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Session 2: The Inflammatory Response: Activation of the Innate Immune System

Transcript of Part 2: Inflammation and Disease Tolerance: Surviving Acute Illness

00:00:15;00 Hello.
00:00:16;00 My name is Ruslan Medzhitov.
00:00:17;00 I'm a professor at Yale University School of Medicine and an Investigator of the
00:00:22;00 Howard Hughes Medical Institute.
00:00:23;13 And in this lecture, I will discuss our recent study on the effect of inflammation in acute illness
00:00:30;11 and the role of disease tolerance in surviving acute illness.
00:00:39;11 As I discussed in the introductory lecture, the costs of inflammation can be broken down
00:00:44;01 into two categories.
00:00:45;10 The first is the intentional suppression of lower priority functions that are incompatible
00:00:51;00 with the goals of the response.
00:00:53;17 And the second type of costs are unintentional but unavoidable loss of function, for example,
00:01:00;05 due to collateral damage.
00:01:02;22 And the sum of these two costs has to be lower than the benefit provided by the inflammation
00:01:07;18 in order to... for the system to evolve the way it is.
00:01:12;28 And this relation between the cost and benefit is what's really essential for understanding
00:01:17;14 many biological functions and their deviations into pathological states.
00:01:22;11 So, every biological trait can be characterized by some benefit it provides and some cost
00:01:28;14 at which it operates.
00:01:30;10 And this can be schematically shown as follows.
00:01:32;26 So, if we plot benefit versus cost for a system, for a biological trait to evolve the benefit
00:01:41;06 has to be higher than the cost.
00:01:43;03 So, any trait that would be in the green triangle part of the plot, where the benefit is higher
00:01:48;27 than the cost, would be evolutionary acceptable.
00:01:54;01 And anything in the red triangle, where the cost is higher than the benefit, would be
00:01:57;25 eliminated by natural selection.
00:02:00;28 And as you can see, the higher the benefit of the trait the higher is the acceptable cost.
00:02:07;27 And this view is from the evolutionary perspective.
00:02:11;14 So, all evolution cares about is that the benefit is higher than the cost.
00:02:17;22 And the same plot from the patient or physician perspective would look like this.
00:02:22;21 Here, again, anything that is in the upper-left triangle, where the benefit is higher than
00:02:29;16 the cost, would be a fair game from evolutionary perspective.
00:02:32;27 But as you move to the right side, when the cost becomes higher and higher, because benefit
00:02:38;09 is high, then this would be associated with conditions we would often refer to as
00:02:44;19 pathological or disease conditions.
00:02:46;09 So, if you're a patient and you're having an acute infection, there are ongoing
00:02:52;07 immune and inflammatory responses, but at the same time you feel very ill as a consequence of
00:02:56;21 these responses.
00:02:59;04 This would be a situation in the upper-right corner, where the benefit is still higher
00:03:04;24 than the cost, but the cost is so high that it makes us feel sick.
00:03:10;03 And it is this position on the plot, on the upper-right corner, where trades that provide
00:03:19;00 very high benefit will have very high acceptable costs.
00:03:22;22 And some diseases can be due to these types of trades, with very high benefits coming
00:03:28;28 with the high costs.
00:03:30;08 And that's the situation we've been interested in investigating.
00:03:34;13 What kind of mechanisms operate when the cost of the response is so high that it makes you
00:03:39;10 feel ill, and you're in fact close to the... to the condition where it could be life-threatening?
00:03:48;01 And one famous set of conditions like this is associated with acute illness.
00:03:53;23 And what's been known for... for a long time is that, during acute illness,
00:03:58;19 humans and other animals experience what's known as sickness behaviors.
00:04:04;04 And these are stereotypical responses that include loss of appetite, social withdrawal,
00:04:11;06 fatigue, altered sleep patterns, cessation of grooming, and suppression of libido.
00:04:17;10 And why they all happen and why there's this particular combination of behaviors is
00:04:23;12 not very clear, but it's clear that they occur in all animals studied.
