Measles and the Immune System: The Surprising Truth

“Don’t worry about vaccination. Just build up your child’s immune system and they’ll be fine.”

“Your child’s immune system is strengthened by encountering diseases like the measles.”

With a measles outbreak in Washington (and now Oregon), I’m seeing statements like this on social media. Some state that they believe that their child won’t get measles with a healthy immune system.  Others maintain that getting measles is beneficial for their child. But what’s the truth about the immune system and the measles? How does measles cause infection? What does it do to the immune system during infection?  How does the vaccine help?

The cells and microbes in your neighborhood

What we call the immune system is a complex network of cells, structures, and processes that monitor the metropolis of cells in our body, determining whether they are pathogenic or not, and then coordinate the appropriate response.  Pathogenic refers to cells (whether microbes or our own cells)  that cause damage. Most microbes do not cause harm, or at least not to us. Microbes reside within us, and we reside in an world abundant with them. Some keep to their neighborhood, content to populate their niche, whether it’s the soil of a potted philodendron or our colons and skin. Others, like the citizens of adjoining nations,  move back and forth across the borders of our body, helping to carry about the needed business of our life, connecting us to the environment around us. Like people, many are helpful or harmless, except perhaps under stressful or abnormal conditions. And then there a few that seem to intend no good to anyone but themselves. The immune system is pretty good overall at figuring out if this is a familiar microbe, a harmless passerby, or if it’s a problem.

Dendritic cells are the “greeters” of the immune system and among the first cells that a microbe will encounter. They  are located in the skin, gut and lungs – anywhere that we interface with the outer world. They also located in concentrations lymphoid tissues such as in the bronchi and gut. Dendritic cells greet what comes by, sample the newcomer, and then communicate to the rest of the immune system what the microbe is. If it’s a problematic microbe, the dendritic cells signal to the rest of the innate immune system to start preventing the microbe from spreading. (Otherwise they signal to let it be.)

Your immune system, once it determines that an organism is a problem, has two major strategies to respond to these problematic pathogens. The first strategy is called innate immunity. This strategy is a general response to the type of problematic microbe: viruses, bacteria, fungi, parasites. Innate immunity, for instance, doesn’t need to know if it’s the flu, a cold, or measles: it just knows that it has encountered a problematic virus, and responds.

The second strategy is called acquired or adaptive immunity. As the dendritic cells and other first-line response cells start to engage with a virus or bacteria, they send information to other cells, such as B-Cells and T-cells, alerting them that there is a problematic microbe. The information includes how to respond in more specific ways, making antibodies (B-cells) and priming T-cells, to respond to a particular pathogen.

Acquired immunity takes roughly 10 to 14 days to produce these pathogen-specific antibodies and cells the first time it  encounters a pathogen. Later, if the immune system encounters this particular pathogen, it can respond much faster to prevent infection taking hold again. But acquired immunity depends upon the innate immune system for the information that it needs to start this process. And passing along that information depends upon the initial signaling process, called interferon (IFN) induction.

Measles first strike advantage: silencing immune system cell-to-cell communication

How does measles virus subvert this complex chain of sampling, evaluating, communicating, and responding? It does so by infecting the cells of the immune system. These cells carry a specific cell marker, CD150+. Measles uses that marker to fuse with the immune system cells and then injects the virus’s contents into the immune cells’ interior.  Measles’ first targets are dendritic cells and macrophages, the first responders of the innate immune system. Once the virus is injected, it severely inhibits the dendritic cells  and macrophages production of interferon[1], which helps initiate and direct the response of both the innate and acquired immune system to pathogens.  It’s the immune system equivalent of putting your smartphone on airplane mode: the dendritic cells and macrophages can’t message other cells. The innate immune system can’t spring into action to shut down the viral invasion by stopping viral replication. And the acquired/adaptive immune system, instead of making measles- specific antibodies and cells, doesn’t get the message.  

Measles: making zombies out of immune cells

The silenced dendritic cells and macrophages, do what they always do when there is an invading pathogen: they travel to nearby (or draining) lymph nodes. Once there they pass the measles virus to other immune cells, cell-to-cell. The measles virus infects the very cells that would otherwise fight it: B-cells that make antibodies to measles,  cytotoxic T-cells that would otherwise dispatch the virus-infected cells, macrophages as well, impairing the body’s ability to clean up dead cells and respond to other microbes.

