Bacteria-fighting cells in airways may boost infection risk

Bacteria-fighting cells in airways may boost infection risk

  • October 20, 2020

Having more bacteria-fighting immune cells in the nose and throat may explain why some people are more likely to be infected by respiratory viruses.

In a study, led by a team from Imperial College London and published in Science, researchers found that volunteers who succumbed to infection from respiratory syncytial virus (RSV) had more specialised white blood cells called neutrophils in their airways before exposure to the virus, compared to those who staved off infection. 

According to the researchers, this type of neutrophil-driven inflammation in the nose and throat – typically associated with fighting off bacterial infections – may compromise our ability to fight off invading viruses and make us more susceptible to viral infections. 

The findings could help researchers to understand why people respond differently to the same viral threat, predict who is more at risk of infection, and even lead to preventative treatments to protect against RSV and potentially other respiratory viruses, including influenza and coronaviruses. 

Dr Ryan Thwaites, from the National Heart and Lung Institute at Imperial and study author, said: “If we think of a group of 10 people all exposed to the same strain of RSV under identical conditions, we’d expect around six of them to become infected and show symptoms, but the rest may be unaffected.  

“To date, we have been unable to fully explain exactly why this is and why, under the same conditions, some people are more likely to succumb to respiratory viral infections. But this study offers tantalising insights into how we might improve defences against respiratory viruses, and potentially even COVID-19.”  

RSV is a common respiratory virus which typically causes the symptoms of a common cold in healthy adults. But for infants and the elderly it can lead to thousands of hospitalisations each year and can be fatal.  

Unlike other respiratory viruses, such as influenza or rhinovirus, people can be infected by the same strain of RSV more than once. People can also react differently when exposed to the virus under the same conditions – some may get a mild infection while others get full-blown symptoms, and some may avoid infection altogether.  

In the latest study, the team aimed to investigate the underlying mechanisms of why people succumb to RSV infection and the factors for the varied immune responses.  

Healthy adults* were enrolled to the study and exposed to RSV in a safe, controlled clinical setting where they were closely monitored. After receiving nasal drops containing the virus, 57% of volunteers became infected. Analysis of blood samples showed that the presence of protective antibodies and B and T cells could only partially explain who became infected. 

However, when they analysed samples from participants’ airways taken before they were exposed to the virus, the team found evidence of neutrophil activation in the nasal mucosa – the cells lining the inside of the nose – in those who became infected with the virus. These immune cells are known to release proteins which help create an antibacterial environment in response to a threat. But the researchers believe this antibacterial immune response may come at a cost, making a host more susceptible to viruses by effectively switching off the early warning system, letting them slip through the net to cause infection. 

Professor Peter Openshaw, Professor of Experimental Medicine at Imperial and co-senior author on the study, said: “The variable transmission we see with respiratory viruses partly depends on the dose and duration of exposure, but also the person’s own inbuilt immune defences. You might assume that it’s down to the presence of specific protective antibodies, but despite an immense effort over many years we have never really understood what makes one person vulnerable to RSV and another person resistant.  

“Our finding that the state of the mucous membrane before the arrival of the virus is the major deciding factor is a real breakthrough. It seems as if the presence of activated neutrophils in the lining of the airways causes the mucous lining to fail to respond to the virus and to nip infection in the bud. Perhaps what’s happening is that being ready to fight bacteria makes it more likely that viruses can gain a foothold. 

“Once the virus does get in, our studies go on to show that there still is a chance that the infection will be terminated but only if the mucosa mounts an early defensive response. People who went on to get colds showed no evidence of an initial response; those who rejected the infection showed an immediate response before symptoms developed.  

“These are the sort of findings that can only come from experimental studies in volunteers. We could never have discovered this by waiting for people with natural infections to present to us for investigation.” 

Dr Christopher Chiu, Clinical Reader in Infectious Diseases at Imperial and co-senior author, said: “Our data highlight the complexity of the immune system, which has different arms providing layers of protection separated by anatomical location (such as the nose, lung or circulation) and timing. These different mechanisms may be directed to focus on a particular type of infection but this may come at the cost of protection against other pathogens.  

“Controlled human infection challenge studies have a unique ability to tease out these complicated interactions and point out potential targets for prevention or treatment that cannot be seen in patients who have infections caused by diverse virus strains, in different amounts, on top of a wide range of other conditions that might affect their immunity.” 

To confirm the idea, they used animal models to test the impact of the neutrophilic pathway on RSV infection. In mice without neutrophilic inflammation, the immune system recognised the virus as a threat, releasing immune-mediating factors which cleared the infection with few symptoms. 

However, in mice with a nasal mucosa rich in neutrophils this early detection of the virus was dampened. Under these antibacterial conditions, the virus was better able to invade the mucosal cells causing infection, worsened symptoms and shedding of the virus – to further transmit the virus. 

The researchers say that if they can demonstrate the same mechanism is occurring in patient groups who are most at risk from RSV (babies under 12 months of age and adults over 65 with chronic conditions, such as COPD or asthma) it could help to identify subsets of patients most at risk. The team is set to explore the mechanism in larger patient groups as well as investigating whether the same immune mechanisms influence other viral respiratory infections, from influenza and coronaviruses.  