00:04:28;24 They've even been observed in insects.
00:04:31;23 And it's been concluded, decades ago, that these are not just debilitations of
00:04:40;18 normal behaviors, but rather these are motivated behaviors.
00:04:43;21 In other words, they occur with a purpose.
00:04:46;14 There is some intentional induction of these responses.
00:04:50;26 But what the purpose of these responses is... is... has been less clear.
00:04:54;28 And that's what we investigated in this study I will describe today.
00:04:59;14 So, we were particularly interested in understanding the phenomenon of disease-induced anorexia.
00:05:09;23 We are all familiar with this phenomenon.
00:05:11;19 When you have acute infection, like flu infection or a severe cold, your appetite goes away.
00:05:18;01 You don't want to eat.
00:05:19;02 You want to sleep a lot.
00:05:20;17 And we asked why is it that we don't eat when we are very sick.
00:05:25;18 And to model that, we studied an infection with a bacterial pathogen called
00:05:32;18 Listeria monocytogenes, which is a very common bacterium that causes food poisoning.
00:05:39;11 And what we did... here, we infected mice with a sublethal dose of Listeria and monitored
00:05:47;18 their food consumption.
00:05:49;09 And as you can see, the red line is mice that are infected with Listeria, and as you
00:05:55;18 can see there is a very profound suppression of food consumption.
00:05:59;28 And go on... into this anorexic state until they start recovering from infection,
00:06:06;26 at which point they will regain food consumption.
00:06:11;08 And we asked, why is it that they don't eat?
00:06:13;21 What would happen if they are forced to eat?
00:06:17;27 And to address that, we fed the mice with the same amount of the same type of food
00:06:24;15 that they normally consume.
00:06:26;16 And we only provided them about 20 percent of normal daily caloric intake.
00:06:32;26 So, it's just a small fraction of what they would normally eat.
00:06:36;28 And we used, in this case, a dose of Listeria that kills 50 percent of mice -- so it's called
00:06:43;02 lethal dose 50 or LD50 -- which is shown in the black line.
00:06:47;25 These are mice that are control mice.
00:06:51;15 And then the experimental mice were given food.
00:06:54;03 And as you can see, all of them died within 10 days, indicating that eating during bacterial infection
00:07:01;17 can be lethal.
00:07:03;13 And that result actually is not new.
00:07:05;02 It was first reported in 1979 with a similar model, with Listeria infection, that force-feeding
00:07:11;08 during infection can be... it can lead... can increased... it can increase lethality.
00:07:16;28 So, then we asked, what is it in the food that causes this effect?
00:07:21;14 And we tested, separately, proteins, carbohydrates, and fats.
00:07:26;19 And found that the effect of the... this effect of feeding was due to carbohydrates,
00:07:32;22 specifically due to glucose, because if we would just give mice glucose at the time of the... of the infection,
00:07:39;25 then 100% of them would succumb to infection.
00:07:45;07 And that was very interesting because it indicated that just glucose -- that simple metabolite,
00:07:50;07 an essential metabolite -- is sufficient to cause such a dramatic effect on survival.
00:07:56;24 And then we asked, what would happen if we do the opposite manipulation, if we
00:08:02;20 prevent glucose utilization?
00:08:04;21 And to do so, we used a metabolite derivative called 2-deoxyglucose, or 2DG, which is
00:08:12;02 a glucose variant that can be taken into the cells but cannot be metabolized, so it
00:08:16;18 prevents glucose utilization even if glucose is present in the system.
00:08:22;00 And when we gave mice 2DG twice a day, by injecting it either intraperitoneally or
00:08:29;01 giving it orally or giving it intravenously... it didn't matter which route we used.
00:08:35;16 And as you can see in the blue line here, 100% of mice now could survive this infection
00:08:41;12 that otherwise would kill 50% of mice.
