The Role of Immunity and immune memory against viruses

As the world continues to deal with the Covid-19 pandemic, the topic of immunity and how to enhance its ability to recognise and act quickly in response to pathogens such as the SARS-CoV-2 virus has received considerable attention.The NRF Research Communications team spoke to Senior Lecturer and NRF-funded researcher Dr Sabelo Hadebe from the Division of Immunology, University of Cape Town, to better understand how the immune system works, how one can develop immunity and the importance of antibodies in fighting pathogens.NRF: Please tell us about how we develop immunity against viruses and bacteria?Sabelo Hadebe (SH):  The immune system has many layers of protection against foreign substances such as viruses and bacteria.

These layers have evolved over time to rid the body of any potential danger. So far, we know of at least three layers of defence immune mechanisms that help in fighting foreign substances. The first layer is called the first line of defence. Think of it as a wall built around your house. This layer includes our skin and mucosal tissues such as the ones lining our lungs, nostrils and gut. Skin is such a crucial organ as it occupies a huge surface area of our body (almost two (2) square meters) and serves as a physical barrier from any outside foreign pathogen. Apart from being a physical barrier that helps cool us down during hot summers and keeps us warm in winter, the skin is also capable of producing anti-bacterial and anti-viral products that either prevent attachment or actively digest pathogens once attached.

Perhaps the most interesting part about the skin is its ability to keep pathogens that are not harmful to our bodies, also known as the “microbiome”. These non-harmful pathogens can help in expelling other pathogens that cause harm by limiting their growth and creating an unfavourable environment for these pathogens to attach to our skin. 

The other physical barriers, although not outside but exposed to external bacteria and viruses, are mucosal surfaces lining our lungs, nostrils and gut. These organs, similar to the skin, have developed ways to deal with foreign pathogens. We breathe through the nostrils and mouth that, at the same time, allows other unwelcomed visitors such as airborne viruses and bacteria. These mucosal surface organs can produce mucus that can trap pathogens so they are unable to penetrate past these layers and cause harm inside our bodies. Once pathogens are trapped by mucus, mucosal surface layers can produce anti-bacterial or anti-viral products to eliminate the pathogen and flush it out. 

Nostrils, through their ability to sense dangerous substances wanting to enter our bodies, can initiate sneezing that pushes out any pathogens trying to enter through the nostril mucosal surface. The lungs can also sense toxic chemicals and substances entering through inhalation or breathing and can initiate a cough, which is a physical force aimed at pushing out any pathogens that have lodged in our mouths or nostrils.

The lungs can also make pipes, with which we breathe, which can also narrow to further prevent bacteria or viruses from entering. The gut is a more fascinating system as it deals with food and other potentially dangerous substances, including bacteria and viruses. In fact, food and pathogens are digested in our stomachs before the body passes them on to the intestines to absorb the nutrients we need for survival. Deciding which of the digested products is needed and which needs to be removed (because of its potential to cause harm) is a balancing act for the gut mucosal surface. 

Whenever a gut mucosal surface experiences what it perceives as a pathogen, it will either produce mucus, similar to nostrils and lung mucosal surfaces, to trap the pathogen. Alternatively, it initiates a process called “peristalses” – a physical force created by intestines that forces out any pathogens that try to evade the gut mucosal layer. The gut mucosal layer, like the skin, also harbours non-harmful pathogens that help in fighting pathogenic bacteria and viruses. 

The stomach and intestines also secrete very toxic fluids which destroy any pathogens that are not meant to grow in such environments.  This makes it difficult for pathogens to survive in such conditions. Therefore, answering your question in a nutshell, all parts of these three (3) layers of immune defence play a crucial role in immunity against viruses and bacteria. NRF: Please explain the role of the innate immune system and the adaptive immune system in fighting diseases? SH: The second line of defence of the immune system against bacteria and viruses is called “innate immunity”. This defence layer has an innate ability to sense pathogens in a non-specific way by recognising patterns that are not common in the human body. By recognising these patterns, the innate defence mechanism can already tell which pathogens are likely to cause harm.

The innate defence is made up of cells that act very quickly. The innate defence is called upon once the first barrier of defence has been defeated or has been breached. The innate defence mechanism sits very close to the mucosal surface area as guardians, should the first barrier be breached. The innate defence is also very specialised in the sense that we have cells and molecules that only detect bacterial pathogens and those that detect viral pathogens. Others detect fungi or parasites. We also have those innate molecules that can detect when cells that protect us have been damaged and signal for help. 