Dr Thwaites added: “Our initial studies show that in healthy people, neutrophilic inflammation in the airways is linked to RSV infection. If we can show this same mechanism is at play in those most at risk from the virus, it could provide opportunities to reduce the harms caused by RSV and other respiratory viruses. 

“Severe bacterial respiratory infections tend to be quite rare in healthy adults so, in theory, it may be more beneficial to nudge the immune response towards fighting viruses during seasonal winter peaks.  

“It might be possible to design therapies to temporarily inhibit some aspect of neutrophilic inflammation, such as through a simple nasal spray, to enhance protection against circulating viruses. This could be used in high risk settings, like hospitals, to enhance protection against respiratory viruses, prevent their spread and reduce the impacts of infection on vulnerable groups.”

The research was supported by funding from the Wellcome Trust and the Medical Research Council and the Imperial NIHR Biomedical Research Centre.  

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Cancer-Killing T Cells “Swarm” Tumors Attracting Other Cells To Fight

Cancer-Killing T Cells “Swarm” Tumors Attracting Other Cells To Fight

  • October 15, 2020

When immune system T cells find and recognise a target, they release chemicals to attract more T cells which then swarm to help subdue the threat, shows a new study published today in eLife.

The discovery of this swarming behaviour, and the chemical attractants that immune cells use to direct swarms towards tumours, could one day help scientists develop new cancer therapies that boost the immune system. This is particularly important for solid tumours, which so far have been less responsive to current immunotherapies than cancers affecting blood cells.

“Scientists have previously thought that cancer-killing T cells identified tumours by randomly searching for them or by following the chemical trails laid by other intermediary immune cells,” says lead author Jorge Luis Galeano Niño, a PhD graduate at UNSW Sydney. “We wanted to investigate this further to see if it’s true, or whether T cells locate tumours via another mechanism.”

Using 3D tumour models grown in the laboratory and in mouse models, the team showed that cancer-killing T cells can home-in on tumour cells independently of intermediary immune cells. When the T cells find and recognise a tumour, they release chemical signals, which then attract more T cells that sense the signals through a receptor called CCR5, and cause a swarm. “These cells coordinate their migration in a process reminiscent of the swarming observed in some insects and another type of immune cell called neutrophils, which help the body respond to injury and pathogens,” Galeano Niño says.

After confirming their results using computer modelling, the team genetically engineered human cells called chimeric antigen receptor (CAR)-T cells and showed they also swarm toward a 3D glioblastoma tumour grown in the laboratory.

CAR-T cells are currently being used to treat certain types of blood cancer. But the new findings suggest that it might also be possible to train these cells to attack solid tumours.

“Although this is fundamental research and at an early stage, the swarming mechanism could be exploited in the future to target CAR-T cells to solid tumours, potentially leading to enhanced immunotherapies that are more effective at infiltrating and destroying these types of tumours,” says senior author Maté Biro, EMBL Australia Group Leader at the Single Molecule Science node, UNSW.

“It will also be important to determine whether silencing the swarming mechanism could be beneficial in dampening overzealous T-cell responses following transplant surgery, in autoimmune conditions, or associated with viral infections,” he adds.

Reference: Niño JLG, Pageon SV, Tay SS, et al. Cytotoxic T Cells swarm by homotypic chemokine signalling. eLife. 2020.doi: 10.7554/eLife.56554

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.


Cancer-killing T cells ‘swarm’ to tumours

Cancer-killing T cells ‘swarm’ to tumours

  • October 15, 2020

When immune system T cells find and recognise a target, they release chemicals to attract more T cells which then swarm to help subdue the threat, according to a new study.

The discovery of this swarming behaviour, and the chemical attractants that immune cells use to direct swarms towards tumours, could one day help scientists develop new cancer therapies that boost the immune system, the researchers suggest.

This is particularly important for solid tumours, which so far have been less responsive to current immunotherapies than cancers affecting blood cells.

“Scientists have previously thought that cancer-killing T cells identified tumours by randomly searching for them or by following the chemical trails laid by other intermediary immune cells,” says lead author Jorge Luis Galeano Niño, from Australia’s UNSW Sydney.

The research carried out in primary mouse and human cells and in animal models found otherwise. The findings are described in a paper in the journal eLife.

Using 3D tumour models grown in the laboratory and in mouse models, the team of Australian and Canadian researchers showed that cancer-killing T cells can home-in on tumour cells independently of intermediary immune cells.

When the T cells find and recognise a tumour, they release chemical signals, which other T cells sense through a receptor called CCR5.

“These cells coordinate their migration in a process reminiscent of the swarming observed in some insects and another type of immune cell called neutrophils, which help the body respond to injury and pathogens,” Galeano Niño says.

After confirming their results using computer modelling, the team genetically engineered human cells called chimeric antigen receptor (CAR)-T cells and showed they also swarm toward a 3D glioblastoma tumour grown in the laboratory.

CAR-T cells are currently being used to treat certain types of blood cancer. The new findings suggest that it might also be possible to train them to attack solid tumours.

“Although this is fundamental research and at an early stage, the swarming mechanism could be exploited in the future to target CAR-T cells to solid tumours, potentially leading to enhanced immunotherapies that are more effective at infiltrating and destroying these types of tumours,” says senior author Maté Biro.