00:08:44;04 So, that was very exciting because it indicated that blocking glucose utilization can
00:08:50;03 protect mice from infection, and giving them glucose can promote mortality.
00:08:57;22 Then we asked whether this is something unique to Listeria or can be generalized to
00:09:02;20 other types of bacterial infections.
00:09:05;28 And to address this, we used a common model of bacterial sepsis that is caused by...
00:09:12;21 not by live bacteria but by specific a bacterial component called lipopolysaccharide, or LPS,
00:09:19;17 which is present in all gram-negative bacteria and which is well-known to induce a very dramatic
00:09:25;20 inflammatory response.
00:09:27;07 So, inflammation caused by gram-negative infections is in large part due to LPS.
00:09:32;24 So, if we just use LPS instead of live pathogens, then we simplify the system and
00:09:38;04 eliminate all the variations due to pathogenicity of different bacteria.
00:09:44;21 And as you can see here, we... when we give an LD50 dose of LPS, which is the line
00:09:50;22 in the middle, we have about 50% of mice that would succumb to sepsis.
00:09:56;11 Then, if we give them either a control -- PBS, phosphate... phosphate-buffered saline,
00:10:03;22 a physiological solution -- or give them food, you can see that there's a dramatic difference
00:10:08;01 in survival.
00:10:09;01 So, mice that received food, most of them would die.
00:10:13;09 And then we asked if this effect, again, is due to glucose.
00:10:16;19 And we performed, again, a similar experiment, giving either glucose or 2DG.
00:10:23;24 And as you can see, now 100% of mice that received glucose would die from LPS sepsis,
00:10:31;00 and 100% would survive if they are given 2-deoxyglucose.
00:10:34;17 So, this was very exciting because this is a very simple manipulation.
00:10:38;22 We're just using either glucose or anti-glucose.
00:10:43;01 And we have this profound, 100% effect on survival in a condition that is
00:10:51;05 otherwise intractable.
00:10:52;16 It's uhh... sepsis is a very complex disease that has a very high mortality rate,
00:11:00;11 and there are still very few treatment options for sepsis.
00:11:02;28 So, we were very excited to see that such a simple manipulation can have such a dramatic
00:11:07;18 effect on survival.
00:11:09;28 Interestingly, these effects of glucose and 2-deoxyglucose were not due to changes in
00:11:17;04 the magnitude of the inflammatory response.
00:11:20;14 So, if we measure the major inflammatory cytokines, including TNF, IL-6, or acute-phase proteins
00:11:28;13 such as serum amyloid protein, you can see that, regardless of whether it's
00:11:33;19 a control mouse or a mouse given glucose or 2DG, the level of inflammatory response was the same.
00:11:39;14 So the fact that mice given glucose died and mice given 2DG survived is not due to changes
00:11:46;02 in the inflammatory response.
00:11:48;04 So, then we asked, what is it due to?
00:11:50;28 And of course, when mice don't eat they undergo a fasting metabolic state.
00:11:57;21 And we then asked whether this fasting metabolism is the one that matters, rather than the inflammation
00:12:03;12 itself.
00:12:05;06 And just to remind you, what happens during fasting is that glucose level goes down and
00:12:12;07 therefore insulin level goes down.
00:12:14;19 And most organs switch from using glucose to switching... to using fatty acids produced...
00:12:23;15 released from adipose tissue.
00:12:25;13 And only brain continues to use glucose, initially.
00:12:28;12 So, during initial stages of fasting, free fatty acids, or FFA, would be released from
00:12:34;27 adipose tissue by a process called lipolysis, or release of fatty acids.
00:12:40;06 And then fatty acids will become main fuel for most organs.
00:12:44;02 And... while brain will continue to use glucose.
00:12:47;24 And then, if fasting is prolonged, then some fatty acids will go into liver and will
00:12:53;15 be converted into a different metabolite called... called ketones, such as beta-hydroxybutyrate,
00:12:59;04 or BHOB here.
