Tag: fever

Categories : Immune SystemTags :

Fever Drives Enhanced Activity and Mitochondrial Damage in Immune Cells

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Photo by Kelly Sikkema on Unsplash

Fever temperatures accelerate immune cell metabolism, proliferation and activity, but in a particular subset of T cells, it also causes mitochondrial stress, DNA damage and cell death, Vanderbilt University Medical Center researchers have discovered. 

The findings, published in the journal Science Immunology, offer a mechanistic understanding for how cells respond to heat and could explain how chronic inflammation contributes to the development of cancer. 

The impact of fever temperatures on cells is a relatively understudied area, said Jeff Rathmell, PhD, Professor of Immunobiology and corresponding author of the new study. Most of the existing temperature-related research relates to agriculture and how extreme temperatures impact crops and livestock, he noted. It’s challenging to change the temperature of animal models without causing stress, and cells in the laboratory are generally cultured in incubators that are set at human body temperature: 37°C. 

“Standard body temperature is not actually the temperature for most inflammatory processes, but few have really gone to the trouble to see what happens when you change the temperature,” said Rathmell, who also directs the Vanderbilt Center for Immunobiology. 

Graduate student Darren Heintzman was interested in the impact of fevers for personal reasons: Before he joined the Rathmell lab, his father developed an autoimmune disease and had a constant fever for months on end. 

“I started thinking about what an increased set point temperature like that might do. It was intriguing,” Heintzman said. 

Heintzman cultured immune system T cells at 39°C. He found that heat increased helper T cell metabolism, proliferation and inflammatory effector activity and decreased regulatory T cell suppressive capacity. 

“If you think about a normal response to infection, it makes a lot of sense: You want effector (helper) T cells to be better at responding to the pathogen, and you want suppressor (regulatory) T cells to not suppress the immune response,” Heintzman said. 

But the researchers also made an unexpected discovery: that a certain subset of helper T cells, called Th1 cells, developed mitochondrial stress and DNA damage, and some of them died. The finding was confusing, the researchers said, because Th1 cells are involved in settings where there is often fever, like viral infections. Why would the cells that are needed to fight the infection die? 

The researchers discovered that only a portion of the Th1 cells die, and that the rest undergo an adaptation, change their mitochondria, and become more resistant to stress. 

“There’s a wave of stress, and some of the cells die, but the ones that adapt and survive are better – they proliferate more and make more cytokine (immune signaling molecules),” Rathmell said.

Heintzman was able to define the molecular events of the cell response to fever temperatures. He found that heat rapidly impaired electron transport chain complex 1 (ETC1), a mitochondrial protein complex that generates energy. ETC1 impairment set off signalling mechanisms that led to DNA damage and activation of the tumour suppressor protein p53, which aids DNA repair or triggers cell death to maintain genome integrity. Th1 cells were more sensitive to impaired ETC1 than other T cell subtypes.

 The researchers found Th1 cells with similar changes in sequencing databases for samples from patients with Crohn’s disease and rheumatoid arthritis, adding support to the molecular signaling pathway they defined. 

“We think this response is a fundamental way that cells can sense heat and respond to stress,” Rathmell said. “Temperature varies across tissues and changes all the time, and we don’t really know what it does. If temperature changes shift the way cells are forced to do metabolism because of ETC1, that’s going to have a big impact. This is fundamental textbook kind of stuff.” 

The findings suggest that heat can be mutagenic, when cells that respond with mitochondrial stress don’t properly repair the DNA damage or die. 

“Chronic inflammation with sustained periods of elevated tissue temperatures could explain how some cells become tumorigenic,” Heintzman said, noting that up to 25% of cancers are linked to chronic inflammation. 

“People ask me, ‘Is fever good or bad?’” Rathmell added. “The short answer is: A little bit of fever is good, but a lot of fever is bad. We already knew that, but now we have a mechanism for why it’s bad.” 

Source: Vanderbilt University Medical Center

Categories : AntibioticsTags :

Temperature may be a New Weapon in the Battle against Antibiotic Resistance

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Scientists from the University of Groningen in the Netherlands, together with colleagues from other European universities, have tested how a fever could affect the development of antimicrobial resistance. In laboratory experiments, they found that a small increase in temperature from 37 to 40 degrees Celsius drastically changed the mutation frequency in E. coli bacteria, which facilitates the development of resistance. If these results can be replicated in human patients, fever control could be a new way to mitigate the emergence of antibiotic resistance.

There are two ways to fight the threat of antimicrobial resistance: by developing new drugs, or by preventing the development of resistance. ‘We know that temperature affects the mutation rate in bacteria’, explains Timo van Eldijk, co-first author of the paper published in JAC-Antimicrobial Resistance. ‘What we wanted to find out was how the increase in temperature associated with fever influences the mutation rate towards antibiotic resistance.’

‘Most studies on resistance mutations were done by lowering the ambient temperature, and none, as far as we know, used a moderate increase above normal body temperature,’ Van Eldijk reports. Together with Master’s student Eleanor Sheridan, he cultured E. coli bacteria at 37 or 40 degrees Celsius, and subsequently exposed them to three different antibiotics to assess the effect. ‘Again, some previous human trials have looked at temperature and antibiotics, but in these studies, the type of drug was not controlled.’ In their laboratory study, the team used three different antibiotics with different modes of action: ciprofloxacin, rifampicin, and ampicillin.

The results showed that for two of the drugs, ciprofloxacin and rifampicin, increased temperature led to an increase in the mutation rate towards resistance. However, the third drug, ampicillin, caused a decrease in the mutation rate toward resistance at fever temperatures. ‘To be certain of this result, we replicated the study with ampicillin in two different labs, at the University of Groningen and the University of Montpellier, and got the same result,’ says Van Eldijk.