“It will also be important to determine whether silencing the swarming mechanism could be beneficial in dampening overzealous T-cell responses following transplant surgery, in autoimmune conditions, or associated with viral infections.”

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Combination therapy boosts the immune system's appetite for cancer

Cancer-killing T cells release chemicals to direct swarms towards tumors

  • October 14, 2020

When immune system T cells find and recognize a target, they release chemicals to attract more T cells which then swarm to help subdue the threat, shows a new study published today in eLife.

The discovery of this swarming behavior, and the chemical attractants that immune cells use to direct swarms towards tumors, could one day help scientists develop new cancer therapies that boost the immune system. This is particularly important for solid tumors, which so far have been less responsive to current immunotherapies than cancers affecting blood cells.

Scientists have previously thought that cancer-killing T cells identified tumors by randomly searching for them or by following the chemical trails laid by other intermediary immune cells. We wanted to investigate this further to see if it’s true, or whether T cells locate tumours via another mechanism.”


Jorge Luis Galeano Niño, lead author, PhD graduate at UNSW Sydney

Using 3D tumor models grown in the laboratory and in mouse models, the team showed that cancer-killing T cells can home-in on tumor cells independently of intermediary immune cells. When the T cells find and recognise a tumor, they release chemical signals, which then attract more T cells that sense the signals through a receptor called CCR5, and cause a swarm. “These cells coordinate their migration in a process reminiscent of the swarming observed in some insects and another type of immune cell called neutrophils, which help the body respond to injury and pathogens,” Galeano Niño says.

After confirming their results using computer modelling, the team genetically engineered human cells called chimeric antigen receptor (CAR)-T cells and showed they also swarm toward a 3D glioblastoma tumor grown in the laboratory.

CAR-T cells are currently being used to treat certain types of blood cancer. But the new findings suggest that it might also be possible to train these cells to attack solid tumors.

“Although this is fundamental research and at an early stage, the swarming mechanism could be exploited in the future to target CAR-T cells to solid tumors, potentially leading to enhanced immunotherapies that are more effective at infiltrating and destroying these types of tumors,” says senior author Maté Biro, EMBL Australia Group Leader at the Single Molecule Science node, UNSW.

“It will also be important to determine whether silencing the swarming mechanism could be beneficial in dampening overzealous T-cell responses following transplant surgery, in autoimmune conditions, or associated with viral infections,” he adds.

Source:

Journal reference:

Galeano Niño, J.L., et al. (2020) Cytotoxic T Cells swarm by homotypic chemokine signalling. eLife. doi.org/10.7554/eLife.56554.

Children's immune response more effective against COVID-19 -- ScienceDaily

Immune T cells swarm to tumours by following a chemical gradient left by other cancer-killing T cells — ScienceDaily

  • October 13, 2020

When immune system T cells find and recognise a target, they release chemicals to attract more T cells which then swarm to help subdue the threat, shows a new study published today in eLife.

The discovery of this swarming behaviour, and the chemical attractants that immune cells use to direct swarms towards tumours, could one day help scientists develop new cancer therapies that boost the immune system. This is particularly important for solid tumours, which so far have been less responsive to current immunotherapies than cancers affecting blood cells.

“Scientists have previously thought that cancer-killing T cells identified tumours by randomly searching for them or by following the chemical trails laid by other intermediary immune cells,” says lead author Jorge Luis Galeano Niño, a PhD graduate at UNSW Sydney. “We wanted to investigate this further to see if it’s true, or whether T cells locate tumours via another mechanism.”

Using 3D tumour models grown in the laboratory and in mouse models, the team showed that cancer-killing T cells can home-in on tumour cells independently of intermediary immune cells. When the T cells find and recognise a tumour, they release chemical signals, which then attract more T cells that sense the signals through a receptor called CCR5, and cause a swarm. “These cells coordinate their migration in a process reminiscent of the swarming observed in some insects and another type of immune cell called neutrophils, which help the body respond to injury and pathogens,” Galeano Niño says.

After confirming their results using computer modelling, the team genetically engineered human cells called chimeric antigen receptor (CAR)-T cells and showed they also swarm toward a 3D glioblastoma tumour grown in the laboratory.

CAR-T cells are currently being used to treat certain types of blood cancer. But the new findings suggest that it might also be possible to train these cells to attack solid tumours.

“Although this is fundamental research and at an early stage, the swarming mechanism could be exploited in the future to target CAR-T cells to solid tumours, potentially leading to enhanced immunotherapies that are more effective at infiltrating and destroying these types of tumours,” says senior author Maté Biro, EMBL Australia Group Leader at the Single Molecule Science node, UNSW.

“It will also be important to determine whether silencing the swarming mechanism could be beneficial in dampening overzealous T-cell responses following transplant surgery, in autoimmune conditions, or associated with viral infections,” he adds.

Story Source:

Materials provided by eLife. Note: Content may be edited for style and length.

New therapy extends breast cancer survival rate, prevents reoccurrence

Cancer-killing T cells ‘swarm’ to tumors, attracting others to the fight

  • October 13, 2020

When immune system T cells find and recognise a target, they release chemicals to attract more T cells which then swarm to help subdue the threat, shows a new study published today in eLife.