00:13:02;06 And this fasting metabolic switch into ketogenesis -- production of ketones -- is controlled
00:13:08;18 by a nuclear receptor called PPAR-alpha, shown here.
00:13:13;06 So, what PPAR-alpha does during this prolonged fasting... it detects fatty acids that are
00:13:19;14 delivered from the adipose tissue and induces enzymes that generate ketones from fatty acids.
00:13:28;06 And the point of that is that ketones now can be used by the brain.
00:13:33;00 And the second thing that PPAR-alpha does, it controls expression of a fasting hormone
00:13:38;02 called FGF21.
00:13:39;15 So, we thought that it's... these PPAR-alpha-regulated processes that are activated during fasting
00:13:47;06 might be involved in controlling survival because when we eat, or consume food or glucose,
00:13:54;12 that would induce insulin production, and insulin will suppress all these processes.
00:13:58;20 It will suppress lipolysis and it will suppress ketogenesis.
00:14:03;00 And we thought that maybe that's why glucose kills and 2-deoxyglucose leads to...
00:14:09;09 promotes survival.
00:14:10;26 So, to test that, we first examined whether, indeed, glucose will prevent these PPAR-alpha-regulated
00:14:20;19 outcomes, such as hydroxybutyrate production and FGF21 expression.
00:14:26;06 And indeed, as you can see on the left side, this is measurement of non-esterified fatty acids,
00:14:32;28 or free fatty acids.
00:14:34;04 So, they are released during fasting.
00:14:35;19 You can see in the black line the fatty acid level in the... in the plasma go up.
00:14:42;25 And later, beta-hydroxybutyrate starts going up and the fasting hormone FGF21 is also
00:14:49;27 strongly induced.
00:14:52;04 But if we give mice glucose, then all these responses are shut down, and none of them happen.
00:14:58;21 And then we asked whether they... this is what contributes to differential survival
00:15:03;13 from feeding.
00:15:05;01 So to address that, we used mice that are deficient PPAR-alpha, where neither ketogenesis
00:15:11;23 nor FGF21 expression can be induced.
00:15:14;19 And we used, also, FGF21 knockout mice.
00:15:18;09 And as you can see in the left panel, both of these mice now succumb to sub-lethal doses
00:15:25;12 of LPS that are survived 100% by control mice.
00:15:30;13 So, that suggested both FGF21 and PPAR-alpha are necessary for survival.
00:15:36;00 And in the absence of PPAR-alpha, on the right panel you can see that there is no production
00:15:40;26 of beta-hydroxybutyrate.
00:15:45;13 But the level of inflammation in all three conditions was the same.
00:15:48;19 So, as you can see in the lower panel, the level of TNF in... in the serum in all three
00:15:55;23 mouse strains was the same.
00:15:59;26 So, what we found also is that glucose supplementation increased, and 2-deoxyglucose decreased oxidative
00:16:09;14 stress in the midbrain area during LPS sepsis.
00:16:13;28 And by performing PET scans to follow where glucose goes during sepsis, we found that,
00:16:20;12 following LPS challenge, the... this area of midbrain was the... showed the
00:16:27;22 greatest difference in glucose consumption.
00:16:29;12 So, there was increased glucose uptake into the... this particular brain area that...
00:16:34;16 where we also saw increased oxidative stress.
00:16:39;08 And so what we concluded from that is that fasting metabolism and ketogenic programs
00:16:45;14 are required for survival of LPS sepsis.
00:16:50;12 And what we noticed also is that the death from sepsis was preceded by seizures or convulsions.
00:16:57;01 And it's also well-known that ketogenic diet is used to treat epilepsy.
00:17:02;01 And all these pieces of the puzzle together led us to ask whether anti-epileptic drugs
00:17:08;04 could be protective from sepsis, which was a very far-fetched idea.
00:17:12;17 But we tested it and, to our surprise and delight, we found that, indeed, the anti-epileptic drug
00:17:20;01 valproic acid could rescue mice from lethal sepsis.
