Posts Tagged ‘antibodies’
Immunology, last encore?…
One way – maybe not a good way – of learning about the immunological system is being alerted to something – a term or an acronym, and going down its rabbit hole to find its connection to things you know a little about. So, neutralising antibodies and Omicron – I’ve taken this phrase from an early episode of The Immunology Podcast (ep 24 – though that wasn’t the main topic of the episode, linked below), Omicron being a late and seemingly less deadly variant of SARS-CoV-2, – what to make of it?
A neutralizing antibody (NAb) is an antibody that is responsible for defending cells from pathogens, which are organisms that cause disease. They are produced naturally by the body as part of its immune response, and their production is triggered by both infections and vaccinations against infections.
Which makes me wonder – aren’t all antibodies neutralising antibodies? Well, there are also binding antibodies, which bind to a pathogen and alert the immune system to its presence so that it can then be destroyed by white blood cells. Neutralising antibodies are a product of B-cells in the bone marrow. They work ‘by affecting how the molecules on the pathogen’s surface can enter cells in the body’. For example, with viruses there are two types, enveloped (they’re inside a lipid membrane) and non-enveloped. The enveloped types are heat-sensitive, the non-enveloped are heat resistant, which sort of makes sense. In the case of the enveloped type, the neutralising antibody blocks its attachment to and entry to the cell, and with the non-enveloped type, the antibody can bind to the capsid protein, which is the protein shell that surrounds the genetic information within a virus cell.
So where do we go from here? Well let’s look at this capsid protein and how the antibody binds to it, presumably to prevent the virus from replicating – what they mean by neutralising? But take this:
Neutralizing antibodies can also stop pathogens from changing their structure and shape, known as conformational changes, in order to enter and replicate within a cell.
So pathogens can change structure and shape once they’re in the body, in order to enter into particular cells within that body? Anyway, there are viruses that can get their way around NAbs by means of regular mutation. Such viruses include Zika and dengue, not to mention influenza. And it can get worse:
A process known as antibody-dependent enhancement (ADE), which leads to more severe infections, can take place when a virus binds to antibodies that help the virus infect cells. The virus is better able to enter into cells in the body and is sometimes more able to replicate once it has entered a host cell.
So it seems these antibodies are a double-edged sword, as these summarising remarks indicate:
Neutralizing antibodies have found application in medicine and are often used as part of vaccines, but they have been found to help viruses enter cells and replicate to cause severe infections, and as such ensuring that neutralizing antibodies will not facilitate infection is an important part of developing vaccines.
So that’s enough of NAbs for now….oh but what about that connection with Omicron? Omicron was/is a highly mutated variant of SARS-CoV-2 which has ‘evolved into many different sub-variants’ according to the abstract of the paper linked below, which lists at least some of these sub-variants, and it’s a long list. It seems these sub-variants may have survived/thrived by being a whole lot less lethal than the original strains. But don’t take my word for it. Anyway the paper was published back in March 2023, and the pandemic was very much on the wane by then I think, so it does seem as if the virus has found an accommodation with our bodies, or antibodies, or whatever.
So enough already, I think it’s time to switch to another topic, I’m way out of my depth with this one. And yet, it’s so…. I’ll keep listening to the podcast, at least.
References
https://pmc.ncbi.nlm.nih.gov/articles/PMC9985919/
https://www.science.org/doi/10.1126/scitranslmed.abn8057
Ep. 24: “Autoimmune Disease” Featuring Dr. Jennifer Gommerman
stuff on the immune system and that recent pandemic: 1 – how to get lost in a single cell
got that?
Canto: So, looking way back to the Covid-19 year or two, which we survived (and I’m wondering if the virus has too), have we retained what we’ve learned from all those Medcram videos we watched, and from the various ‘vaccine hesitant’ characters we encountered…
Jacinta: One of whom was a nurse as I recall, but I must say, mind like a sieve, I don’t feel I’ve retained much, so we’re reading Nobel Prize-winning immunologist Peter Doherty’s An insider’s plague year, to help us set down some info and promote our lifelong learning.
Canto: So what’s the difference between a drug and a vaccine, Doherty asks, noting that even experienced journalists confuse the two. Drug of course is a broad term, for anything chemical used to treat people, by pill, injection, bottle, patch or suppository. At the beginning of his ‘plague journal’ Doherty mentions two drugs I recall from our Medcram viewings, hydroxychloraquine, an anti-malarial, and remdesivir, ‘an experimental anti-Ebola drug’.