The discovery of this swarming behaviour, and the chemical attractants that immune cells use to direct swarms towards tumours, could one day help scientists develop new cancer therapies that boost the immune system. This is particularly important for solid tumours, which so far have been less responsive to current immunotherapies than cancers affecting blood cells.

“Scientists have previously thought that cancer-killing T cells identified tumours by randomly searching for them or by following the chemical trails laid by other intermediary immune cells,” says lead author Jorge Luis Galeano Niño, a PhD graduate at UNSW Sydney. “We wanted to investigate this further to see if it’s true, or whether T cells locate tumours via another mechanism.”

Using 3D tumour models grown in the laboratory and in mouse models, the team showed that cancer-killing T cells can home-in on tumour cells independently of intermediary immune cells. When the T cells find and recognise a tumour, they release chemical signals, which then attract more T cells that sense the signals through a receptor called CCR5, and cause a swarm. “These cells coordinate their migration in a process reminiscent of the swarming observed in some insects and another type of immune cell called neutrophils, which help the body respond to injury and pathogens,” Galeano Niño says.

After confirming their results using computer modelling, the team genetically engineered human cells called chimeric antigen receptor (CAR)-T cells and showed they also swarm toward a 3D glioblastoma tumour grown in the laboratory.

CAR-T cells are currently being used to treat certain types of blood cancer. But the new findings suggest that it might also be possible to train these cells to attack solid tumours.

“Although this is fundamental research and at an early stage, the swarming mechanism could be exploited in the future to target CAR-T cells to solid tumours, potentially leading to enhanced immunotherapies that are more effective at infiltrating and destroying these types of tumours,” says senior author Maté Biro, EMBL Australia Group Leader at the Single Molecule Science node, UNSW.

“It will also be important to determine whether silencing the swarming mechanism could be beneficial in dampening overzealous T-cell responses following transplant surgery, in autoimmune conditions, or associated with viral infections,” he adds.

###

Reference


The paper ‘Cytotoxic T cells swarm by homotypic chemokine signalling’ can be freely accessed online at https://doi.org/10.7554/eLife.56554. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

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Therapy using immune system cells preserves vision in mice implanted with rare eye cancer

Therapy using immune system cells preserves vision in mice implanted with rare eye cancer

  • October 12, 2020
Therapy using immune system cells preserves vision in mice implanted with rare eye cancer
Barbara Savoldo, MD, PhD, and colleagues at the University of North Carolina Lineberger Comprehensive Cancer Center report that a treatment that uses immune system T cells, combined with an immune-boosting drug packaged in an injectable gel, preserved the vision of mice implanted with retinoblastoma tissue. The cancer, which is most commonly diagnosed in infants and young children, is treatable in early stages but can still lead to the loss of vision in about 5% of cases. Credit: UNC Lineberger

A treatment that uses immune system T cells, combined with an immune-boosting drug packaged in an injectable gel, was found to preserve the vision of mice implanted with tissue from a human eye cancer known as retinoblastoma. The cancer is treatable in early stages but can still lead to the loss of vision in about 5% of cases.

The research findings from scientists at the University of North Carolina Lineberger Comprehensive Cancer Center were published is Nature Cancer on Oct. 12, 2020.

Retinoblastoma is primarily diagnosed in infants and young children. It is considered rare, with approximately 200-300 children diagnosed with the each year in the U.S. Current treatments for retinoblastoma use cold, heat, chemotherapy, lasers or radiation but vision loss still occurs, so the UNC researchers wanted to search for methods that could preserve vision.

“Based on our mouse study and the existence of an active cell immunotherapy program at UNC Lineberger, along with infrastructure for generation of CAR-Ts for clinical use, we feel confident that our efforts could be translated into a phase I in people,” said Zongchao Han, MD, Ph.D., an associate professor in the UNC School of Medicine and UNC Eshelman School of Pharmacy and a UNC Lineberger member.

The researchers used an incremental process to determine the best method for treatment of retinoblastoma. First, the researchers turned to chimeric antigen receptor-T (CAR-T) cell therapy, a type of immunotherapy where T cells that comprise the are modified in the laboratory to express chimeric antigen receptors, CARs, that target surface proteins on cancer cells. In a lab test, they found that a molecule, GD2, is expressed in retinoblastoma but the possibility to target this molecule to safely eliminate the in the eye was unknown.

Next, to test the safety and benefit of targeting GD2, the investigators injected the CAR-T that recognizes this molecule into the retina of mice implanted with retinoblastoma cancer cells and found the therapy delayed tumor development but did not eradicate the tumor. Then they combined the CAR-Ts with interleukin (IL)-15, a protein that can boost immune response, and found that 60% of mice were tumor-free for up to 70 days.

Finally, they injected a water-based gel containing the CAR-Ts and IL-15 into the retinas of the mice. The CAR-Ts and IL-15 retained an extended ability to attack the cancer , control tumor growth and prevent tumor recurrence. They corroborated the lack of tumor growth with several imaging exams of the retina.