00:17:25;24 And interestingly, the second anti-epileptic drug, called Keppra, did not have such an effect.
00:17:31;06 And that is very informative for us because these two drugs have very different
00:17:34;08 mechanisms of action.
00:17:37;02 So, we then tested whether valproic acid can protect upstream or downstream of the effect
00:17:45;22 of glucose.
00:17:47;10 And what we found was that valproic acid protected against LPS sepsis even in PPAR-alpha knockout mice,
00:17:57;12 which as you remember cannot produce ketone bodies.
00:18:02;12 So... as if valproic acid substitutes to the protective effect of ketones.
00:18:08;01 But 2-deoxyglucose cannot protect PPAR-alpha knockout mice from LPS sepsis because it acts
00:18:13;04 upstream of PPAR-alpha.
00:18:15;17 So, that indicated that valproic acid has its effect very downstream in the fasting pathway,
00:18:22;22 at the same level, perhaps, as ketone bodies.
00:18:26;19 And the conclusion to this part is that during sepsis -- endotoxin sepsis, LPS sepsis --
00:18:37;05 LPS induces inflammatory cytokines, and which of these is most important here is...
00:18:41;16 is not clear, and probably several of them can lead to similar effects of increasing
00:18:47;20 generation of reactive oxygen species in the midbrain area.
00:18:51;25 And glucose promotes this effect and 2DG inhibits it.
00:18:57;08 And ketones also inhibit that effect.
00:18:59;20 And consumption of food or glucose prevents ketogenesis and therefore interferes with
00:19:07;02 the protective effect from... protection from this damage by ROS.
00:19:12;22 And during fasting, a PPAR-alpha-dependent mechanism generates ketones, which lead to
00:19:19;00 reduced ROS production and adaptation to the stress of inflammation, and survival, ultimately.
00:19:26;10 And we think one of the effects, common targets, here, could be histone deacetylase... deacetylases,
00:19:33;11 because both ketones and valproic acid are known to inhibit histone deacetylases.
00:19:38;27 And this is something we are currently testing.
00:19:41;05 So, that's the part of the study that had to do with bacterial infection and bacterial sepsis,
00:19:49;01 where we found that eating during bacterial infection or sepsis interferes with
00:19:55;02 this normal protective effect of fasting metabolism, and therefore the anorexia that we feel
00:20:01;08 when we have infections has to do with promoting these types of protective mechanisms
00:20:09;22 associated with fasting metabolism.
00:20:13;12 And then we... what we found here, therefore, is that this increased glucose level, if it
00:20:21;06 goes above some upper threshold level, can be deadly in the context of bacterial sepsis.
00:20:30;05 And another recent study examined the role of glucose in a very different model,
00:20:35;16 where they looked at the lower threshold level, where they used mice which are unable to
00:20:41;20 produce glucose from the liver.
00:20:44;19 And this was... this... and that also leads to mortality.
00:20:47;20 This was a study by Miguel Soares from Instituto Gulbenkian in Lisbon, where they found that
00:20:53;23 there is also a lower boundary for the glucose level.
00:20:58;10 So, both upper boundary and lower boundary, if they're exceeded in the glucose level,
00:21:03;06 can lead to mortality.
00:21:04;19 So, it's important to keep that in mind, that it's not an excess or depletion; it's a maintenance
00:21:12;00 of the... the right amount of glucose that is required for survival.
00:21:17;00 And this is not surprising, of course, because glucose is still essential for many cells,
00:21:21;25 especially neuronal cells, for survival.
00:21:29;01 And... well, we found this very dramatic effect of glucose and 2-deoxyglucose on
00:21:35;27 bacterial infection in sepsis.
00:21:37;06 We then asked whether this is more a general phenomenon and whether it applies to all infections.
00:21:44;16 And to address that, we used a mouse model of influenza infection, where mice are infected
00:21:52;02 with the flu virus.