Jacinta: Yes, hydroxychloraquine was touted early on in the year (2020) as being of some use. A USA site, Drugbank online, said this:
Chloroquine and hydroxychloroquine are both being investigated for the treatment of SARS-CoV-2
followed by this:
The FDA emergency use authorization for hydroxychloroquine and chloroquine in the treatment of COVID-19 was revoked on 15 June 2020.
Remdesivir seems to have been somewhat more effective in reducing symptoms, as was seen earlier in treating MERS-CoV sufferers. It received the FDA’s authorisation just a few weeks before the other drug’s authorisation was revoked.
Canto: The word drug features in the USA’s FDA (Food and Drug Administration), while in Australia we have the TGA (Therapeutic Goods Administration), and therapeutic is simply medicalese for drug. The first of these tended to be natural remedies such as quinine, a useful anti-malarial extracted from Cinchona tree bark. Tonic water has quinine in it, hence the name. Another natural anti-malarial is artemisinin, from sweet wormwood. These ingredients, extracted and purified, have been extremely important in combatting the biggest killer disease in the global south.
Jacinta: In treating SARS-CoV2, remdesivir was the only effective antiviral in the first 12 months, apart from – monoclonal antibodies. I’ve heard of them, now I’m going to try and explain them. I’ll start with this quote from the Mayo Clinic:
Monoclonal antibodies are laboratory-produced molecules engineered to serve as substitute antibodies that can restore, enhance, modify or mimic the immune system’s attack on cells that aren’t wanted, such as cancer cells.
Antibodies (aka immunoglobulin, of which there are 5 types) are Y-shaped proteins that can bind to specific antigens (the foreign nasties) via a lock-and-key mechanism. Monoclonal antibodies, as mentioned above, have been particularly effective in some cancer treatments.
Canto: Well, only this month our TGA has posted an update on the decreased effectiveness of monoclonal antibodies against emerging SARS-CoV2 variants:
emerging data show that anti-spike protein monoclonal antibodies demonstrate a significant decrease in their in-vitro neutralising activities against many newer circulating SARS-CoV-2 variants, particularly Omicron and its subvariants.
Jacinta: Mmm. So let’s go on with our very basic training in immunology. So it’s the organs of the lymphatic system – the lymph nodes, the thymus, the spleen and the bone marrow – that produce or harbour and further develop our immune cells. Now, these immune cells come in different types with different names, such as phagocytes, which are a type of white blood cell (WBC)…
Canto: Yes, this immune system stuff might require dozens or hundreds of posts. Phagocytes can be ‘professional’ or non-professional’ depending on effectiveness. The professionals include neutrophils, macrophages, mast cells, dendritic cells and monocytes – all WBCs. They’re all more or less good at detecting antigens. And I believe these WBCs form what’s called the innate, rather than adaptive, immune system.
Jacinta: So getting back to the SARS-CoV2 Betacoronavirus – we’ll be jumping around a lot in these posts, methinks – it has this thing called a spike protein on its outer coat, and this protein has a receptor-binding domain (RBD) with binds to the angiotensin-converting enzyme (ACE) receptor, or ACE2 receptor. ACE2 receptors exist throughout the body but the principal pathway for this virus involves the epithelial cells at the base of the lungs and in the blood vessels. So I’m reading a Nature article, referenced below, entitled ‘Mechanisms of SARS-CoV-2 entry into cells’, and I want to frame this stuff in my own words to understand it. Apparently ACE2 is the receptor for other Betacoronaviruses and Alphacoronaviruses, so immunologists and virologists are pretty familiar with it.
Canto: Yes, and there’s all this terminology – for example a virion is the whole viral particle – not just the DNA or RNA core and its proteins but the external envelope – everything that allows it to exist extra-cellularly. So a coronavirus virion is made up of nucleocapsid and other proteins, including the spike proteins that facilitate entry into potential host cells via the ACE2 receptors.
Jacinta: So let’s focus for now on the nucleocapsid (N) protein. Another Nature article, with multiple authors, has this title: ‘The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA’, which sounds ominous. And the article starts with a problem:
The SARS-CoV-2 nucleocapsid (N) protein is an abundant RNA-binding protein critical for viral genome packaging, yet the molecular details that underlie this process are poorly understood.