This gel-encapsulated therapy is currently being tested in clinical trials in children with neuroblastoma, an embryonal tumor that can progress rapidly and has some of the same genetic characteristics of retinoblastoma.

“We are always looking to improve the lives of children at Lineberger,” said Barbara Savoldo, MD, PHD, professor of pediatric Hematology/Oncology at UNC School of Medicine and UNC Lineberger member. “Therefore, we hope to look at the safety of gel injection in a clinical trial of in children, and if that proves safe, we could move on to see if our methodology can reduce or eliminate these tumors.”


Genetically modified virus shown able to kill tumors in mice with retinoblastoma


More information:
GD2-specific CAR T cells encapsulated in an injectable hydrogel control retinoblastoma and preserve vision, Nature Cancer (2020). DOI: 10.1038/s43018-020-00119-y

Citation:
Therapy using immune system cells preserves vision in mice implanted with rare eye cancer (2020, October 12)
retrieved 12 October 2020
from https://medicalxpress.com/news/2020-10-therapy-immune-cells-vision-mice.html

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A woman with a cold

Bacteria-fighting cells in the airways boost infection risk from viruses | Imperial News

  • October 10, 2020
A woman with a cold




Having more bacteria-fighting immune cells in the nose and throat may explain why some people are more likely to be infected by respiratory viruses.

In a study, led by a team from Imperial College London and published today in Science, researchers found that volunteers who succumbed to infection from respiratory syncytial virus (RSV) had more specialised white blood cells called neutrophils in their airways before exposure to the virus, compared to those who staved off infection.

According to the researchers, this type of neutrophil-driven inflammation in the nose and throat – typically associated with fighting off bacterial infections – may compromise our ability to fight off invading viruses and make us more susceptible to viral infections.

The findings could help researchers to understand why people respond differently to the same viral threat, predict who is more at risk of infection, and even lead to preventative treatments to protect against RSV and potentially other respiratory viruses, including influenza and coronaviruses.

Same virus, different response

Dr Ryan Thwaites, from the National Heart and Lung Institute at Imperial and study author, said: “If we think of a group of 10 people all exposed to the same strain of RSV under identical conditions, we’d expect around six of them to become infected and show symptoms, but the rest may be unaffected.

“To date, we have been unable to fully explain exactly why this is and why, under the same conditions, some people are more likely to succumb to respiratory viral infections. But this study offers tantalising insights into how we might improve defences against respiratory viruses, and potentially even COVID-19.”

RSV is a common respiratory virus which typically causes the symptoms of a common cold in healthy adults. But for infants and the elderly it can lead to thousands of hospitalisations each year and can be fatal.

This study offers tantalising insights into how we might improve defences against respiratory viruses, and potentially even COVID-19. Dr Ryan Thwaites NHLI, Imperial College London

Unlike other respiratory viruses, such as influenza or rhinovirus, people can be infected by the same strain of RSV more than once. People can also react differently when exposed to the virus under the same conditions – some may get a mild infection while others get full-blown symptoms, and some may avoid infection altogether.

In the latest study, the team aimed to investigate the underlying mechanisms of why people succumb to RSV infection and the factors for the varied immune responses.

Healthy adults* were enrolled to the study and exposed to RSV in a safe, controlled clinical setting where they were closely monitored. After receiving nasal drops containing the virus, 57% of volunteers became infected. Analysis of blood samples showed that the presence of protective antibodies and B and T cells could only partially explain who became infected.

Slipping through the net

However, when they analysed samples from participants’ airways taken before they were exposed to the virus, the team found evidence of neutrophil activation in the nasal mucosa – the cells lining the inside of the nose – in those who became infected with the virus.

These immune cells are known to release proteins which help create an antibacterial environment in response to a threat. But the researchers believe this antibacterial immune response may come at a cost, making a host more susceptible to viruses by effectively switching off the early warning system, letting them slip through the net to cause infection.

Our finding that the state of the mucous membrane before the arrival of the virus is the major deciding factor is a real breakthrough Professor Peter Openshaw NHLI, Imperial College London

Professor Peter Openshaw, Professor of Experimental Medicine at Imperial and co-senior author on the study, said: “The variable transmission we see with respiratory viruses partly depends on the dose and duration of exposure, but also the person’s own inbuilt immune defences.

“You might assume that it’s down to the presence of specific protective antibodies, but despite an immense effort over many years we have never really understood what makes one person vulnerable to RSV and another person resistant.

“Our finding that the state of the mucous membrane before the arrival of the virus is the major deciding factor is a real breakthrough. It seems as if the presence of activated neutrophils in the lining of the airways causes the mucous lining to fail to respond to the virus and to nip infection in the bud. Perhaps what’s happening is that being ready to fight bacteria makes it more likely that viruses can gain a foothold

“Once the virus does get in, our studies go on to show that there still is a chance that the infection will be terminated but only if the mucosa mounts an early defensive response. People who went on to get colds showed no evidence of an initial response; those who rejected the infection showed an immediate response before symptoms developed.

“These are the sort of findings that can only come from experimental studies in volunteers. We could never have discovered this by waiting for people with natural infections to present to us for investigation.”

