORT by iv IL-1 (Watanobe et al., 1994). Thus peripheral afferents may also play an important role in brain signaling by peripheral cytokines. Finally, it is also possible that invoking different mechanisms may not necessarily be mutually exclusive. Different mechanisms for brain signaling by peripheral cytokines may operate simultaneously or under specific circumstances depending on the body compartment in which the primary cytokine stimulus arises.
The Role of the Locus of Origin of IL-1
Increasingly, a consensus has been developing among researchers in the field that many mechanisms may be responsible for cytokine stimulation of the HPAA by an inflammatory, infectious, or immune stress and that the body compartment in which the stimulus originates may primarily dictate the main mechanism involved. Experimental corollaries of this view are that the administration of a cytokine such as IL-1 by a different route (e.g., iv, ip, intracerebroventricular [icv]) may result in the utilization of different mechanisms of activation of the HPAA (Rivier, 1995 Tilders et al., 1994).
Different modulatory effects of various regulatory factors on IL-1 activation of the HPAA have been reported depending on the route of IL-1 administration. Whereas inhibition of prostaglandin synthesis does not consistently and potently inhibit stimulation of ACTH or CORT by ip IL-1, this treatment virtually abolishes stimulation by iv IL-1 (Dunn and Chuluyan, 1992 Rivier, 1993). Lesioning of central noradrenergic pathways that modulate activity of the HPAA has different effects on stimulation of the HPAA
depending on whether IL-1 is administered centrally or peripherally (e.g., intra-arterially) (Barbanel et al., 1993). Removal of CS negative feedback by adrenalectomy abolished IL-1 stimulation of ACTH secretion when IL-1 was given centrally (Weidenfeld et al., 1989), but did not diminish stimulation when IL-1 was given peripherally (iv or ip) (Selmanoff et al., 1996). Finally, peripherally (ip or iv) administered IL-1 in doses that potently stimulated ACTH and CORT secretion did not stimulate gene expression of CRH and AVP in PVN as did centrally administered IL-1 (Lee and Rivier, 1994). Altogether, these observations support the likelihood of a developing overview that cytokine activation of the HPAA is quite complex and involves a multiplicity of mechanisms.
Use of LPS to Elucidate the Effects of IL-1
LPS, derived from the cell wall of gram-negative bacteria, induces the septic shock syndrome and is often used as a model for studying the sepsis syndrome in experimental animals or conditions associated with marked induction of cytokines. Not surprisingly, LPS is a potent activator of the HPAA, which has been recognized for many years. This action occurs via its stimulation of the production and release of cytokines (Bateman et al., 1989 Chrousos, 1995 1993 Dunn, 1992 Ebisui et al., 1994 Perlstein et al., 1993 Vogel and Hogan, 1990), particularly IL-1 and TNF, but also perhaps IL-6. It has been proposed that LPS activates the HPAA mainly via generation of IL-1 (Rivier et al., 1989 Schotanus et al., 1993). It has also been proposed that induction of septic shock (Ohlsson et al., 1990 Pruitt et al., 1995 Russell and Tucker, 1995 Wakabayashi et al., 1991) by LPS may also be highly dependent on IL-1 because antagonism of IL-1 with IL-1ra was therapeutic. The level of circulating LPS, and correspondingly, the level of cytokines generated by LPS may also be important for determining the mechanism of HPAA stimulation. One study showed that low doses of LPS activated the HPAA mainly via TNF but that higher doses invoked an important role for IL-1 (Ebisui et al., 1994), suggesting that a different intensity of immune stimulation by the same factor may operate through different mechanisms. Other studies showed that macrophage depletion (DeRijk et al., 1991) and blockade of IL-6 actions (Perlstein et al., 1993) selectively attenuated relatively low-dose LPS stimulation. These results also support different mechanisms of HPAA stimulation depending on the magnitude of stimulation by LPS.
Despite beliefs that LPS stimulates the HPAA via induction of cytokines that acutely act primarily centrally, it seems likely that LPS may also stimulate ACTH and glucocorticoid secretion by generating cytokines that act directly on the anterior pituitary and possibly on the adrenal cortex. A variety of studies show that rats with hypothalamic resection, lesions, deafferentation, and pituitary stalk section (Elenkov et al., 1992 Makara et al., 1970, 1971) were still able to increase plasma CORT after LPS. Consequently, it appears that immune
stimulation of the stress axis may operate through several fail-safe mechanisms that facilitate at least a partial activation of this critically important response.