The innate defence system has many strategies to help defend our bodies. The innate defence has molecules situated on the surface of cells that can sense foreign pathogens, or at least, components of pathogens. Once it has recognised these pathogens, it can then overtake that pathogen and produce anti-bacterial or antiviral products that can digest that pathogen and destroy it. The innate defence can also send signals to other neighbouring cells to alert them of the dangerous pathogen. These signals are sent via molecules called “cytokines” and “chemokines” which can alert neighbouring (and also distant) cells and tissues that may be better equipped to fight that particular pathogen. The innate defence system also knows it can be easily overwhelmed and exhausted by pathogens, particularly those that can create a niche in the body and cause disease for a longer period. So, as part of its job to keep out pathogens, the innate defence also has cells that can overtake pathogens and chop them up, called “natural killer cells”. These cells are real killers as they can sense other innate cells that have been infected by bacteria or viruses and kill those cells to prevent the spread of the infection to other healthy cells.

Natural killer cells also act in a non-specific way and secrete molecules that kill cells without discriminating against the type of pathogen that infected that cell. The really smart thing that the innate defence can do is to take up pathogens they have engulfed and chopped up, and show them to other cells that belong to the third layer of defence called the “adaptive immune defence”. The adaptive immune Unlike the first and second defence systems, the adaptive immune defence system creates a tailor-made defence for an individual pathogen and also sends specific cells that are adaptable to fight that specific pathogen. The main arms of the adaptive defence system are cellular-mediated and humoral mediated defences. The cellular mediated arm mainly deals with components of the pathogen that were shown to it by the innate defence cells.

The cellular mediated arm is made up of two types of cells – those that can help other cells (for example, innate cells) to kill pathogens they have engulfed or those that can kill infected cells similar to natural killer cells. The cellular mediated helper-arm can secrete cytokines and chemokines that can send signals to distant cells in other tissues, or allow those cells or the cells of the humoral defence arm to become more specialised in fighting that pathogen.

The humoral defence arm is made up of cells that secrete antibodies, called “B cells”. These cells are in many ways similar to the cellular mediated defence arm but differ in that they do not require cells of the innate immune defence to show them chopped up pathogens. Humoral defence antibodies can directly bind to invading pathogens and trap them, preventing further expansion of the pathogen. In many cases, antibodies work with innate defence cells to destroy the trapped pathogen. In such cases, antibodies will allow themselves and the trapped pathogen to be engulfed by innate defence cells – once inside, they will release the trapped pathogen to the innate defence cell for destruction.  

NRF: Why do we develop lifelong immunity to some diseases but not others? Why does immunologic memory fade?

SH: This is still a mystery as it is unclear why, for example, some of the vaccines we get as children are able to protect us for the rest of our lives and others only last for 10 years or, in some cases, fewer than 6 months. For example, we only get vaccinated once for smallpox or polio but need six-month shorts for flu vaccines. In the case of the Bacillus Calmette Guérin (BCG) vaccination, which prevents tuberculosis disease, immunity is thought to last for 10 to 15 years or so. By comparing different vaccines, this is exactly how we could describe this short-term and long-term memory to pathogens. It is rather difficult to measure the longevity of immunity to different pathogens in individuals, particularly because we will never know when a person gets infected and the severity of the infection.

We can only know this when someone overcomes the infection the first time and is positively diagnosed – we can then measure the magnitude of that protective response when they are re-exposed. Of course, in the case of a pandemic where a large number of people get infected at once by the same pathogen, one is then able to measure magnitudes of immune responses and able to have a good measure of type, magnitude and quality of immune defence that protects against that particular pathogen. 

There are probably hundreds of reasons why we develop lifelong immunity to some diseases, but not others. One striking factor that we have seen during the SARS-CoV-2 infections is that not everyone gets really ill.  In fact, only a very small proportion of people get severely ill and end up in hospital with many complications, including death. The vast majority of people get a mild infection even when other people are infected at the same time within the same household.

So, the fascinating question is, why do some people get a severe infection while most do not, and why do some people get re-infected even when they survived the first infection? A lot of pathogens, particularly viruses, mutate more frequently since this enables their survival. Most pathogenic pathogens need a host to survive while the host tries very hard to rid itself of the pathogen. You can, therefore, end up with both the host and the pathogen battling to survive. Some pathogens choose to transmit widely (airborne or through bodily fluids) and infect as many people as they can in order to survive longer. Some choose to mutate or change themselves a lot in order to evade immune pressure created by the host. Other pathogens choose to remain dormant.  Although they infect the host, they do not cause disease immediately or in a visible way. 

