Acute measles virus (MeV) infection can be serious

You may have heard that the United States is having a multistate outbreak of MeV infections, mainly causing its worst outcomes among the unvaccinated.

Measles is the result of a systemic viral infection that enters through the airways, damaging the epithelial cell airway lining, which opens the way for opportunistic secondary infections by bacteria and other viruses. MeV penetrates that lining and then infects and kills a proportion of highly specialised and important immune cells (called lymphocytes). It’s in these cellular vaults that our immune memories are held. MeV rides these infectious cellular carriages through the blood vessel networks and lymph node stations, spreading far and wide around the body, where it causes short-term and long-term harms. We’re left to pay its fare.

A measles infographic: virus, symptoms and white blood cells

According to the United States-based non-profit organisation, National Foundation for Infectious Diseases and other sources, those harms include:

• About 1 in 5 unvaccinated people in the US who get symptomatic measles after MeV infection will be hospitalised
• 1 out of every 1,000 people with symptomatic measles will develop brain swelling, which could lead to brain damage
• As many as 1 in 20 children with symptomatic measles gets pneumonia
• 1 out of 1,000 people with symptomatic measles will die, even with the best care. This can rise to 15% in low and middle-income countries.

The targeted depletion of lymphocytes by MeV can leave a symptomatic measles case – usually an unvaccinated child – vulnerable for months to serious reinfections by disease-causing viruses and bacteria to which they had once developed moderating immunity.

Immune memory and virus-fighting is a lymphocyte thing

Killing cells infected by a virus? A lymphocyte thing. Making antibodies to a specific virus? A lymphocyte thing. Creating a rainbow of defence memories of past infections to fire up a faster and more specific immune response next time?

Priceless.

And also a lymphocyte thing.

The three kinds of lymphocytes are natural killer (NK) cells, T lymphocytes (T cells) and B lymphocytes (B cells).

NK cells kill infected and cancerous cells when they find them, without needing to have interacted with them before. They’re not as specific as T cells.

T cells learn and adapt to specifically destroy cells infected with a specific pathogen, and they have a role in the overall cellular immune response and its control.

B cells are needed for antibody production. Antibodies target a part of a specific pathogen and can then prevent it from infecting new cells inside the body.

An important cell type, in addition to lymphocytes, is the dendritic cell. These are often found at the entry points of infection. Like macrophages, they graze on viruses, bacteria and their components. Dendritic cells focus on offering up the specific antibody-generating (antigen) components of what they ingest, using these to teach and train lymphocytes within the lymph node arena. By comparison, macrophages are a bit more about destruction, degradation and digestion.

Disease-causing viruses and bacteria have multiple distinct antigens. Dendritic cells also recruit cells, help control the immune response and have a central role in reactivating immune memory. Newly challenged T and B cells learn from this meeting, and when they interact with that antigen next time – like a lock interacting with a matching key – they unleash a faster response to that antigen and its parent pathogen, attacking the infected cell or producing specific antibodies that bind and block new infections by the pathogen.

Both cellular and antibody-based immunity are required to maximise an anti-MeV response.

Among the T and B cells are those that have yet to meet a pathogen and those already trained; the latter group hold a veteran-like status due to their parental clone’s past actions overcoming infections of all sorts. They retain a memory of combat and a higher state of readiness when – and not if – that same enemy appears again.

It’s in this space that we’ll explore why measles is much more than just a disease due to MeV. As well as making you sick, measles takes your immune memories.

MeV infection: Measles takes your immune memories

For over 150 years, it’s been known that measles leaves behind a harmfully weakened immune system, lasting until well after the acute symptoms of measles fade.

And even when this immediate danger has passed by, the disease too often leaves chronic pulmonary mischief behind it. In scrofulous children, and young persons, it frequently awakens the slumbering germs of consumption. And when that specific effect is not produced, it is apt in adults, to inflict upon the constitution a blow which is never thoroughly recovered from; the aptient becoming, from that time forwards, delicate and valetudinary [suffering from poor health]

Watson, T., Stanton A. Friedberg, M. Rare Book Collection of Rush University Medical Center at the University of Chicago., King’s College London. (1844). Lectures on the principles and practice of physic: delivered at King’s College, London. Philadelphia: Lea and Blanchard.

Initially, this was seen through a very wide lens – there was more post-measles death among non-immune children. After this pattern was accepted, the hunt switched to uncovering the specific cause(s)

What hints at immune memory loss?

