Measles and Immune AmnesiaThe risk associated with measles infection is much greater than the sum of its observable symptoms. The immune memories that you have acquired are priceless, built over many years and from countless exposures to a menagerie of germs. Measles virus is especially dangerous because it has the ability to destroy what’s been earned: immune memory from previous infections. Meanwhile, the process of fighting measles infection leaves patients especially vulnerable to secondary infection. The worldwide increase in measles prevalence is cause for concern because morbidity and mortality from the disease extends far beyond acute measles infection. How exactly can one virus wreak so much havoc?
Measles TransmissionPerhaps the best-known characteristic of measles is its extreme contagiousness. The measles virus (MV), a single-stranded (-)RNA virus that belongs to the genus morbillivirus, has only one natural host: humans. MV is extremely transmissible by aerosol droplets; in a room full of exposed people, 90% who are unvaccinated will develop the disease. To complicate matters, this microbe can linger in the air for up to 2 hours.
Measles SymptomsInfected individuals show symptoms 10-12 days after exposure, including fever, cough, runny nose, watery eyes, Koplik spots, and rash. Typically, measles infection is self-limiting and requires nothing more than palliative care to treat these symptoms. Immune-mediated clearance of the virus results in recovery and life-long immunity to the disease.
More serious complications such as pneumonia, encephalitis, and even death can occur during acute infection. Statistics show that 2-3 out of every 1000 cases will result in brain damage or death. In 2017 alone, the WHO estimated that measles and its related secondary infections were responsible for approximately 110,000 deaths worldwide. Most of these were in children less than 5 years of age.
Immune Amnesia: How Your Immune System Forgets to FightOne of the most unique -- and most dangerous -- features of measles pathogenesis is its ability to reset the immune systems of infected patients. During the acute phase of infection, measles induces immune suppression through a process called immune amnesia. Studies in non-human primates revealed that MV actually replaces the old memory cells of its host with new, MV-specific lymphocytes. As a result, the patient emerges with both a strong MV-specific immunity and an increased vulnerability to all other pathogens.
Many pathogens suppress immune function; the influenza virus damages airway epithelial cells and increases patient susceptibility to pneumonia-causing bacterial species. However, the ability to destroy immunological memory and replace memory lymphocytes is unique to MV. This MV-specific phenomenon raises a number of questions:
- How is immune amnesia accomplished?
- How long does the amnesia last?
- What can be done to correct or prevent the problem?
How Does Measles Virus Cause Immune Amnesia?MV causes infection by fusing with the plasma membranes of host cells in a receptor-dependent manner. When MV enters the respiratory tract, it infects alveolar macrophages in the lungs first. The primary role of these specialized immune cells is to engulf and destroy foreign substances like dust, bacteria, and viral particles. Alveolar macrophages also possess a membrane glycoprotein called Signaling Lymphhocytic Activation Molecule (SLAM) that has been identified as the high affinity cellular receptor for MV. MV uses SLAM to fuse directly with the plasma membrane, bypass destructive phagocytosis, and release its genome and replication machinery directly into the cell cytoplasm. Instead of destroying the measles virus upon contact, hijacked macrophages transport viral copies straight to the closest lymph nodes for dissemination.
Infected macrophages travel to lymph tissue, where the virus comes in contact with the memory cells of the immune system (memory T-cells and B-cells). These lymphocytes are recon strategists. They identify foreign invaders through antigen detection and process these molecular patterns to generate long-lived memory cells for future protection. If a second encounter occurs, memory cells will mount a faster and stronger immune response to that pathogen than during the first encounter.
Memory T-cells and B-cells contain SLAM surface receptors as well. Research has shown that MV binds and infects memory T-cells, memory B-cells, and naive B-cells of the immune system. Once infection is established, the virus spreads through the body by budding from infected cells. Clearance of MV requires the elimination of virally-infected lymphocytes. Immune-mediated destruction of memory T cells and B cells is initiated, and memories of past infections are destroyed along with them.
The number of T cells and B cells significantly decreases during the acute stage of measles infection, but there is a rapid return to normal WBC levels after the virus is cleared from the system. This observation masked what was really going on until researchers were able to evaluate the qualitative composition of recovered lymphocyte populations. We now know that the memory T-cells and B-cells that are produced immediately following infection are dramatically different from those that existed before the measles infection. Not only have pre-existing immune memory cells been erased, but there has been a massive production of new lymphocytes. And these have only one memory. Measles. Thus, the host is left totally immune to MV and significantly vulnerable to all other secondary infections. But for how long?
We now know that the memory T-cells and B-cells that are produced immediately following infection are dramatically different from those that existed before the measles infection.
How Long Does the Amnesia Last?Michael Mina and colleagues at Emory University in Atlanta, Georgia, developed a statistical model to analyze the duration of measles-induced immune suppression in children. Examination of child mortality rates in the US, UK, and Denmark in the decades before and after the introduction of the measles vaccine revealed that nearly half of all childhood deaths from infectious disease could be related to MV infection when the disease was prevalent. That means infections other than measles resulted in death, due to the MV effect on the immune system.
Furthermore, it was determined that it takes approximately 2-3 years post-measles infection for protective immune memory to be restored. The average duration of measles-induced immune amnesia was 27 months in all 3 countries. Corresponding evidence indicates that it may take up to 5 years for children to develop healthy immune systems even in the absence of the immune suppressing effects of MV infection. If MV infection essentially resets a child’s developing immunity to that of a newborn, re-vaccination or exposure to all previously encountered microbes will be required in order to rebuild proper immune function.
What Can Be Done to Correct or Prevent the Problem?Fortunately, the measles vaccine is highly effective at protecting against not only MV but also many of the opportunistic pathogens that are eager to take advantage of measles-induced immune amnesia. According to the Centers for Disease Control and Prevention (CDC), the measles, mumps, and rubella (MMR) vaccine is 97% effective at preventing measles after 2 doses, and widespread vaccination has led to a greater than 99% reduction in disease in the United States.
Why Measles Vaccination MattersMeasles continues to be one of the most highly contagious diseases in the world. The Centers for Disease Control and Prevention (CDC) reported 839 individual cases in the U.S. from January 1 to May 10, 2019. Outbreaks of this magnitude have not been seen since the Vaccines for Children (VFC) program was initiated 25 years ago and the subsequent absence of continuous disease transmission in the United States for 12+ months declared measles eliminated in the year 2000. Lack of vaccination and acquired immunity, as well as international travel, are all contributing factors to the current state of affairs.
The World Health Organization (WHO) calculated a 300% increase in measles cases in the first quarter of 2019 compared to this time last year. Madagascar, Brazil, India, the Philippians, Ukraine, and Venezuela have all been hit hard, while France, Greece, Israel, and Georgia have each endured smaller outbreaks of the disease.
Altogether, the situation has become a global crisis that is generating a lot of discussion about our collective and individual susceptibilities to measles infection. Fortunately, vaccination not only prevents the spread of measles, but also reduces the impact of immune amnesia and the subsequent secondary infections that are associated with this MV-specific phenomenon.
- ASM Article: ASM Applauds Subcommittee Hearing on Measles Outbreaks in the U.S.
- Stat News: The Tricks that Make Measles so Infectious
- ASM Resource Pages: What You Need to Know About the Measles Outbreak