Mycobacterium tuberculosis is one such pathogen that has survived since 1000 years before Christ (BC) and continues to be responsible for 1.2 million deaths per year. While many people walk around without even knowing they have been infected, others can lose their lives to this infection. So, the question is: why does the immune system fail to build enough memory to eliminate such pathogens?  We know that it is unlikely that people die from their first infections, except perhaps for very virulent viruses e.g. SARS-CoV-2 or Ebola. What is becoming very clear is that people do develop lifelong immunity to almost all pathogens we encounter. 

However, in cases where people have other underlying conditions such as malnutrition; non-communicable disorders such as cardiovascular diseases, diabetes, chronic respiratory diseases (asthma and COPD); co-infections with unrelated pathogens; or co-morbidities or other hereditary genetic disorders, it may lead to someone not developing an adequate immune memory the first time they encounter a pathogen. Because of such complications, the memory that is developed is inadequate and will simply not endure. The immune system is sophisticated enough that it hardly keeps long-term memory cells that are unlikely to be protective in the future.  It would, therefore, rather generate that adequate memory again.

This is one of the reasons why vaccines are monitored closely to enable an understanding of whether people have developed adequate memory, in the form of antibodies or T cells responses, to make sure they will be able to fight a real infection in future encounters. In cases of natural infection, which is how most people acquire lifelong memory to pathogens, there have been some suggestions that people who get severe infections are likely to develop better lifelong memory compared to those who get mild infections. This is not conclusive as mild infections may also suggest a stronger immune response at first encounter.

This could be due partly to similar infections or cross-reactive immune memory – for example, cowpox protecting against smallpox or other coronaviruses protecting against SARS-CoV-2 This is the main reason why most, if not all, vaccines have to be tested in multiple countries, in different demographics, and against co-morbidities to ensure we understand how immunity develops in different scenarios.

Immunological memory also fades as we get older, mainly because the engines or organs that generate immune cells, such as antibodies and T cells, are not as efficient. In fact, our immune cell function drops by more than a third by the time we turn 45 years old. It would, therefore, make sense that older people get sicker more frequently – not because they didn’t generate long-term immunological memory at a younger age, but because the cells that produce antibodies or T cells are not as active in doing so, resulting in poor quality and slower immune responses to infections. 

NRF: Why is it important to understand more about antibodies and T cells to combat Covid-19?

SH: Antibodies and T cells are central in fighting any pathogens. These cells are studied a lot in immunology simply because they are specific to each pathogen, easier to measure in a human body, and accessible – especially antibodies. Many vaccine design strategies have focused on these cells to direct a more specific and lifelong immunological memory. What we have seen over the last year is something completely unprecedented in terms of the importance of antibodies and more recently T cells in the fight against Covid-19. Innate antibodies are one of the first cells to encounter pathogens as they do not depend on other cell types to do this.

T cells do require innate cells to engulf and chop up pathogens before they can recognise a pathogen component and initiate a specific immune response to that pathogen. Over the last 12 months, we have seen how quickly vaccines against SARS-CoV2 were created. 

These are mainly targeting the antibody-secreting capacity of the immune system. The antibodies mainly targeted surface proteins of the virus that helps it to attach to epithelial cells. Enabling the immune system to secrete antibodies through vaccination allows antibodies to see the virus component that attaches to the cells immune system and blocks it from attaching. What has come out more recently is the ability of T cells to help B cells in producing more specific antibodies that are more potent in binding to the virus. The advantage with T cells is that they rely on the whole pathogen components being presented to them, so they have a wider range of viral components to which they can respond, albeit a little longer. This means that their response is more calculated and likely to last longer – beyond the time that antibodies are present.

T cells are also more likely to generate immune responses to parts of the virus that are not on the surface and are less likely to mutate and evade immune recognition. There are more vaccines in the pipeline looking at targeting T cells, which would mean that people can be vaccinated once and acquire lifelong immunity. There are, obviously, still many unknowns about how T cells mediate immunity to SARS-CoV2.  We also do not know enough about the cells that kill viral infected cells, the killer cells, and how they can be harnessed for vaccine strategies.