The researchers hypothesized that a temperature dependence of the efficacy of ampicillin could explain this result, and confirmed this in an experiment. This explains why ampicillin resistance is less likely to arise at 40 degrees Celsius. ‘Our study shows that a very mild change in temperature can drastically change the mutation rate towards resistance to antimicrobials,’ concludes Van Eldijk. ‘This is interesting, as other parameters such as the growth rate do not seem to change.’

If the results are replicated in humans, this could open the way to tackling antimicrobial resistance by lowering the temperature with fever-suppressing drugs, or by giving patients with a fever antimicrobial drugs with higher efficacy at higher temperatures. The team concludes in the paper: ‘An optimized combination of antibiotics and fever suppression strategies may be a new weapon in the battle against antibiotic resistance.’

Source: University of Groningen

Categories : Immune SystemTags :

Elevated Body Temperature Helps Gut Microbiota to Fight Viruses

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Researchers from The University of Tokyo have helped unravel the connection between high body temperature and increased viral resistance. Older adults are at a higher risk of contracting viral infections, research shows. Quite notably, they also have lower mean body temperatures – yet the effects of increased body temperature on fighting viral infections remain largely unexplored. The researchers found that higher temperature increased bile acids along with the infection-fighting capability of the gut microbiota. Their study was published in Nature Communications.

To conduct their experiments, the team used mice which were heat- or cold-exposed at 4°C, 22°C, or 36°C a week before influenza virus infection. After the viral infection was induced, the cold-exposed mice mostly died due to severe hypothermia, whereas the heat-exposed mice were highly resistant to the infection even at increasing doses of the virus. “High-heat-exposed mice raise their basal body temperature above 38°C, allowing them to produce more bile acids in a gut microbiota-dependent manner,” remarks Dr Takeshi Ichinohe from the Division of Viral Infection, The University of Tokyo, Japan.

The authors speculated that signalling of deoxycholic acid (DCA) from the gut microbiota and its plasma membrane-bound receptor “Takeda G-protein-coupled receptor 5” (TGR5) increased host resistance to influenza virus infection by suppressing virus replication and neutrophil-dependent tissue damage.

While working on these experiments, the team noticed that mice infected with the influenza virus showed decreased body temperatures nearly four days after the onset of the infection, and they snuggled together to stay warm!

The team noticed similar results after switching the influenza virus with SARS-CoV-2 and the study results were also validated using a Syrian hamster model. Their experiments revealed that body temperature over 38°C could increase host resistance to influenza virus and SARS-CoV-2 infections. Moreover, they also found that such increase in body temperature catalyzed key gut microbial reactions, which in turn, led to the production of secondary bile acids. These acids can modulate immune responses and safeguard the host against viral infections.

Dr. Ichinohe explains, “The DCA and its nuclear farnesoid X receptor (FXR) agonist protect Syrian hamsters from lethal SARS-CoV-2 infection. Moreover, certain bile acids are reduced in the plasma of COVID-19 patients who develop moderate I/II disease compared with the minor severity of illness group.”

The team then performed extensive analysis to gain insight into the precise mechanisms underlying the gut-metabolite-mediated host resistance to viral infections in heat-exposed rodents. Besides, they also established the role of secondary bile acids and bile acid receptors in mitigating viral infections.

“Our finding that reduction of certain bile acids in the plasma of patients with moderate I/II COVID-19 may provide insight into the variability in clinical disease manifestation in humans and enable approaches for mitigating COVID-19 outcomes,” concludes Dr. Ichinohe.

To briefly summarize, the published study reveals that the high-body-temperature-dependent activation of gut microbiota boosts the serum and intestinal levels of bile acids. This suppresses virus replication and inflammatory responses that follow influenza and SARS-CoV-2 infections.

A heartfelt appreciation to the Japanese researchers for placing their trust in their intuition and gut instincts!

Source: University of Tokyo

Categories : Diseases, Syndromes and Conditions Immune SystemTags :

Research Supports Letting A Moderate Fever Run its Course

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Photo by Mockup Graphics on Unsplash

It may be better to let a mild fever run its course instead of automatically reaching for medication, new University of Alberta research suggests. Researchers found that, in fish models, untreated moderate fever helped them to quickly their infections, keep inflammation in check and repair damaged tissue. “We let nature do what nature does, and in this case it was very much a positive thing,” says Professor Daniel Barreda, immunologist and lead author on the study which is published in eLife.

Moderate fever is self-resolving, meaning that the body can both induce it and shut it down naturally without medication, Barreda explains. The health advantages of natural fever to humans still have to be confirmed through research, but the researchers say because the mechanisms driving and sustaining fever are shared among animals, it is reasonable to expect similar benefits are going to happen in humans.

That suggests the need to resist taking non-steroidal anti-inflammatory drugs at the first signs of a mild temperature, he says. “They take away the discomfort felt with fever, but you’re also likely giving away some of the benefits of this natural response.”

The study also sheds light on some benefits of moderate fever, which Barreda notes has been evolutionarily conserved across the animal kingdom for 550 million years. “Every animal examined has this biological response to infection.”

For the study, fish were given a bacterial infection and their behaviour was then tracked and evaluated using machine learning. Outward symptoms were similar to those seen in humans with fever, including immobility, fatigue and malaise. These were then matched to important immune mechanisms inside the animals.

The research showed that natural fever offers an integrative response that not only activates defences against infection, but also helps control it. The researchers found that fever helped to clear the fish of infection in about seven days – half the time it took for those animals not allowed to exert fever. Fever also helped to shut down inflammation and repair injured tissue.

“Our goal is to determine how to best take advantage of our medical advances while continuing to harness the benefits from natural mechanisms of immunity,” says Barreda.

Source: University of Alberta