Human challenge studies

Dr Christopher Chiu, Clinical Reader in Infectious Diseases at Imperial and co-senior author, said: “Our data highlight the complexity of the immune system, which has different arms providing layers of protection separated by anatomical location (such as the nose, lung or circulation) and timing. These different mechanisms may be directed to focus on a particular type of infection but this may come at the cost of protection against other pathogens.

“Controlled human infection challenge studies have a unique ability to tease out these complicated interactions and point out potential targets for prevention or treatment that cannot be seen in patients who have infections caused by diverse virus strains, in different amounts, on top of a wide range of other conditions that might affect their immunity.”

Neutrophil on a blood smear
Activated neutrophils are typically associated with fighting off bacterial infections. But their presence in the airways may make us more susceptible to viral infections. (Image: Flickr / Magdalena Wiklund)

To confirm the idea, they used animal models to test the impact of the neutrophilic pathway on RSV infection. In mice without neutrophilic inflammation, the immune system recognised the virus as a threat, releasing immune-mediating factors which cleared the infection with few symptoms.

However, in mice with a nasal mucosa rich in neutrophils this early detection of the virus was dampened. Under these antibacterial conditions, the virus was better able to invade the mucosal cells causing infection, worsened symptoms and shedding of the virus – to further transmit the virus.

The researchers say that if they can demonstrate the same mechanism is occurring in patient groups who are most at risk from RSV (babies under 12 months of age and adults over 65 with chronic conditions, such as COPD or asthma) it could help to identify subsets of patients most at risk.

Extending to other viruses

The team is set to explore the mechanism in larger patient groups as well as investigating whether the same immune mechanisms influence other viral respiratory infections, from influenza and coronaviruses.

Dr Thwaites added: “Our initial studies show that in healthy people, neutrophilic inflammation in the airways is linked to RSV infection. If we can show this same mechanism is at play in those most at risk from the virus, it could provide opportunities to reduce the harms caused by RSV and other respiratory viruses.

“Severe bacterial respiratory infections tend to be quite rare in healthy adults so, in theory, it may be more beneficial to nudge the immune response towards fighting viruses during seasonal winter peaks.

“It might be possible to design therapies to temporarily inhibit some aspect of neutrophilic inflammation, such as through a simple nasal spray, to enhance protection against circulating viruses. This could be used in high risk settings, like hospitals, to enhance protection against respiratory viruses, prevent their spread and reduce the impacts of infection on vulnerable groups.”

Dr Cecilia Johansson, from Imperial’s NHLI and study author, added: “Understanding the underlying mechanisms of susceptibility and protection against respiratory viruses is key for the development of treatments and therapies. By studying RSV infection in both human volunteer and in mice we are now one step closer in determining the delicate balance of resistance to virus infections and the lung disease these viruses can cause”

The research was supported by funding from the Wellcome Trust and the Medical Research Council and the NIHR Imperial Biomedical Research Centre. 

– 

Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection’ by Maximillian S. Habibi et al. is published in Science. DOI:10.1126/science.aba9301

Hippocratic Post

Bacteria-fighting cells may boost infection risk from respiratory viruses

  • October 10, 2020

Having more bacteria-fighting immune cells in the nose and throat may explain why some people are more likely to be infected by respiratory viruses.

In a study, led by a team from Imperial College London and published today in Science, researchers found that volunteers who succumbed to infection from respiratory syncytial virus (RSV) had more specialised
white blood cells called neutrophils in their airways before exposure to the virus, compared to those who staved off infection.

According to the researchers, this type of neutrophil-driven inflammation in the nose and throat – typically associated with fighting off bacterial infections – may compromise our ability to fight off
invading viruses and make us more susceptible to viral infections.

The findings could help researchers to understand why people respond differently to the same viral threat, predict who is more at risk of infection, and even lead to preventative treatments to protect against
RSV and potentially other respiratory viruses, including influenza and coronaviruses.

Dr Ryan Thwaites, from the National Heart and Lung Institute at Imperial and study author, said: “If we think of a group of 10 people all exposed to the same strain of RSV under identical conditions, we’d expect around six of them to become infected and show symptoms, but the rest may be unaffected.

“To date, we have been unable to fully explain exactly why this is and why, under the same conditions, some people are more likely to succumb to respiratory viral infections. But this study offers tantalising
insights into how we might improve defences against respiratory viruses, and potentially even COVID-19.”

RSV is a common respiratory virus which typically causes the symptoms of a common cold in healthy adults. But for infants and the elderly it can lead to thousands of hospitalisations each year and can be fatal.

Unlike other respiratory viruses, such as influenza or rhinovirus, people can be infected by the same strain of RSV more than once. People can also react differently when exposed to the virus under the same
conditions – some may get a mild infection while others get full-blown symptoms, and some may avoid infection altogether.

In the latest study, the team aimed to investigate the underlying mechanisms of why people succumb to RSV infection and the factors for the varied immune responses.

Healthy adults* were enrolled to the study and exposed to RSV in a safe, controlled clinical setting where they were closely monitored. After receiving nasal drops containing the virus, 57% of volunteers became
infected. Analysis of blood samples showed that the presence of protective antibodies and B and T cells could only partially explain who became infected.