The Role of IL-1&beta
Expression of the IL-1&beta gene in brain can be induced by various stimuli including LPS, immobilization stress, ischemia, mechanical injury, and various pharmacological treatments (Ban et al., 1992 Dantzer et al., 1994 Higgins and Olschowka, 1991 Laye et al., 1995 Minami et al., 1991, 1992 Takao et al., 1993 van Dam et al., 1992, 1995 Yan et al., 1992). Although IL-1&beta mRNA has been reported to be present throughout several rat brain regions in the basal state (Bandtlow et al., 1990), and immunocytochemical IL-1&beta has been found in rat brain (Lechan et al., 1990), after central colchicine administration and in human brain (Breder et al., 1988) at autopsy, a consensus view among many investigators is that expression of brain IL-1&beta mRNA is minimal under basal, unstimulated conditions (Ban et al., 1992 Dantzer et al., 1994 Higgins and Olschowka, 1991 Laye et al., 1995 Minami et al., 1991, 1992 Takao et al., 1993 van Dam et al., 1992, 1995 Yan et al., 1992). Consistent with this perspective, this author (He et al., 1996) has found that peripherally (ip) administered LPS potently stimulates expression of IL-1&beta mRNA in specific brain regions including circumventricular organs (OVLT, median eminence, subfornical organ, area postrema) and parenchymal sites (PVN, arcuate-periarcuate region, vagal nucleus) that do not normally express this mRNA in the unstimulated state. Although peripherally administered IL-1&beta also induced IL-1&beta mRNA in these same regions, the intensity of stimulation was much weaker than LPS based on the number of cells expressing the mRNA and the signal intensity per cell. Considering that these stimuli activate the HPAA and that extremely small doses of centrally administered IL-1 potently activate the HPAA (Kapcala et al., 1995), induction of brain IL-1 expression particularly in hypothalamus by cytokines originating in the periphery has been considered as a potential mechanism by which amplification of immune activation of the HPAA could occur (Tilders et al., 1994) especially as a mechanism to prolong HPAA activation.
Immune System Activation of the HPAA Counterregulates Cytokines and Protects Against an Excessive Host Response to Inflammatory, Immune, and Infectious Insults
Lethality of IL-1 in Adrenalectomized or Hypophysectomized Animals
It has been proposed that CS secretion (Munck et al., 1984) protects against potentially deleterious, catabolic effects of cytokines produced during immune,
infectious, or inflammatory processes by downmodulating the production, release, and actions of cytokines. In support of this hypothesis is the markedly increased sensitivity to lethal effects in animals with a defective HPAA or surgically induced compromise of the HPAA (Table 19-1) after exposure to LPS, various inflammatory conditions that stimulate cytokine production, and cytokines themselves (Bertini et al., 1988 Butler et al., 1989 Harbuz et al., 1993 MacPhee et al., 1989 Nakano et al., 1987 Sternberg et al., 1989). Glucocorticoid treatment administered in some of these studies (Bertini et al., 1988 Butler et al., 1989 MacPhee et al., 1989 Nakano et al., 1987) protected against lethal effects (Table 19-1), which strongly suggests that the HPAA plays a protective role against immune or inflammatory stimuli.
Adrenalectomy (ADX) or hypophysectomy (HYPOX) (removal of the pituitary) also results in LPS stimulation of higher serum levels of IL-1 and TNF for longer periods, which indicates a modulatory role of the endogenous HPAA (Butler et al., 1989, Zuckerman et al., 1989). Increased sensitivity to lethal effects of IL-1 has been described in mice following ADX or HYPOX (Bertini et al., 1988 Butler et al., 1989), and enhanced lethal sensitivity to LPS has been reported in the rat (Nakano et al., 1987) (perhaps the most commonly studied
TABLE 19-1 Conditions Producing Lethal Effects in Animals with an Abnormal Hypothalamic-Pituitary-Adrenal Axis (HPAA)
T cells are required for immune surveillance of the central nervous system (CNS) however, they can also induce severe immunopathology in the context of both viral infections and autoimmunity. The mechanisms that are involved in the priming and recruitment of T cells to the CNS are only partially understood, but there has been renewed interest in this topic since the 'rediscovery' of lymphatic drainage from the CNS. Moreover, tissue-resident memory T cells have been detected in the CNS and are increasingly recognized as an autonomous line of host defence. In this Review, we highlight the main mechanisms that are involved in the priming and CNS recruitment of CD4 + T cells, CD8 + T cells and regulatory T cells. We also consider the plasticity of T cell responses in the CNS, with a focus on viral infection and autoimmunity.