In a 1911 report, there was a well-observed introduction of MeV into an isolated, immunologically naive population. More than half of the children in the 1910 and 1911 birth-year cohorts of the Fijian island of Rotuma died during the next two years of life after MeV exposure. Overall, 13% of the population died due to causes that were attributed to the measles outbreak. Gastrointestinal complications were the main feature among fatal cases on Rotuma. Tuberculosis-related death rates were also higher among those studied in 1911 than among the same group in any of the following 50 years.

After a symptomatic infection, children with measles are significantly more likely to develop subsequent infections than children who do not have measles.

A drop in total lymphocyte numbers that lasts for months afterwards allows other infections to quickly follow measles. This reduction causes a drop in all sorts of previous immune protection, including that from previous vaccination.

In one example, anti-tetanus antibody levels dropped among measles-unvaccinated children compared to their measles-vaccinated peers, even though they had all been previously vaccinated with tetanus toxoid. In another example, reduced skin test reactivity against Tuberculin was reported in BCG-vaccinated children after measles; the time for that reactivity to return was extended in children who had a more intense rash or suffered complications after the rash.

In a 1984 report of an analysis of children in Guinea-Bissau who had measles but were not vaccinated, the authors reported a higher rate of death than among those children who were vaccinated. They went on to opine that neither malnourishment nor comorbidity drove death after measles ‘natural selection’ (😒). This had been ascribed by some to low and middle-income living conditions. Instead, they made a case for measles and its aftereffects causing excess mortality. Interestingly, others have noted that measles may lead to weight loss.

In contrast to these harmful aftereffects in non-immune people, studies show that after standard measles vaccination, there is a reduced risk of death due to any cause, not just death due to measles.

The safe and highly effective measles vaccine has reduced the impact of other infections following measles, providing much broader health benefits than simply the obvious dramatic reduction of symptomatic and severe MeV disease. In 2013, the World Health Organization agreed and concluded that measles vaccination may have a beneficial effect on reducing all-cause mortality.

All these observations of events are well and good, but let’s dig a bit deeper into what’s happening that could take away our immune memories.

What’s happening in your blood during measles?

The mechanism for increased death after measles is driven by two main things: a suppressed and dysfunctional immune response and the development of immune amnesia. These two outcomes are driven by multiple events that impact certain cell numbers, types and functions.

Initially, there is a measurable but temporary drop in total lymphocyte numbers (lymphopaenia). Some of the disappearance of these cells from the blood is likely due to them moving into different body compartments – the lymph nodes in particular. Initial lymphopaenia depresses total lymphocyte numbers, then MeV-specific lymphocytes surge back and clear the virus. However, the composition of the rest of the newly made and released lymphocytes is changed.

There is also a major impact related to which cells MeV infects, manipulates and destroys. You may have guessed already. MeV targets and kills the T and B cells that excel at rapidly responding to the return of many viral and bacterial nemeses from days gone by.

The loss of specific lymphocyte subsets that hold our immune memories can last two to three years, and it drives the observable increase in human deaths over this longer period, well after recovery from measles.

MeV can also kill the long-lived memory B cells. Between 11% and 73% of the existing antibody repertoire was lost after MeV infection of measles-unvaccinated children in one study. However, these harmful long-lived effects were not seen after the vaccination of children.

The presence and normal function of dendritic cells (see a deep dive into their complex developmental pathways in the image and link below) are also precious for our ongoing health.

There’s also reduced production of crucial immune response control chemicals like interleukin 12 (IL-12). Suppressive structural changes also occur in T cells as a result of MeV infection.

Another cause of immune uppression has been blamed on interference with normal cellular control. Even a small portion of MeV-infected dendritic cells can block the immune stimulatory influence of 1,000-fold more uninfected dendritic cells. However, it’s hard to reconcile this suppression with the dramatic increase in MeV-specific lymphocytes seen during recovery.

Suppression of the immune response isn’t just about a reduced ability to fight off new infections. Suppression also affects the containment and management of existing “commensal” bacteria as well as viruses we otherwise live alongside and often don’t notice. Reduced control permits secondary infections to cause complications like gastroenteritis, pneumonia (MeV can also cause pneumonia directly), and middle ear infection as opportunistic and commensal viral and bacterial microorganisms make the most of their moment.