The silenced, virus-infected immune cells continue moving  through the lymph nodes to the thymus, the spleen, infecting – and silencing – still more immune cells along the way. Lymphocyte production is reduced;  macrophages and monocytes die through apoptosis. This further reduces the body’s ability to respond to infections.

The viral infection travels to the bronchus-associated lymphoid tissue (BALT) and the gut-associated lymphoid tissues (GALT). These are key areas for the body’s defense against problematic microbes in the air we breathe and the food we eat. A curious thing happens: Once infected, these crucial lymphoid tissues go into overdrive, churning out B-cells that are unresponsive to the measles virus. Unable to defend against problematic microbes in the lungs and gut, 6% of those infected develop pneumonia; 8% develop diarrhea. This frantic lymphocyte overproduction leads to B-cell depletion and B-cell exhaustion. This is called “the measles paradox”: there is a massive expansion of lymphocytes, and yet the immune system is unresponsive, not just to measles, but to infections in general.[2]

With the main defenses rendered powerless, the wild-type measles virus then goes on to infect the rest of the body. It infects the cornea, blinding children to this day; it infects the capillaries of the skin; the kidneys, the gut. Measles infect neurons, leading to measles encephalitis, with a 15% risk of death.  During this time the virus continues to multiply, and the infected person coughs out the virus from the lungs and nasopharynx. One person can infect up to an estimated 19 other people.

The wild type measles virus also takes aim at the “memory” cells of the immune system, wiping out the memory of all the infections the body has encountered before, and ensuring it can’t form a “memory” against new ones – including the measles.  This means the measles-infected person is more vulnerable to infections that they might otherwise fend off. This is why children (and adults) who have measles become easily infected with pneumonia and other illnesses, both during the measles and for months to years afterwards [3]. When looking at the death rate for measles prior to vaccination, it’s important to realize that many deaths from measles were recorded as being due to secondary infections, such as pneumonia.

What brings measles  to a stop? Enter Mr T.

While measles suppresses immune cell signaling through interferons, there are other signals given off by stressed, virus-infected cells [1,2].   Eventually  a special type of immune cell, the CD8+ (cytotoxic T-cells) develop the ability to target and kill measles-infected cells. As these T-cells clear the virus, the characteristic skin rash appears, produced by inflammation from the cytotoxic T-cells clearing the virus from the capillaries of the skin.

Once the rash appears, the fever falls and the person starts to recover.

But, the bad news

Even in developed areas, even with good nourishment, 20% or more of those infected with measles will need hospitalization. Measles hospitalization costs range from $5000 up to nearly $50,000.[4] What type of measles infections lead to hospitalization? Infected lung cells lead to pneumonia in 6% of cases. Infected neurons may lead to seizures in 0.6% to 0.7% of cases; or to encephalitis in 1 out 1000 (or 0.1% of cases); 15% of those with encephalitis die. Diarrhea develops in 8% of cases.[5] Children under age 1 at the time of infection have a ~ 1 in 609 chance of developing sub-sclerosing measles panencephalitis (SSPE), a devastating and fatal neurological degenerative disease that can develop some years after measles infection. Those under 5 have a 1 in 1367 chance of developing SSPE [6].

Furthermore, even with excellent medical care and hospitalization, the death rate for measles is still 0.1% to 0.2%, including in recent outbreaks.  WIthout good medical care, death rates are much higher [7].  Additionally  the immune system continues to be suppressed for months to years, leading to increased deaths of children long after the measles rash has faded. When looking at historical death rates for children in the pre-vaccination era, researchers found that death rates increased for up to three years following measles epidemics. Once the vaccine was introduced, the death rate for children fell by far more than expected. (Vaccinated children, by contrast, are more likely to be alive three years later than a child who has had a measles infection.)[3]

One or two dead children out of a thousand may not sound like a high death rate. But suppose you were told you could send your child to a football game, in a stadium filled to capacity at 72,000 children.  And you were told that of all the children attending, 64,800 would become sick. 453 children would have seizures; 518 children would have diarrhea; 12,960 to 16,200 children would be sent to the hospital; 64 children would have encephalitis; 64 children would die while attending the game. Out of those under age one, one out of every 600 would have SSPE, so if the stadium was filled with babies under a year, 108 would eventually develop degenerative neurological disease and die.