What are the main mechanisms of interaction between the nervous and immune systems? - Biology
Background The gut–brain axis facilitates a critical bidirectional link and communication between the brain and the gut. Recent studies have highlighted the significance of interactions in the gut–brain axis, with a particular focus on intestinal functions, the nervous system and the brain. Furthermore, researchers have examined the effects of the gut microbiome on mental health and psychiatric well-being.
The present study reviewed published evidence to explore the concept of the gut–brain axis.
Aims This systematic review investigated the relationship between human brain function and the gut–brain axis.
Methods To achieve these objectives, peer-reviewed articles on the gut–brain axis were identified in various electronic databases, including PubMed, MEDLINE, CIHAHL, Web of Science and PsycINFO.
Results Data obtained from previous studies showed that the gut–brain axis links various peripheral intestinal functions to brain centres through a broad range of processes and pathways, such as endocrine signalling and immune system activation. Researchers have found that the vagus nerve drives bidirectional communication between the various systems in the gut–brain axis. In humans, the signals are transmitted from the liminal environment to the central nervous system.
Conclusions The communication that occurs in the gut–brain axis can alter brain function and trigger various psychiatric conditions, such as schizophrenia and depression. Thus, elucidation of the gut–brain axis is critical for the management of certain psychiatric and mental disorders.
Biofilms: Discovery of a new mechanism of virus propagation
Researchers at the Institut Pasteur and CNRS have shown for the first time that certain viruses are capable of forming complex biofilm-like assemblies, similar to bacterial biofilms. These extracellular infectious structures may protect viruses from the immune system and enable them to spread efficiently from cell to cell. "Viral biofilms" would appear to be a major mechanism of propagation for certain viruses. They are therefore emerging as new and particularly attractive therapeutic targets.
Researchers from the Institut Pasteur and CNRS, headed by Maria-Isabel Thoulouze and Andrés Alcover within the Lymphocyte Cell Biology Unit, in collaboration with Antoine Gessain from the Oncogenic Virus Epidemiology and Physiopathology Unit and with the Imagopole, recently identified, for the first time in viral research, "biofilm" like structures, formed by the HTLV-1 retrovirus on the surface of infected cells. These are aggregates of viruses embedded in a carbohydrate-rich structure containing cell-secreted extracellular matrix, whose synthesis is controlled by the virus.
The HTLV-1 virus (human T-cell leukemia virus type 1) was the first human retrovirus to be isolated, in 1980, three years prior to the discovery of HIV, the retrovirus that causes AIDS. It infects 15 to 20 million people worldwide and causes various diseases, ranging from adult T-cell leukemia/lymphoma to forms of neuromyelopathy (tropical spastic paraparesis) or other chronic inflammatory syndromes, such as infectious dermatitis, uveitis and myositis. The dissemination of HTLV-1 was known to require infected cells and cell-cell contacts, but the transmission mechanism itself was still a mystery.
In the biofilm -- an effective protective and adhesive barrier -- HTLV-1 is far more easily transmitted than in its free, isolated state. By removing the viral biofilm from the surface of the infected cells, researchers achieved an 80% reduction in infection rates, thus underlining the importance of this transmission mode for HTLV-1.
In bacteria, the existence of biofilms has been known for many years. They form the dental plaque on the enamel surface of teeth and are also found in industrial systems and in our own intestinal flora. When they colonize medical implants, such as prosthesis or catheters, they can cause repeated infection. For these reasons, bacterial biofilms have been the focus of intensive research in the aim to limit their development and render them responsive to anti-bacterial treatment.
Scientists are currently seeking to characterize the mechanisms of viral biofilm generation, and to determine whether viruses other than HTLV-1 form this kind of structure. For viruses forming biofilms, it would be useful to define new anti-viral therapeutic strategies, which would target, not only the virus itself, but the formation of these viral biofilms.