After recovery from MeV infection, cell numbers return to normal levels. We can once again mount new responses to infections. However, we now lack a portion – it may be big or small – of the strength and spectrum of our previous immune memory function.

Ironically, measles doesn’t stop us from mounting a really robust immune response to MeV. However, measles can reset the clock and restock our immune pantry with lots of anti-MeV responses but with less of everything else.

We’ve now forgotten a lot about our infectious enemies and may be infected by them all over again! Immune amnesia may even lead to outbreaks of other vaccine-preventable diseases.

How does MeV leave us with fewer immune memories?

Wild MeV uses CD150 (also known as Signalling Lymphocyte-Activation Molecule, SLAM), a molecule found on the surface of many of our immune cells, as a receptor for infection.

It turns out that our lung macrophages, dendritic cells, T-cells, antibody-secreting plasma cells and our memory B cells have lots of CD150 molecules per cell, expressing more than naive or resting T cells. Both naive and memory T and B cells are susceptible to MeV infection, but memory T and B cells are moreso. Cells with immune memory are especially targeted by MeV in a study of primates. Infection leads to cell death and this is a key aspect of how Measles takes your immune memories.

MeV also enhances the expression of CD150 on infected macrophages and dendritic cells, and even a small proportion of infected dendritic cells blocks many others from fulfilling their role in stimulating T cells to develop. MeV may also destroy the young cells that would otherwise repopulate the missing B cell populations and limit B cell diversity.

Apart from CD150, MeV can also use a molecule called nectin-4 (poliovirus-receptor-like-4, PVRL4; named a bit prematurely, huh!) found on a different kind of cell called epithelial cells.

Following infection events in macaques, humans and mice revealed that lung alveolar macrophages and dendritic cells are infected early and are the predominant cells infected, transporting MeV to nearby lymphoid tissues and lymph nodes. Next, nearby immune cells are infected, spreading MeV outward to the peripheries through the bloodstream.

Historically, CD46 was once listed as the MeV receptor, but it turned out that was only the case for the lab-adapted viruses like the Edmonston strain (science is always learning). Measles literature provides a fantastic example of science adding, subtracting, replacing and learning new things in careful increments.

Trying to picture all of that

So, immune amnesia, like all things biological, isn’t exactly straightforward. It doesn’t affect all cells. It doesn’t last forever. It doesn’t always wipe out all immune memory. But it can very often result in increased risk of all-new harms to complicate what can be a nasty acute disease to start with. If you don’t have any symptoms – asymptomatic measles – you are generally at reduced risk of severe disease from measles.

Below, I’ve broken down the course of where and when measles takes your immune memories and suppresses your immune system into three complicated panels:

• The healthy, unvacinated person before MeV infection. Normal levels of lymphocytes, some naive/unchallenged, await their first encounter with an antigen, and some veteran cells are ready-to-kill, produce antibodies or quickly recruit and divide (clone themselves) to gather reinforcements.
• The now acutely ill, MeV-infected person with measles. They’ve lost lymphocytes, including those from their naive and their veteran subsets. The extent of the loss can vary as biology does. But they’ve quickly started to gain a high presence of anti-MeV lymphocytes. The virus is being cleared from their system, and they will be immune.
• Months later, the now healthy person has immunity to measles but is living with reduced defences to pathogens and vaccinations they’d previously fought off. The extent of the loss can vary depending on a range of variables. They’re now at risk – once again – from serious symptomatic infections by non-MeV things to which they were previously immune, and which they were previously better able to manage and control without getting very sick. Overall, their lymphocyte counts are back to normal, but they have new naive cells released by the bone marrow stock and have met new pathogens since their bout of measles, so they have a different immune profile.

Final point: a note on vaccines

Our measles vaccines are based on a live attenuated (which means they’re weakened) MeV. So, why don’t they also give us immune amnesia? It comes down to the bit about them being weakened. Measles takes your immune memories, but a measles vaccine helps protect and treasure them.

The vaccine virus does replicate within infected B cells; MeV RNA detection does persist, but vaccine virus doesn’t kill anything like as many cells as a “wild-type” or naturally acquired MeV infection does. Vaccination also doesn’t appear to produce culturable infectious MeV, so a vaccinated person is not transmitting MeV to another person.

All of this means that vaccination does not produce immune amnesia like a natural infection does. It’s a safe, effective and easy way to avoid all the harms listed above, including the harms that can drag on for years.