Would you attend the game? Would you take your child to the game?  Probably not. Yet that’s the odds your unvaccinated child faces with measles. And that doesn’t include the increased odds of death – or long term damage – in the two years following measles.

How does measles vaccination help, and what is different about how the body responds?

Vaccine type strains have been cultured and bred until they are no longer virulent (e.g. capable of causing disease). Yet measles vaccine strains still having the cell markers that allow the immune system to make antibodies and cellular responses that identify the measles virus. Unlike wild-type measles, the vaccine strains do not suppress the immune system [8]. So the body can suppress viral replication. The dendritic cells can signal the acquired immune system to get to work building antibodies and setting up cellular responses. Meanwhile,  the body is able to fight off any other infections that the person is exposed to. Measles vaccines do not weaken the immune system. Wild-type measles infection does weaken the immune system.

Additionally the vaccine measles strains  infect fewer cells, and fewer types of cells, than wild-type strains do – which is desirable. Vaccine strains don’t spread to the eyes; they don’t spread to the body at large. Measles vaccine strains do not spread to the respiratory system, which means that the vaccinated person cannot infect others. Immune cells infected by vaccine measles strains develop responses that  inhibit the spread of the virus to other cells [9]. Measle vaccine strains spare memory B-cells and memory T-cells[10]. This allows the body to form immune memory to the measles – and to keep the memory of the other infections it has fought. The vaccinated person is able to fully respond to other infections [3].

Because the measles vaccine strains do not spread to the lungs and nasopharynx, the vaccinated person cannot infect others. The vaccine strains do not the damage in the body that the wild-type measles does [10]. In short, the measles vaccines gets in, gives its information to the immune cells, and allows the immune system to do its job of preparing defenses for the wild-type measles virus. Then the measles vaccine virus dies off. As one publication puts it, the vaccine “may elicit an earlier and more-efficient immune response [than wild-type measles infection]” [10].

If, in the future, your vaccinated child meets the wild-type measles virus, their body will immediately recognize it, and the immune system will be able to take the virus down with ready-to-hand production of antibodies that will prevent infection. The vaccinated child (and adult) will have measles-specific CD8+ cells available to clear any cells that do get infected. They will not have to suffer months and years of increased susceptibility to increased infections.   And they will not have to run the risks of hospitalization, pneumonia, the increased risk of seizures, or the dread of wondering if, some years later, they are going to start developing seizures and a degenerative brain disease.

So what is the take-home here?

Your child may have a great immune system. Your child’s immune system does need to develop. It does need to learn to deal with microbes. And it can do that on a daily basis, with the everyday microbes of your child’s biome, their ‘neighborhood’.

But there is a reason measles has been infecting the vast majority of the population since at least the 7th century CE: it’s good at being bad. By the time measles gets through with your child, your child has significant chances of being hospitalized, having had diarrhea, pneumonia, or ear infections, or develping more severe complications. Your child will end up being sicker than they would have been otherwise for a long time afterwards as well. And your child may die. A lot of people died from measles, and still die from it. This isn’t your child versus the grouchy but otherwise decent guy down the street. This is your child versus Internecivus raptus from Alien crossed with a zombie.

Don’t ask your child to take on measles.

The technical details:

The details of how measles infections begins, proceeds, and resolves are more complex than I have presented them here. However, the critical aspects are presented here.

Measles initially enters through the respiratory tract (and perhaps the conjuctivae of the eye). There it encounters pulmonary dendritic cells and alveolar macrophages, which transport it to the regional lymph nodes [9,11] where it then proceeds to infect B-Cells, CD4+ and CD8+ memory T-cells, and monocytes. These in turn spread to lymphoid tissues such as the spleen, lymph nodes and thymus, traveling via the circulation, as well as to non-lymphoid organs such as the liver, kidneys, conjunctivae, lungs, and skin. There the measles virus proceeds to multiply in additional lymphocytes and macrophages as well as in epithelial and endothelial cells [1]. The virus enters using the CD150+ receptor, expressed on the surface of numerous immune cells [12–15] and then proceeds to inhibit lymphocytic proliferation as well as IFN production [8]. Infection proceeds by cell-to-cell contact [5,12].

The humoral response protects against infection, but the cellular response is required to clear established infection; studies have noted that those with defective T-cell response [16] will not develop the characteristic rash (caused by the CD8+ activity in the skin) and instead have a high mortality rate.