What We Know So Far about How COVID Affects the Nervous System
Neurological symptoms might arise from multiple causes. But does the virus even get into neurons?
Many of the symptoms experienced by people infected with SARS-CoV-2 involve the nervous system. Patients complain of headaches, muscle and joint pain, fatigue and &ldquobrain fog,&rdquo or loss of taste and smell&mdashall of which can last from weeks to months after infection. In severe cases, COVID-19 can also lead to encephalitis or stroke. The virus has undeniable neurological effects. But the way it actually affects nerve cells still remains a bit of a mystery. Can immune system activation alone produce symptoms? Or does the novel coronavirus directly attack the nervous system?
Some studies&mdashincluding a recent preprint paper examining mouse and human brain tissue&mdashshow evidence that SARS-CoV-2 can get into nerve cells and the brain. The question remains as to whether it does so routinely or only in the most severe cases. Once the immune system kicks into overdrive, the effects can be far-ranging, even leading immune cells to invade the brain, where they can wreak havoc.
Some neurological symptoms are far less serious yet seem, if anything, more perplexing. One symptom&mdashor set of symptoms&mdashthat illustrates this puzzle and has gained increasing attention is an imprecise diagnosis called &ldquobrain fog.&rdquo Even after their main symptoms have abated, it is not uncommon for COVID-19 patients to experience memory loss, confusion and other mental fuzziness. What underlies these experiences is still unclear, although they may also stem from the body-wide inflammation that can go along with COVID-19. Many people, however, develop fatigue and brain fog that lasts for months even after a mild case that does not spur the immune system to rage out of control.
Another widespread symptom called anosmia, or loss of smell, might also originate from changes that happen without nerves themselves getting infected. Olfactory neurons, the cells that transmit odors to the brain, lack the primary docking site, or receptor, for SARS-CoV-2, and they do not seem to get infected. Researchers are still investigating how loss of smell might result from an interaction between the virus and another receptor on the olfactory neurons or from its contact with nonnerve cells that line the nose.
Experts say the virus need not make it inside neurons to cause some of the mysterious neurological symptoms now emerging from the disease. Many pain-related effects could arise from an attack on sensory neurons, the nerves that extend from the spinal cord throughout the body to gather information from the external environment or internal bodily processes. Researchers are now making headway in understanding how SARS-CoV-2 could hijack pain-sensing neurons, called nociceptors, to produce some of COVID-19&rsquos hallmark symptoms.
Neuroscientist Theodore Price, who studies pain at the University of Texas at Dallas, took note of the symptoms reported in the early literature and cited by patients of his wife, a nurse practitioner who sees people with COVID remotely. Those symptoms include sore throat, headaches, body-wide muscle pain and severe cough. (The cough is triggered in part by sensory nerve cells in the lungs.)
Curiously, some patients report a loss of a particular sensation called chemethesis, which leaves them unable to detect hot chilies or cool peppermints&mdashperceptions conveyed by nociceptors, not taste cells. While many of these effects are typical of viral infections, the prevalence and persistence of these pain-related symptoms&mdashand their presence in even mild cases of COVID-19&mdashsuggest that sensory neurons might be affected beyond normal inflammatory responses to infection. That means the effects may be directly tied to the virus itself. &ldquoIt&rsquos just striking,&rdquo Price says. The affected patients &ldquoall have headaches, and some of them seem to have pain problems that sound like neuropathies,&rdquo chronic pain that arises from nerve damage. That observation led him to investigate whether the novel coronavirus could infect nociceptors.
The main criteria scientists use to determine whether SARS-CoV-2 can infect cells throughout the body is the presence of angiotensin-converting enzyme 2 (ACE2), a protein embedded in the surface of cells. ACE2 acts as a receptor that sends signals into the cell to regulate blood pressure and is also an entry point for SARS-CoV-2. So Price went looking for it in human neurons in a study now published in the journal PAIN.
Nociceptors&mdashand other sensory neurons&mdashlive in discreet clusters, found just outside the spinal cord, called dorsal root ganglia (DRG). Price and his team procured nerve cells donated after death or cancer surgeries. The researchers performed RNA sequencing, a technique to determine which proteins a cell is about to produce, and they used antibodies to target ACE2 itself. They found that a subset of DRG neurons did contain ACE2, providing the virus a portal into the cells.