However, when they analysed samples from participants’ airways taken before they were exposed to the virus, the team found evidence of neutrophil activation in the nasal mucosa – the cells lining the inside
of the nose – in those who became infected with the virus. These immune cells are known to release proteins which help create an antibacterial environment in response to a threat. But the researchers believe this antibacterial immune response may come at a cost, making a host more susceptible to viruses by effectively switching off the early warning system, letting them slip through the net to cause infection.

Professor Peter Openshaw, Professor of Experimental Medicine at Imperial and co-senior author on the study, said: “The variable transmission we see with respiratory viruses partly depends on the dose and duration of exposure, but also the person’s own inbuilt immune defences. You might assume that it’s down to the presence of specific protective antibodies, but despite an immense effort over many years we have never really understood what makes one person vulnerable to RSV and another person resistant.

“Our finding that the state of the mucous membrane before the arrival of the virus is the major deciding factor is a real breakthrough. It seems as if the presence of activated neutrophils in the lining of the airways causes the mucous lining to fail to respond to the virus and to nip infection in the bud. Perhaps what’s happening is that being ready to fight bacteria makes it more likely that viruses can gain a foothold.

“Once the virus does get in, our studies go on to show that there still is a chance that the infection will be terminated but only if the mucosa mounts an early defensive response. People who went on to get colds
showed no evidence of an initial response; those who rejected the infection showed an immediate response before symptoms developed.

“These are the sort of findings that can only come from experimental studies in volunteers. We could never have discovered this by waiting for people with natural infections to present to us for investigation.”

Dr Christopher Chiu, Clinical Reader in Infectious Diseases at Imperial and co-senior author, said: “Our data highlight the complexity of the immune system, which has different arms providing layers of protection separated by anatomical location (such as the nose, lung or circulation) and timing. These different mechanisms may be directed to focus on a particular type of infection but this may come at the cost of protection against other pathogens.

“Controlled human infection challenge studies have a unique ability to tease out these complicated interactions and point out potential targets for prevention or treatment that cannot be seen in patients who have infections caused by diverse virus strains, in different amounts, on top of a wide range of other conditions that might affect their immunity.”

To confirm the idea, they used animal models to test the impact of the neutrophilic pathway on RSV infection. In mice without neutrophilic inflammation, the immune system recognised the virus as a threat,
releasing immune-mediating factors which cleared the infection with few symptoms.

However, in mice with a nasal mucosa rich in neutrophils this early detection of the virus was dampened. Under these antibacterial conditions, the virus was better able to invade the mucosal cells causing infection, worsened symptoms and shedding of the virus – to further transmit the virus.

The researchers say that if they can demonstrate the same mechanism is occurring in patient groups who are most at risk from RSV (babies under 12 months of age and adults over 65 with chronic conditions, such as COPD or asthma) it could help to identify subsets of patients most at risk. The team is set to explore the mechanism in larger patient groups as well as investigating whether the same immune mechanisms influence other viral respiratory infections, from influenza and coronaviruses.

Dr Thwaites added: “Our initial studies show that in healthy people, neutrophilic inflammation in the airways is linked to RSV infection. If we can show this same mechanism is at play in those most at risk from the virus, it could provide opportunities to reduce the harms caused by RSV and other respiratory viruses.

“Severe bacterial respiratory infections tend to be quite rare in healthy adults so, in theory, it may be more beneficial to nudge the immune response towards fighting viruses during seasonal winter peaks.

“It might be possible to design therapies to temporarily inhibit some aspect of neutrophilic inflammation, such as through a simple nasal spray, to enhance protection against circulating viruses. This could be
used in high risk settings, like hospitals, to enhance protection against respiratory viruses, prevent their spread and reduce the impacts of infection on vulnerable groups.”

The research was supported by funding from the Wellcome Trust and the Medical Research Council and the Imperial NIHR Biomedical Research Centre.

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Bacteria-fighting cells in the airways boosts infection risk from viruses

Bacteria-fighting cells in the airways boosts infection risk from viruses

  • October 9, 2020
RSV (respiratory syncytial virus)
Transmission electron micrograph of RSV. Credit: CDC/ Dr. Erskine Palmer / Public Domain

Having more bacteria-fighting immune cells in the nose and throat may explain why some people are more likely to be infected by respiratory viruses.

In a study, led by a team from Imperial College London and published today in Science, researchers found that volunteers who succumbed to from (RSV) had more specialized called neutrophils in their airways before exposure to the virus, compared to those who staved off infection.

According to the researchers, this type of neutrophil-driven inflammation in the nose and throat—typically associated with fighting off bacterial infections—may compromise our ability to fight off invading viruses and make us more susceptible to viral infections.

The findings could help researchers to understand why people respond differently to the same viral threat, predict who is more at risk of infection, and even lead to preventative treatments to protect against RSV and potentially other respiratory viruses, including influenza and coronaviruses.

Same virus, different response

Dr. Ryan Thwaites, from the National Heart and Lung Institute at Imperial and study author, said: “If we think of a group of 10 people all exposed to the same strain of RSV under identical conditions, we’d expect around six of them to become infected and show symptoms, but the rest may be unaffected. To date, we have been unable to fully explain exactly why this is and why, under the same conditions, some people are more likely to succumb to respiratory . But this study offers tantalizing insights into how we might improve defenses against respiratory viruses, and potentially even COVID-19.”