Immunosuppression caused by measles from eMedicine Medscape:

“Measles virus infection causes a generalized immunosuppression marked by decreases in delayed-type hypersensitivity, interleukin (IL)-12 production, and antigen-specific lymphoproliferative responses that persist for weeks to months after the acute infection. Immunosuppression may predispose individuals to secondary opportunistic infections, [15] particularly bronchopneumonia, a major cause of measles-related mortality among younger children. The replacement of memory cells specific for other infections, with measles-specific cells, leaves children vulnerable to secondary infections for up to two years after measles infection [2]. In individuals with deficiencies in cellular immunity, measles virus causes a progressive and often fatal giant cell pneumonia.”

In contrast to wild-type measles infection, in subcutaneous vaccination with attenuated strain, muscle cells were not infected; dendritic cells and macrophages were the primary targets. In intratracheal or aerosol infection of macaques, only wild-type measles virus led to viremia and dissemination to lymphoid tissues, respiratory submucosa, and the skin [9]. Both wild-type measles RNA and vaccine-type measles RNA are detected in urine [17], but vaccine-type measles RNA is only rarely detected in throat or nasopharyngeal specimens [9] – which is how it is transmitted in humans. No person to person transmission of measles vaccine has been reported. Vaccination prevents the post-infection immunosuppression of wild-type measles infection, preserves “polymicrobial herd immunity”,  and improves mortality from other infectious diseases in vaccinated children vs unvaccinated children [3].

With thanks to The Mad Virologist for the technical review on the virology aspects. Any errors in fact or conclusion (or typos) are my own. 

References

1. Griffin DE. The Immune Response in Measles: Virus Control, Clearance and Protective Immunity. Viruses. 2016;8. doi:10.3390/v8100282
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3. Mina MJ, Metcalf CJE, de Swart RL, Osterhaus ADME, Grenfell BT. Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Science. 2015;348: 694–699. doi:10.1126/science.aaa3662
4. VFC | Publication on Cost-Benefits | Vaccines | CDC [Internet]. 17 Apr 2018 [cited 8 Feb 2019]. Available: https://www.cdc.gov/vaccines/programs/vfc/pubs/methods/index.html?fbclid=IwAR25J1ENYpbQp4lzshyxRBR0LvJu4K-Kho6YVI_ePvCR9OH2MH7O7KTm-IM
5. Pinkbook | Measles | Epidemiology of Vaccine Preventable Diseases | CDC [Internet]. 27 Jul 2018 [cited 28 Jan 2019]. Available: https://www.cdc.gov/vaccines/pubs/pinkbook/meas.html
6. Wendorf KA, Winter K, Zipprich J, Schechter R, Hacker JK, Preas C, et al. Subacute Sclerosing Panencephalitis: The Devastating Measles Complication That Might Be More Common Than Previously Estimated. Clin Infect Dis. 2017;65: 226–232. doi:10.1093/cid/cix302
7. Moss WJ. Measles still has a devastating impact in unvaccinated populations. PLoS Med. 2007;4: e24. doi:10.1371/journal.pmed.0040024
8. Shingai M, Ebihara T, Begum NA, Kato A, Honma T, Matsumoto K, et al. Differential Type I IFN-Inducing Abilities of Wild-Type versus Vaccine Strains of Measles Virus. The Journal of Immunology. 2007;179: 6123–6133. doi:10.4049/jimmunol.179.9.6123
9. Baldo A, Galanis E, Tangy F, Herman P. Biosafety considerations for attenuated measles virus vectors used in virotherapy and vaccination. Hum Vaccin Immunother. 2016;12: 1102–1116. doi:10.1080/21645515.2015.1122146
10. Condack C, Grivel J-C, Devaux P, Margolis L, Cattaneo R. Measles virus vaccine attenuation: suboptimal infection of lymphatic tissue and tropism alteration. J Infect Dis. 2007;196: 541–549. doi:10.1086/519689
11. Griffin DE, Pan CH. Measles: old vaccines, new vaccines. Curr Top Microbiol Immunol. 2009;330: 191–212. Available: https://www.ncbi.nlm.nih.gov/pubmed/19203111
12. Erlenhoefer C, Wurzer WJ, Löffler S, Schneider-Schaulies S, ter Meulen V, Schneider-Schaulies J. CD150 (SLAM) is a receptor for measles virus but is not involved in viral contact-mediated proliferation inhibition. J Virol. 2001;75: 4499–4505. doi:10.1128/JVI.75.10.4499-4505.2001
13. de Vries RD, Mesman AW, Geijtenbeek TBH, Duprex WP, de Swart RL. The pathogenesis of measles. Curr Opin Virol. 2012;2: 248–255. doi:10.1016/j.coviro.2012.03.005
14. Laksono BM, de Vries RD, McQuaid S, Duprex WP, de Swart RL. Measles Virus Host Invasion and Pathogenesis. Viruses. 2016;8. doi:10.3390/v8080210
15. Laksono BM, Grosserichter-Wagener C, de Vries RD, Langeveld SAG, Brem MD, van Dongen JJM, et al. In Vitro Measles Virus Infection of Human Lymphocyte Subsets Demonstrates High Susceptibility and Permissiveness of both Naive and Memory B Cells. J Virol. 2018;92. doi:10.1128/JVI.00131-18
16. Morris SE, Yates AJ, de Swart RL, de Vries RD, Mina MJ, Nelson AN, et al. Modeling the measles paradox reveals the importance of cellular immunity in regulating viral clearance. PLoS Pathog. 2018;14: e1007493. doi:10.1371/journal.ppat.1007493
17. Rota PA, Khan AS, Durigon E, Yuran T, Villamarzo YS, Bellini WJ. Detection of measles virus RNA in urine specimens from vaccine recipients. J Clin Microbiol. 1995;33: 2485–2488. Available: https://www.ncbi.nlm.nih.gov/pubmed/7494055
18. World Health Organization. WHO position on measles vaccines. Vaccine. 2009;27: 7219–7221. doi:10.1016/j.vaccine.2009.09.116