Yes, especially by me. I get that these N proteins bind and ‘package’ the RNA, but I don’t get ‘phase separation’…
Canto: Phase separation is a key biological concept, it seems, but complex, and probably something that requires lab work to fully comprehend. Here’s a quote from ScienceDirect that might help:
Many biological macromolecules, such as proteins and nucleic acids, exert their biological functions by forming phase-separated condensates, and phase separation is closely related to various human diseases. Gene transcriptional regulation is an indispensable part of gene expression and normal function in cells. Its abnormal regulation often causes the occurrence of different diseases. In recent years, the occurrence of phase separation during transcriptional regulation has become an area of intense research.
It sounds like problems with phase separation may lead to irregular transcription, or vice versa, resulting in variants, mutations and such, but I’m guessing.
Jacinta: So reading further into the ScienceDirect article, you’re right, it’s near impossible to understand this stuff just through reading – you surely need to see it happening in cells. And cells, such as our own, are effing complex. Here’s another (long) quote to prove it:
In cells, which are the basic unit of the structure and function of organisms, the need for various components to perform their corresponding functions at the correct time and space is a problem that cells continuously need to solve. To this end, cells have evolved a set of organelles, including membrane-encapsulated organelles (such as mitochondria, nuclei, lysosomes, the Golgi apparatus, and endoplasmic reticulum) and membrane-less organelles (such as nucleoli, Cajal bodies, stress granules, P bodies, U bodies, and signaling bodies) …. Membrane-encapsulated organelles enclose specific proteins, nucleic acids and other substances to perform their functions within a particular space. Still, how other types of membrane-less organelles form and exert their biological functions has eluded investigators for many years. In recent years, it has been discovered that different intracellular biological macromolecules assemble and separate from each other to form liquid-like structures called “biomolecular condensates”….
and it goes on. It’s dauntingly complex, but I must say I wish I was 40 years younger and working in this fascinating field. To work out more precisely the processes involved and then to be able to manipulate them…
Canto: Homo deus indeed.
Jacinta: Femo deus if you don’t mind, and that’s not even a recognised term. I just can’t wait for the 31st century.
Canto: Well let’s just stay in the shallows and say a few words about these membraned and unmembraned intracellular organelles. Mitochondria we know a bit about, the ATP-yielding (making?) organelles that existed separately eons ago as prokaryotes…
Jacinta: Thank the indefatigable iconoclast Lynn Margulis for presenting this argument, and endosymbiosis in general, against vociferous mostly male opposition…
Canto: Lysosomes are the ‘digestive system’ of the cell, containing enzymes that break down the polymeric structures of proteins, lipids, nucleic acids and carbohydrates. They vary greatly in size depending on the digestive tasks they work on. The Golgi apparatus or complex is, unsurprisingly, a complex organelle that packages proteins to be sent out into the intracellular or intercellular world – nuff said. The endoplasmic reticulum has two sub-units, rough and smooth. They’re kind of attached to the nuclear membrane of the cell, the smooth further out than the rough. It’s involved in transportation and protein folding, let’s say no more.
Jacinta: So now to the membrane-less organelles – but it looks like phase transition as a subject for analysis is about how these organelles transition from dormant to active states or how they transition from one task to another. Anyway, just a few words to introduce these organelles. Nucleoli are defined briefly as ‘small dense spherical structures in the nucleus of a cell during interphase’. They also appear to segregate in unexpected ways as cells divide – again something about phase transition. Cajal bodies are often associated with nucleoli and are involved in the processing of some RNA molecules. They appear to have other roles that aren’t yet fully understood. Stress granules are these changeable, dynamic, liquid-solid entities made from RNP (ribonucleoprotein). P bodies are somewhat similar, as are U bodies, named for being ‘uridine-rich’, whatever that may mean. In any case P and U bodies appear to act co-operatively. Signalling bodies, according to Khan Academy:
A signaling molecule is released by one cell, then travels through the bloodstream to bind to receptors on a distant target cell elsewhere in the body.
Canto: Okay, that’s enough terminology, and we won’t do all the references as nobody reads this stuff anyway.
Jacinta: Fine, we’re having fun, though it may take till doomsday to get our heads around this stuff. Wish I could afford a lab, and all its equipment….