Sensory neurons send out long tendrils called axons, whose endings sense specific stimuli in the body and then transmit them to the brain in the form of electrochemical signals. The particular DRG neurons that contained ACE2 also had the genetic instructions, the mRNA, for a sensory protein called MRGPRD. That protein marks the cells as a subset of neurons whose endings are concentrated at the body&rsquos surfaces&mdashthe skin and inner organs, including the lungs&mdashwhere they would be poised to pick up the virus.
Price says nerve infection could contribute to acute, as well as lasting, symptoms of COVID. &ldquoThe most likely scenario would be that the autonomic and sensory nerves are affected by the virus,&rdquo he says. &ldquoWe know that if sensory neurons get infected with a virus, it can have long-term consequences,&rdquo even if the virus does not stay in cells.
But, Price adds, &ldquoit does not need to be that the neurons get infected.&rdquo In another recent study, he compared genetic sequencing data from lung cells of COVID patients and healthy controls and looked for interactions with healthy human DRG neurons. Price says his team found a lot of immune-system-signaling molecules called cytokines from the infected patients that could interact with receptors on neurons. &ldquoIt&rsquos basically a bunch of stuff we know is involved in neuropathic pain.&rdquo That observation suggests that nerves could be undergoing lasting damage from the immune molecules without being directly infected by the virus.
Anne Louise Oaklander, a neurologist at Massachusetts General Hospital, who wrote a commentary accompanying Price&rsquos paper in PAIN, says that the study &ldquowas exceptionally good,&rdquo in part because it used human cells. But, she adds, &ldquowe don&rsquot have evidence that direct entry of the virus into [nerve] cells is the major mechanism of cellular [nerve] damage,&rdquo though the new findings do not discount that possibility. It is &ldquoabsolutely possible&rdquo that inflammatory conditions outside nerve cells could alter their activity or even cause permanent damage, Oaklander says. Another prospect is that viral particles interacting with neurons could lead to an autoimmune attack on nerves.
ACE2 is widely thought to be the novel coronavirus&rsquos primary entry point. But Rajesh Khanna, a neuroscientist and pain researcher at the University of Arizona, observes that &ldquoACE2 is not the only game in town for SARS-CoV-2 to come into cells.&rdquo Another protein, called neuropilin-1 (NRP1), &ldquocould be an alternate doorway&rdquo for viral entry, he adds. NRP1 plays an important role in angiogenesis (the formation of new blood vessels) and in growing neurons&rsquo long axons.
That idea came from studies in cells and in mice. It was found that NRP1 interacts with the virus&rsquos infamous spike protein, which it uses to gain entry into cells. &ldquoWe proved that it binds neuropilin and that the receptor has infectious potential,&rdquo says virologist Giuseppe Balistreri of the University of Helsinki, who co-authored the mouse study, which was published in Science along with a separate study in cells. It appears more likely that NRP1 acts as a co-factor with ACE2 than that the protein alone affords the virus entry to cells. &ldquoWhat we know is that when we have the two receptors, we get more infection. Together, it&rsquos much more powerful,&rdquo Balistreri adds.
Those findings piqued the interest of Khanna, who was studying vascular endothelial growth factor (VEGF), a molecule with a long-recognized role in pain signaling that also binds to NRP1. He wondered whether the virus would affect pain signaling through NRP1, so he tested it in rats in a study that was also published in PAIN. &ldquoWe put VEGF in the animal [in the paw], and lo and behold, we saw robust pain over the course of 24 hours,&rdquo Khanna says. &ldquoThen came the really cool experiment: We put in VEGF and spike at the same time, and guess what? The pain is gone.&rdquo
The study showed &ldquowhat happens to the neuron&rsquos signaling when the virus tickles the NRP1 receptor,&rdquo Balistreri says. &ldquoThe results are strong,&rdquo demonstrating that neurons&rsquo activity was altered &ldquoby the touch of the spike of the virus through NRP1.&rdquo
In an experiment in rats with a nerve injury to model chronic pain, administering the spike protein alone attenuated the animals&rsquo pain behaviors. That finding hints that a spike-like drug that binds NRP1 might have potential as a new pain reliever. Such molecules are already in development for use in cancer.