00:21:54;04 And in this case, we are giving a sub-lethal dose of flu.
00:21:57;10 And then we follow, again, the food consumption.
00:21:59;26 And just like with bacterial infection, you can see that mice, when they...
00:22:03;19 at the peak of infection, they stop eating.
00:22:06;16 And then as they start recovering from infection, they... they resume food consumption.
00:22:13;02 And we asked again, what would happen if we feed them at the time when they are anorexic?
00:22:20;07 And what we found was very surprising, and opposite to what we expected and opposite
00:22:24;19 to what we found with bacterial infection.
00:22:27;14 As you can see here, if we feed the mice, they actually survive better compared to mice
00:22:32;21 that received control PBS solution.
00:22:36;26 And if we just give them glucose, they also do better.
00:22:40;01 And glucose partially protects from mortality.
00:22:42;14 And we think the... the rest of the protection is provided by sodium.
00:22:50;06 And when we ask the question, the converse question, what 2DG will do, we found that
00:22:56;05 2DG actually was lethal in the context of viral infection.
00:23:00;16 As shown here in the blue line, when mice are given 2DG in the context of viral infection,
00:23:07;04 they all died 100%.
00:23:09;22 Interestingly, this difference in survival was not due to tissue damage that was normally
00:23:16;27 caused by flu virus.
00:23:18;11 So, this is a lung pathology.
00:23:21;06 On the left side is the control and on the right side is 2DG-treated mice, and they're
00:23:26;02 basically the same.
00:23:27;10 There is no difference in the degree of tissue damage caused by the virus.
00:23:31;12 And also there is the same level of hemorrhage, edema, and inflammatory infiltrates.
00:23:37;08 So, that did not explain 100% differences in survival.
00:23:43;06 And also, there was no difference in the magnitude of the inflammatory response, as shown on
00:23:49;27 the left side by measuring interferon-alpha in the plasma.
00:23:55;02 And interestingly and importantly, there's no difference, also, in viral burden.
00:23:59;05 If we measure the amount of viruses during infection, they are similar between
00:24:04;18 control and 2DG-treated mice.
00:24:06;07 And again, 2DG-treated mice are the ones that succumb 100% to this infection.
00:24:12;22 So, what we then noticed, by performing other measurements on these mice, is that
00:24:22;07 the death from viral inflammation caused by either flu virus or some mimics of viral infection
00:24:29;22 was associated with decline in vital functions, such as heart rate, respiratory rate,
00:24:35;00 and so on.
00:24:36;00 And that suggested that there perhaps is a failure of the autonomic control centers that
00:24:40;16 reside in the brainstem.
00:24:43;08 And moreover, when we performed PET scans on these mice, again we found that
00:24:48;09 glucose was preferentially taken into the brainstem area during viral inflammation.
00:24:54;14 And remember, during bacterial inflammation it was preferentially taken into the midbrain area.
00:24:59;24 So, that was puzzling but suggested a possible scenario where viral infection somehow interfaces
00:25:08;09 with glucose metabolism, and the only type of connection that we could find in the prior literature
00:25:15;02 that would suggest the mechanism had to do with endoplasmic reticulum stress,
00:25:21;02 or ER stress.
00:25:22;02 So, ER stress is normally induced by unfolded protein response in the endoplasmic reticulum,
00:25:29;16 and it leads to adaptation to the unfolded protein accumulation through induction of
00:25:35;24 chaperones and various proteases and so on.
00:25:38;06 And that leads to resolution of the ER stress.
00:25:40;13 However, if ER stress is excessive, then the second branch of the pathway is induced by
00:25:49;04 leading to transcriptional induction of a transcription factor called CHOP that
00:25:56;15 leads to cell death through apoptosis.
00:26:00;15 And because glucose availability can also impact on protein glycosylation in the ER,
00:26:05;10 it can also lead to ER stress.
00:26:07;14 So, when cells are deprived of glucose, that can lead to ER stress.