References
Peter Doherty, An insider’s plague year, 2021
https://go.drugbank.com/drugs/DB01611
https://www.nejm.org/doi/full/10.1056/nejmoa2007764
https://www.tga.gov.au/news/news/update-effectiveness-monoclonal-antibodies-against-covid-variants
the science of Covid-19: possible treatments, herd immunity
Australia is now 22nd in the list of total COVID-19 cases and dropping down. There are still of course new cases every day, but far fewer than many countries below us on the list. Experts are now talking about a flattening curve, but they also warn that the virus is ‘here to stay’. Here in South Australia, there were no fatalities when I last posted, but there have been three in the last couple of days. There are a large number of cases recently linked to our Barossa wine-growing region, a popular tourist destination.
So let me take a closer look at the SARS-CoV-2 virus. It’s a positive-sense single-stranded RNA virus. RNA is generally single-stranded in nature, though apparently can be double-stranded on occasion. The positive-sense term refers to the polarity, or sense, of the RNA. It’s also called ‘positive-strand’, facing 5’ to 3’, which means it acts as mRNA and can be translated into viral proteins in the host cell.
These types of virus are very common. They include common cold rhinoviruses as well as the SARS and MERS coronoviruses. SARS-CoV-2 is genetically similar to bat coronaviruses, causing virologists to believe that it was transmitted from bats to humans through an intermediate species such as a pangolin. The reproduction number of the virus (R0) is currently ranged from 1.4 to 3.9, in a scenario of no immunity and no preventive measures taken.
It has often been repeated that a vaccine will take 12-18 months, if not longer, to be safe, ready and effective. Science communicators such as the ABC’s Dr Norman Swann are telling us that stay-at-home orders may need to stay in place until that time, which is surely alarming economists and the business community. So, unsurprisingly, people are looking to short-cuts and desperate remedies. Perhaps the most publicised of these is the anti-malarial drug hydroxychloroquine, aggressively promoted by the US President. It turns out, also not surprisingly, that he has some financial interest in the French company that has branded the drug, according to the New York Times. There doesn’t appear to be any clear evidence on the benefits of the drug. Best reports speak of ‘mixed results’.
There are reports also of the benefits of blood plasma from people who have recovered from Covid-19. A small Chinese study involved 10 severely affected patients being given a few hundred millilitres of ‘convalescent plasma’ containing viral antibodies, and results were described as promising. The approach is being tried in the US, with the Red Cross and the American Association of Blood Banks seeking to recruit suitable ‘fully recovered’ donors.
As people continue to be alarmed and frustrated at the massive disruption to their working and social lives caused by Covid-19, some world leaders (e.g Boris Johnson and his chief science adviser Patrick Vallance, and Netherlands PM Mark Rutte) have come up with not-so-encouraging solutions, such as allowing the virus to run its course so that the population can build up herd immunity. This would actually be a disastrous policy in the case of a virus with a high (but not precisely known) fatality rate, involving millions of severe cases requiring intensive care treatment at any one time.
Herd immunity occurs when enough people have antibodies to the virus that it has nowhere to go. This can occur through the work of our immune systems or through antibodies created by effective vaccination. The former obviously comes at a much greater cost in terms of lives lost, in the case of a highly infectious (the R0 is now estimated – the data changes as I write – at between 2.0 and 2.5), high-fatality virus. Also, because Covid-19 is new, we don’t have sufficient data as yet about the degree of immunity it confers upon recovered patients, or whether it is able to mutate to any degree. Experts are generally counting on low or no mutation, but none of them see relying on herd immunity to be a humane solution to the problem. Suppression is the name of the game at the moment (even though it will reduce herd immunity). That’s to say, the R0 mentioned above (which might be higher) is the figure without the application of physical distancing or other containment measures. The R0 number, if it can be ascertained, gives an indication of the percentage of immunity required to ‘protect the herd’. An R0 number of 2 will require about 50% immunity. If the R0 number is 3, some 66% immunity will be required. Measles has a very high R0 of 12, requiring 90% immunity, which explains why anti-vaccination movements can imperil whole communities.
So it’s a trade-off. Physical distancing measures will reduce the possibility of herd immunity – the production of antibodies. Going back to business as usual will increase infection rates – ok for those who recover, not so much for those who don’t. The cost of the second option, most will agree, is just too great.
References