New defense against viral lung infections discovered

New defense against viral lung infections discovered

Researchers have uncovered a previously unknown arm of the immune defense system that protects the lung from lethal viral infections.

Respiratory diseases caused by viruses such as influenza A and SARS-CoV-2 cause damage not just through their own actions, but also from collateral damage as the immune system reacts to fight the infection.

A timely and proportionate response identifies viruses, isolating them in tiny vesicles called phagosomes that are then targeted for breakdown. This processalso triggers production of cytokines to alert the immune system.

Cytokine responses represent a fine balancing act that can sometimes tip over to an excessive state known as the cytokine storm. This has serious consequences for viral lung infections, as it leads to inflammation, fluid building up in the lungs and eventually death.

Given the impact of respiratory conditions, brought into sharp focus by the COVID-19 pandemic, there’s a clear need to fully understand the complexities of this immune response to develop better treatments or targets for drugs that can protect against infections taking hold.

To address this teams from the Quadram Institute and universities of Liverpool, East Anglia (UEA), and Bristol have worked together to studythe immune response to influenza A virus infection in the lungs of mice. Animal models provide a way of understanding how the immune system works, and as with SARS-CoV-2, animals may be a significant reservoir for viruses that, if transferred to humans, can trigger pandemics.

Funded by the Biotechnology and Biological Sciences Research Council, they focussed on a recently characterized form of non-canonical autophagy called LC3-associated phagocytosis (LAP) that recognizes pathogens as they enter cells.

Professor Tom Wileman at the Quadram Institute has worked with Dr. Penny Powell and Professor Ulrike Mayer at UEA to develop a LAP-deficient mouse to study viral infection. Unique to this study, the mice were designed to retain the normal autophagy machinery, and target LAP within immune cells, so are the best available option for understanding the precise role of this newly uncovered immune defense.

Prof James Stewart at the University of Liverpool characterized the function of LAP by infecting the transgenic mice with influenza virus and studying the response to infection.

The mice were found to be much more susceptible to the virus, with it triggering a cytokine storm leading to pneumonia. The researchers showed that LAP prevented a lethal cytokine storm by supressing lung inflammation.

So where does this protection come from? Dr. Yohei Yamauchi and colleagues from the University of Bristol provided the answer by looking at the cells lining the surface of the lung. There was no difference in how the virus initially binds to these cells, but they did see that non-canonical autophagy/LAP did slow the way the virus enters the cell. It may work by preventing the virus fusing with endosomes, which are the cell’s way of importing materials from outside.

Non-canonical autophagy/LAP is likely to be important as a first defense against infection, where there is no immunity from previous infections, especially in the specific case of influenza and SARS-CoV-2.

“Being able to describe this novel part of the immune defense system against respiratory infections in very exciting, especially given the current pandemic,” commented Professor Tom Wileman from the University of East Anglia and Quadram Institute.

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Researchers discover hidden link between cellular defense systems

UIC researchers discover hidden link between cellular defense systems

Researchers at the University of Illinois Chicago have discovered that heparanase, HPSE, a poorly understood protein, is a key regulator of cells’ innate defense mechanisms.

Innate defense responses are programmed cellular mechanisms that are triggered by various danger signals, which have been conserved in many species throughout evolution. These systems can be set into action by pathogens, such as viruses, bacteria and parasites, as well as by environmental toxins and dysfunctional cells that can accumulate in the body over time. A more thorough understanding of the commonalities and connections between these processes has the potential to generate multi-target therapy against a variety of human diseases.

In a multi-institution team led by Alex Agelidis, a UIC MD/Ph.D. dual degree medical student, and Dr. Deepak Shukla, the UIC Marion Schenk Professor of Ophthalmology and UIC professor of microbiology and immunology at the College of Medicine, researchers used a systems approach to track shifts in important cellular building blocks in cells and mice genetically engineered to lack HPSE.

In this collaborative multidisciplinary study, Agelidis and coauthors show for the first time that HPSE acts as a cellular crossroads between antiviral immunity, proliferative signals and cell death.

“HPSE has been long known to drive late-stage inflammatory diseases yet it was once thought that this was primarily due to enzymatic activity of the protein breaking down heparan sulfate, a sugar molecule present in chains on the surface of virtually all cells,” Agelidis said.

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What are the Three Lines of Defense?

The human body has three primary lines of defense to fight against foreign invaders, including viruses, bacteria, and fungi. The immune system’s three lines of defense include physical and chemical barriers, non-specific innate responses, and specific adaptive responses.

Image Credit: Yurchanka Siarhei/

What is the immune system?

The immune system is a complex network of specific immune cells and proteins that work in synergy to protect the body against foreign invaders and harmful toxic materials coming from the environment.

Foreign substances that trigger an immune response are called antigens. However, under certain circumstances, such as in autoimmune diseases, the immune system can be activated by self-antigens, leading to the destruction of the body’s cellular components.

In general, the immune system can be activated to generate two types of immune responses: nonspecific response (innate immunity) and specific adaptive response (acquired immunity).