RSV is a common respiratory virus which typically causes the symptoms of a common cold in healthy adults. But for infants and the elderly it can lead to thousands of hospitalisations each year and can be fatal.

Unlike other respiratory viruses, such as influenza or rhinovirus, people can be infected by the same strain of RSV more than once. People can also react differently when exposed to the virus under the same conditions—some may get a mild infection while others get full-blown symptoms, and some may avoid infection altogether.

In the latest study, the team aimed to investigate the underlying mechanisms of why people succumb to RSV infection and the factors for the varied immune responses.

Healthy adults were enrolled to the study and exposed to RSV in a safe, controlled clinical setting where they were closely monitored. After receiving nasal drops containing the virus, 57% of volunteers became infected. Analysis of blood samples showed that the presence of protective antibodies and B and T cells could only partially explain who became infected.

Slipping through the net

However, when they analyzed samples from participants’ airways taken before they were exposed to the virus, the team found evidence of neutrophil activation in the nasal mucosa—the cells lining the inside of the nose—in those who became infected with the virus.

These are known to release proteins which help create an antibacterial environment in response to a threat. But the researchers believe this antibacterial immune response may come at a cost, making a host more susceptible to viruses by effectively switching off the early warning system, letting them slip through the net to cause infection.

Professor Peter Openshaw, Professor of Experimental Medicine at Imperial and co-senior author on the study, said: “The variable transmission we see with respiratory viruses partly depends on the dose and duration of exposure, but also the person’s own inbuilt immune defenses. You might assume that it’s down to the presence of specific protective antibodies, but despite an immense effort over many years we have never really understood what makes one person vulnerable to RSV and another person resistant. Our finding that the state of the mucous membrane before the arrival of the virus is the major deciding factor is a real breakthrough. It seems as if the presence of activated neutrophils in the lining of the airways causes the mucous lining to fail to respond to the virus and to nip infection in the bud. Perhaps what’s happening is that being ready to fight bacteria makes it more likely that viruses can gain a foothold. Once the virus does get in, our studies go on to show that there still is a chance that the infection will be terminated but only if the mucosa mounts an early defensive response. People who went on to get colds showed no evidence of an initial response; those who rejected the infection showed an immediate response before symptoms developed. These are the sort of findings that can only come from experimental studies in volunteers. We could never have discovered this by waiting for people with natural infections to present to us for investigation.”

Human challenge studies

Dr. Christopher Chiu, Clinical Reader in Infectious Diseases at Imperial and co-senior author, said: “Our data highlight the complexity of the immune system, which has different arms providing layers of protection separated by anatomical location (such as the nose, lung or circulation) and timing. These different mechanisms may be directed to focus on a particular type of infection but this may come at the cost of protection against other pathogens. Controlled human infection challenge studies have a unique ability to tease out these complicated interactions and point out potential targets for prevention or treatment that cannot be seen in patients who have infections caused by diverse virus strains, in different amounts, on top of a wide range of other conditions that might affect their immunity.”

To confirm the idea, they used animal models to test the impact of the neutrophilic pathway on RSV infection. In mice without neutrophilic inflammation, the immune system recognized the virus as a threat, releasing immune-mediating factors which cleared the infection with few symptoms.

However, in mice with a nasal mucosa rich in neutrophils this early detection of the virus was dampened. Under these antibacterial conditions, the virus was better able to invade the mucosal cells causing infection, worsened symptoms and shedding of the virus—to further transmit the virus.

The researchers say that if they can demonstrate the same mechanism is occurring in patient groups who are most at risk from RSV (babies under 12 months of age and adults over 65 with chronic conditions, such as COPD or asthma) it could help to identify subsets of patients most at risk.

Extending to other viruses

The team is set to explore the mechanism in larger patient groups as well as investigating whether the same immune mechanisms influence other viral respiratory infections, from influenza and coronaviruses.

Dr. Thwaites added: “Our initial studies show that in healthy people, neutrophilic inflammation in the airways is linked to RSV infection. If we can show this same mechanism is at play in those most at risk from the virus, it could provide opportunities to reduce the harms caused by RSV and other respiratory viruses. Severe bacterial respiratory infections tend to be quite rare in so, in theory, it may be more beneficial to nudge the towards fighting viruses during seasonal winter peaks. It might be possible to design therapies to temporarily inhibit some aspect of neutrophilic inflammation, such as through a simple nasal spray, to enhance protection against circulating viruses. This could be used in high risk settings, like hospitals, to enhance protection against respiratory viruses, prevent their spread and reduce the impacts of infection on vulnerable groups.”

Dr. Cecilia Johansson, from Imperial’s NHLI and study author, added: “Understanding the underlying mechanisms of susceptibility and protection against is key for the development of treatments and therapies. By studying RSV infection in both human volunteer and in mice we are now one step closer in determining the delicate balance of resistance to infections and the lung disease these viruses can cause.”


Common cold combats influenza


More information:
Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection. Science, science.sciencemag.org/cgi/doi … 1126/science.aba9301

Citation:
Bacteria-fighting cells in the airways boosts infection risk from viruses (2020, October 9)
retrieved 9 October 2020
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