In a more provocative and untested hypothesis, Khanna speculates that the spike protein might act at NRP1 to silence nociceptors in people, perhaps masking pain-related symptoms very early in an infection. The idea is that the protein could provide an anesthetic effect as SARS-CoV-2 begins to infect a person, which might allow the virus to spread more easily. &ldquoI cannot exclude it,&rdquo says Balistreri. &ldquoIt&rsquos not impossible. Viruses have an arsenal of tools to go unseen. This is the best thing they know: to silence our defenses.&rdquo
It still remains to be determined whether a SARS-CoV-2 infection could produce analgesia in people. &ldquoThey used a high dose of a piece of the virus in a lab system and a rat, not a human,&rdquo Balistreri says. &ldquoThe magnitude of the effects they&rsquore seeing [may be due to] the large amount of viral protein they used. The question will be to see if the virus itself can [blunt pain] in people.&rdquo
The experience of one patient&mdashRave Pretorius, a 49-year-old South African man&mdashsuggests that continuing this line of research is probably worthwhile. A motor accident in 2011 left Pretorius with several fractured vertebrae in his neck and extensive nerve damage. He says he lives with constant burning pain in his legs that wakes him up nightly at 3 or 4 A.M. &ldquoIt feels like somebody is continuously pouring hot water over my legs,&rdquo Pretorius says. But that changed dramatically when he contracted COVID-19 in July at his job at a manufacturing company. &ldquoI found it very strange: When I was sick with COVID, the pain was bearable. At some points, it felt like the pain was gone. I just couldn&rsquot believe it,&rdquo he says. Pretorius was able to sleep through the night for the first time since his accident. &ldquoI lived a better life when I was sick because the pain was gone,&rdquo despite having fatigue and debilitating headaches, he says. Now that Pretorius has recovered from COVID, his neuropathic pain has returned.
For better or worse, COVID-19 seems to have effects on the nervous system. Whether they include infection of nerves is still unknown like so much about SARS-CoV-2. The bottom line is that while the virus apparently can, in principle, infect some neurons, it doesn&rsquot need to. It can cause plenty of havoc from the outside these cells.
Read more about the coronavirus outbreak from Scientific American here. And read coverage from our international network of magazines here.
Center for Infectious Diseases Metabolomics at PHRI
The Center for Infectious Diseases Metabolomics (CIDM) at the Public Health Research Institute (PHRI) carries out metabolomics studies to improve prognosis, prevention and monitoring of many infectious diseases. Host-pathogen interactions are known to alter the metabolic state of both the host and the pathogen. Metabolic homeostasis in the host is regulated in part by the pathogen to promote its survival, persistence, and drug resistance. Many factors, including diet, exercise and drugs, affect the host metabolic homeostasis both during acute infection and, especially profoundly, during chronic infectious disease. The global profiling of small metabolites involved in micro (cellular) and macro (organ) physiology, such as glycolytic, TCA and pentose cycle metabolites, essential and non-essential amino acids, and lipid metabolites (fatty acids, acyl carnitines, phospholipids, di- and tri-glycerides), is a powerful approach to study pathophysiology and to predict cellular and organ function. The CIDM is focused on identifying novel metabolomics biomarkers that will help diagnose and prevent infectious diseases including tuberculosis, Chagas Disease, HIV, multi drug resistant bacterial infections, fungal infections, etc.). The CIDM supports investigators in the design and execution of multi-faceted metabolomics studies of infectious disease.
The CIDM is developing and applying mass spectrometry-based quantitative global analysis of endogenous metabolites from cells, tissues, fluids or whole organisms at different stages and states of infection. The CIDM also provides a resource facility for storing biopsy samples.
The objective of the CIDM is to help the investigators studying infectious diseases and interested in carrying out metabolomics studies as follows:
- Providing support in the development of a research study
- Finding potential collaborators and funding
- Matching your research needs with resources available at CIDM, PHRI Rutgers and other collaborative centers (e.g. imaging mass spectroscopy, grant writing assistance, data management services, outsourced services, and more)
- Identifying mentors and collaborators for your project from within the International Center for Public Health, from other institutions, and from the scientific community at large
- Offering educational programs and workshops
By fitting our services to the individual needs of each investigator/team, we provide seamless support from concept to closure.