What are the three lines of defense of the immune system?

The immune system comprises three levels of defense mechanism that a pathogen needs to cross to develop infection inside the body.

Physical barrier

The innate immune system provides the first line of defense, which is divided broadly into two categories – physical/chemical barriers and nonspecific resistance.

Physical barriers, including the skin and mucosa of the digestive and respiratory tracts, help eliminate pathogens and prevent tissue and/or blood infections. Moreover, components that are secreted by the skin or mucosa, such as sweat, saliva, tears, mucous, help provide a basic barrier against invading pathogens.

The skin is the impermeable physical/mechanical barrier that protects many pathogens from entering the body. Similarly, mucosa or mucous membranes that line the immediate internal systems help trap pathogens by producing mucous. Hairs inside the nasal cavity as well as cerumen (earwax) also trap pathogens and environmental pollutants.

Some acidic fluids, such as gastric juice, urine, and vaginal secretions, destroy pathogens by creating low pH conditions. Also, lysozyme found in tears, sweat, and saliva acts as a vital antimicrobial agent to destroy pathogens.    

Image Credit: Kateryna Kon/

Nonspecific innate response

Pathogens that successfully cross the physical barriers are next encountered by the second line of defense. This innate immune response mostly involves immune cells and proteins to nonspecifically recognize and eliminate any pathogen that enters the body.

Phagocytosis is a crucial phenomenon of the innate immune system that utilizes a special type of immune cells called phagocytes. There are two types of phagocytes namely macrophages and neutrophils. These cells are found in the tissues and blood.

In the beginning, phagocytes recognize and bind pathogens and then use the plasma membrane to surround and engulf pathogens inside the cell. As a result, a separate internal compartment (phagosome) is generated, which subsequently fuses with another type of cellular compartment called the lysosome. The digestive enzymes present inside lysosomes finally destroy pathogens by breaking them into fragments.       

Digestion of pathogens inside a phagosome produces indigestible materials and antigenic fragments; of which, indigestible materials are removed by exocytosis. However, the antigenic fragments are displayed on the surface of phagocytes, which are subsequently recognized and destroyed by cytotoxic T cells.

In addition, complement proteins are activated, which in turn recruit more white blood cells (neutrophils, eosinophils, and basophils) at the site of infection, leading to an inflammatory response (swelling, redness, pain).

Specific adaptive response

The third line defense aims at eliminating specific pathogens that have been encountered by the immune system previously (adaptive or acquired immune response). Instead of being restricted to the site of infection, the adaptive immune response occurs throughout the body.

The adaptive immune system mainly involves two types of white blood cells (lymphocytes) – B lymphocytes (B cells) and T lymphocytes (T cells). B cells are involved in antibody-mediated immune responses (humoral immunity), whereas T cells are involved in cell-mediated immune responses.

In antibody-mediated immunity, B cells are activated when they encounter a ‘known’ antigen. Activated B cells then engulf and digest the antigen, which is followed by a representation of MHC (major histocompatibility complex)-bound antigenic fragments on the B cell surface.

The combination of antigen-MHC further activates helper T cells, which in turn secrete cytokines (interleukins) to trigger the growth and maturation of antigen-presenting B cells into antibody-producing B cells (plasma cells). At this point, some B cells are transformed into memory cells to keep the immune system ready for the next attack.

Antibodies produced by the plasma cells are secreted into the bloodstream where they execute their functions in different ways. For example, by forming the antigen-antibody complex, antibodies can prevent antigens from binding host cells, leading to the prevention of infection. Antibodies also bind and mark pathogens for destruction through phagocytosis.

The antigen-antibody complex can initiate a series of signaling events to activate complement proteins, which in turn kills pathogens by rupturing their cell membrane. Complement proteins also trigger an inflammatory response, leading to the accumulation of white blood cells at the infection site.

In cell-mediated immunity, T cells are activated when they encounter antigen-presenting cells, such as B cells or dendritic cells. Activated T cells then secrete cytokines that further trigger the production and maturation of T cells.

T cells that mature into cytotoxic or killer T cells mainly destroy pathogen-infected cells, damaged cells, and cancer cells by rupturing the cell membrane. Whereas, T cells that mature into helper T cells facilitate B cells to execute antibody-mediated immune responses.   

Some T cells that mature into regulatory T cells help cease the immune response and maintain the immune system homeostasis when the threat is eliminated. Also, some T cells that mature into memory T cells remember the pathogen and initiate an immediate response when the body encounters the same pathogen for the second time.

Image Credit:


  • Science Olympiad. Immune System.…/2018_IMMUNE_SYSTEM_HANDOUT.pdf
  • Let’s talk science. 2019. The immune response.…/immune-response
  • Austin Community College. Immune System.
  • NCBI. 2020. How does the immune system work?

Further Reading

  • All Immune System Content
  • What is the difference Between a Phagocyte, Macrophage, Neutrophil and Eosinophil?
  • Does the Immune System Differ between Men and Women?
  • Effects of Tobacco on the Immune System

Last Updated: Jul 30, 2020

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.

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