00:26:14;21 And viral infection can also lead to ER stress.
00:26:17;15 So we thought, perhaps these two conditions may somehow conspire to trigger excessive
00:26:24;13 ER stress, leading to induction of this transcription factor, CHOP, leading to neuronal damage in
00:26:30;24 the brainstem.
00:26:33;11 And we tested whether CHOP is indeed induced under those conditions anywhere in the brain
00:26:38;08 and found that, indeed, when mice have viral inflammation -- in this case induced by
00:26:44;24 a viral mimic called poly(I:C) -- either alone or together with 2DG, and then we monitored
00:26:52;02 CHOP expression by Western blot, and we found that it was only induced in hindbrain area,
00:26:59;04 and only when mice received both poly(I:C) and 2DG.
00:27:04;17 And then we tested whether CHOP is involved in mortality caused by infection and 2DG.
00:27:12;18 And to test that, we used either wild-type or CHOP-deficient mice.
00:27:17;12 The gene name for CHOP is Ddit3, so those are Ddit3 knockout mice in open... open symbols.
00:27:25;08 And as you can see, wild type mice that received poly(I:C) and 2DG die 100%; that's the blue triangles.
00:27:32;23 And CHOP-deficient mice receiving the same combination of poly(I:C) and 2DG survive 100%,
00:27:40;10 indicating that, indeed, this particular transcription factor is a critical mediator of mortality
00:27:46;03 from viral infection combined with 2DG.
00:27:50;24 And again, as shown on the right slide, there was no difference in the inflammatory response,
00:27:55;07 as measured here by interferon-alpha in the serum.
00:27:59;12 So, the summary for this part is, during viral infection, or more generally during
00:28:05;03 viral inflammation, because we could find the same exact phenomenon with just using poly(I:C),
00:28:10;26 there is a production of type-1 interferons -- interferon alpha and beta -- and that leads
00:28:15;28 to activation of the unfolded protein response, or UPR, combined with glucose consumption
00:28:29;00 in the brainstem area.
00:28:31;27 Why it's specifically brainstem that's affected in this manner we don't know.
00:28:35;22 It's a very interesting question which we hope to understand someday.
00:28:41;13 But what happens in the context of this response with metabolites is that glucose ameliorates
00:28:48;07 this response -- it prevents induction of CHOP and neuronal dysfunction and... and death --
00:28:55;19 whereas 2DG exacerbates it and leads to CHOP induction and subsequent loss of function
00:29:03;20 of the brainstem and autonomic control centers, resulting in death.
00:29:09;06 So, these are two very different effects of metabolism on bacterial and viral inflammation.
00:29:16;26 And all of it could be tied down to utilization of glucose or block of glucose utilization.
00:29:25;09 And it's completely independent of pathogenicity.
00:29:29;04 It's independent of pathogen burden.
00:29:32;00 And it's independent on the magnitude of inflammation.
00:29:34;25 So, this is what we refer to as being able to tolerate a given level of inflammation,
00:29:41;09 rather than controlling the level of inflammation.
00:29:44;19 So, this study was done by three very talented scientists in my group -- shown from right to left,
00:29:52;17 Andrew Wang, Sarah Huen, and Harding Luan
00:29:57;09 -- and two talented technicians -- Cuiling and Shuang -- who helped with the study,
00:30:03;15 and... as well as Carmen Booth and Jean-Dominique Gallezot, who are...
00:30:08;27 helped with pathology and PET scans.
00:30:11;20 And our funding is shown at the bottom of this slide.
00:30:15;27 And thank you for your attention.

This material is based upon work supported by the National Science Foundation and the National Institute of General Medical Sciences under Grant No. 2122350 and 1 R25 GM139147. Any opinion, finding, conclusion, or recommendation expressed in these videos are solely those of the speakers and do not necessarily represent the views of the Science Communication Lab/iBiology, the National Science Foundation, the National Institutes of Health, or other Science Communication Lab funders.

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