Additional references:

Grosjean I, Caux C, Bella C, et al. Measles virus infects human dendritic cells and blocks their allostimulatory properties for CD4+ T cells. J Exp Med. 1997;186(6):801-812. doi:10.1084/jem.186.6.801

Naniche D, Garenne M, Rae C, et al. Decrease in measles virus-specific CD4 T cell memory in vaccinated subjects. J Infect Dis. 2004;190(8):1387-1395. doi:10.1086/424571

Lucas CJ, Biddison WE, Nelson DL, Shaw S. Killing of measles virus-infected cells by human cytotoxic T cells. Infect Immun. 1982;38(1):226-232. https://www.ncbi.nlm.nih.gov/pubmed/6982861.

Jirapinyo P, Thakerngpol K, Chaichanwatanakul K. Cytopathic effects of measles virus on the human intestinal mucosa. J Pediatr Gastroenterol Nutr. 1990;10(4):550-554. https://www.ncbi.nlm.nih.gov/pubmed/2358987.

Esolen LM, Park SW, Hardwick JM, Griffin DE. Apoptosis as a cause of death in measles virus-infected cells. J Virol. 1995;69(6):3955-3958. https://www.ncbi.nlm.nih.gov/pubmed/7745753.

Valsamakis A, Kaneshima H, Griffin DE. Strains of measles vaccine differ in their ability to replicate in an damage human thymus. J Infect Dis. 2001;183(3):498-502. doi:10.1086/318073

Lin W-HW, Pan C-H, Adams RJ, Laube BL, Griffin DE. Vaccine-induced measles virus-specific T cells do not prevent infection or disease but facilitate subsequent clearance of viral RNA. MBio. 2014;5(2):e01047. doi:10.1128/mBio.01047-14

Holmgren AM, McConkey CA, Shin S. Outrunning the Red Queen: bystander activation as a means of outpacing innate immune subversion by intracellular pathogens. Cell Mol Immunol. 2017;14(1):14-21. doi:10.1038/cmi.2016.36

Yanagi Y, Takeda M, Ohno S. Measles virus: cellular receptors, tropism and pathogenesis. J Gen Virol. 2006;87(10):2767-2779. doi:10.1099/vir.0.82221-0

Al Ani SS. Measles. https://www.slideshare.net/alanisaad/measles-5230049. Published September 18, 2010. Accessed January 27, 2019.

Kondamudi NP, Waymack JR. Measles. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2018. https://www.ncbi.nlm.nih.gov/pubmed/28846330.