The research in the Chauhan lab focuses on the biology and disease mechanisms of fungal pathogens of the Candida genus, predominantly C. albicans and C. glabrata. Over the last decade, we have focused our efforts on the discovery and characterization of fungal virulence factors. We are interested in understanding the fungal-host interactions and the mechanisms through which chromatin-mediated gene regulation modulates the commensal-pathogen switch in Candida spp. Current research is focused on a principally novel and unexplored area of Candida biology – the role of post-translational modification of proteins via lysine acetylation. Lysine acetylation is a well-established major mechanism of regulating protein function, and lysine acetylases (KATs) have been shown to play important roles in many cellular processes. However, while C. albicans contains several conserved lysine acetylases, their functions in fungal morphogenesis and virulence have remained unexplored. Current efforts are focused on deciphering the molecular roles of KATs/KDACs in fungal virulence, especially concerning the non-histone lysyl targets of KATs/KDACs. Our approaches include genetic, biochemical, immunological, proteomic and metabolomics techniques for the study of fungal-host interactions.
Nutritional immunity is a component of the innate immune response that reduces availability and restricts access of infecting microorganisms to essential micronutrients, like metal ions. The Rodriguez lab investigates the adaptive response of M. tuberculosis to iron deficiency imposed by the host. Because iron is essential for basic cellular functions, M. tuberculosis reprograms its metabolic activity in response to iron limitation. We are currently studying the metabolic signature of iron-limited M. tuberculosis to dissect its adaptive response to the host environment and identify new targets of therapeutic intervention. We also hope to identify metabolic markers of M. tuberculosis persisting in the host for diagnostic applications.
The Nagajyothi lab is currently analyzing the effect of metabolic regulators, such as drugs and diets, on the pathogenesis of chronic infectious diseases like Chagas disease and M. tuberculosis. The survival and persistence of the pathogen depends on the metabolic status and the immune response of the host. The metabolic status of the host can regulate immune response and vice-versa in chronic infections. Our objective is to identify key metabolites as biomarkers (both host and pathogen) that can be used as a therapeutic targets to prevent the pathogenesis of chagasic cardiomyopathy. In collaboration with Drs. Vinnard and Subbian we have initiated studies to elucidate the cross-talk between TB and Type-2 diabetes using a metabolomics approach.
The Pinter lab is currently characterizing the human humoral immune response to M. tuberculosis antigens. We are utilizing a retroviral vector generated in our lab that transduces several genes that stabilize memory B cells to long-term culture in vitro. These cells can be selected by binding specific antigens, and used to clone out the heavy and light chain antibody genes for further expression and characterization. Our initial studies are focused on surface glycolipids, particularly lipoarabinomannan (LAM), which are potential targets for point-of care immunodiagnostic applications. We hope to extend these studies to additional M. tuberculosis targets, and eventually to other bacterial pathogens as well. These antibodies will be useful for identifying and quantitating pathogen-specific biomarkers and metabolomics. In addition to diagnostic applications, we expect that many of these antibodies may possess therapeutic activity as well, and that these could be useful for treatment of antibiotic-resistant strains.
The Xue lab studies how human fungal pathogens sense extracellular signals and control intracellular signal transduction pathways that are important for cell development and virulence in Cryptococcus neoformans. Their approach is to apply genetics, biochemistry and molecular biology to investigate fungal-host interactions. They are particularily focused on the regulation of inositol metabolism and inositol-mediated signal pathways in fungal development and virulence. They demonstrated that inositol, an abundant metabolite in the brain, promotes fungal traversal of the BBB and plays a critical role in host-pathogen interactions during infection of the central nervous system (CNS). They showed that C. neoformans utilizes the inositol stores of its plant niches to complete its sexual cycle. C. neoformans is likely to be uniquely adapted to thrive in the inositol-rich environment of the CNS and to utilize inositol-dependent pathways for pathogenesis. Their preliminary results suggest that inositol can promote formation of a unique capsule structure enriched in M3 mannosyl triad structure reporter group that can help the fungus evade the host immune response. They aim to define inositol sensing and metabolic pathways required for modifying fungal cell surface structure by employing fungal mutagenesis analysis, metabolomic assays and polysaccharide structural analysis. They will attempt to elucidate the transcriptional circuits regulating inositol functions during cryptococcal infection. They will characterize the mechanisms of inositol-mediated promotion of Cryptococcus BBB crossing and CNS infection using an in vitro model of human BBB and animal infection models of CNS cryptococcosis.