Introduction

Measles, also known as rubeola, is a highly contagious, airborne childhood disease.¹ Described by symptoms such as fever, cough and distinctive rash, the virus causes both acute and profound long-lasting impacts on the immune system. In this article, the biology of the measles virus and its impact on immunity, including immune amnesia will be explored.

The pathogen

Measles Virus (MeV) is a single-stranded, negative-sense RNA virus, which is a member of the Paramyxoviridae family, a genus of the Morbillivirus. Although other members of the Paramyxoviridae family infect animals, such as rinderpest virus and canine distemper virus, MeV has exclusively human reservoirs.¹

From the RNA genome, viral mRNAs are transcribed to encode several proteins, with two surface glycoproteins around the nucleocapsid playing a crucial role in host cell infection: hemagglutinin (H) and membrane fusion protein (F). H protein is involved in receptor binding for virus attachment to the host cell, while F protein facilitates the fusion of the viral envelope with the host cell membrane, allowing viral entry.^1,2

The usage of H protein to bind to different receptors explains MeV’s ability to cause both immunosuppression and respiratory symptoms as the virus primarily uses two receptors to transfect the cells: CD150 and nectin-4 (PVRL4).^2,3,11 CD150, also known as SLAM (signalling lymphocyte activation molecule) is expressed on lymphocytes (T and B cells), dendritic cells (DCs) and macrophages⁴ while nectin-4 is found on the basolateral surface of epithelial tissues, including the respiratory tract.³

Symptoms

The initial prodromal phase starts 10-12 days after the incubation period(10)(16), symptoms include:

• High fever
• Cough
• Coryza (runny nose)
• Conjunctivitis (red eyes)

The characteristic maculopapular rash appears a few days later, starting at the hairline and spreading downward. Additionally, Koplik’s spots, are small white lesions on the buccal mucosa and are pathognomonic for measles thus can aid in early diagnosis.⁵

Immune response to measles infection

In response to infection, both the innate and adaptive immune systems play a crucial role, where the initial response is mediated by innate immunity, including macrophages and dendritic cells (9) that attempt to control the virus’s replication.

Both the macrophages and the dendritic cells help to control the virus through phagocytosis while producing a variety of cytokines to signal additional molecules and recruit other immune cells to the site of the infection.⁴ They process the antigens of the virus and present it on their surface in conjunction with MHC (major histocompatibility complex) molecules. This antigen presentation is important for the activation of T cells, a pivotal component of the adaptive immune response. With the interaction with B cells, dendritic cells play a pivotal role in initiating and shaping the adaptive immune response. This includes the production of virus-specific antibodies by B cells and the generation of memory T and B cells, which provide long-term immunity against the measles virus.^6,7

Transmission and pathogenesis

Measles is transmitted through respiratory droplets and can remain viable for up to two hours,⁸ contributing to its high contagion potential. Previously, it has been believed that the virus enters the host through epithelial cells in the airway with the help of the nectin-4 receptor. Recent studies however have shown that the primary targets of MV are the alveolar macrophages, while the respiratory epithelial cells are infected later by PVRL4 receptor.³

After its entry via inhalation from the external environment, the H protein of the virus encounters CD150-positive alveolar macrophages and dendritic cells in the upper and lower respiratory tract.⁹ F protein then facilitates the infection of these white blood cells, which carry the virus to draining lymph nodes, enhancing the amplification of the pathogen and hence establishing primary viremia. This incubation period is typically 10-14 days long.^10,16 The amplified virus then disseminates to secondary lymphoid organs such as the thymus, spleen, and tonsils where secondary viremia and acute immunosuppression occur.² The virus then spreads to distal sites such as the skin kidneys, liver, gastrointestinal tract, and respiratory tract.

Contact of the infected immune cells with the airway epithelial cells occurs via Nectin-4, which is located on the basolateral side of the lung airway epithelium, allowing MV to enter the epithelial cell. Here, a final virus amplification happens, which is then followed by the shedding of the virus from the apical surface to the airway lumen where the pathogen can exit the host via air droplets to infect other individuals.³

Immune suppression induced by measles

Measles has a profound impact on the immune system, with immune-mediated destruction of T and B lymphocytes,¹⁷ leading to significant lymphopenia¹² which impairs the body’s ability to mount effective immune response to other pathogens. This state of transient immunosuppression causes increased susceptibility to secondary infections.

As the virus mainly targets memory B cells,¹³ a particularly concerning effect of measles results in the repression of immune memory, a phenomenon known as “immune amnesia”.¹⁴ By wiping out 11-73% of the body’s antibody repertoire,¹⁵ this effect reduces the diversity of the memory B cells and erases adapted immunological memories. This depletion hinders the body’s ability to respond to previously encountered pathogens and vaccines (such as pertussis, diphtheria and influenza). Due to this, individuals who recover from measles have 90% risk of other infections for several years,¹⁶ whilst being resistant to the measles itself. This indicates a long-term impact on immune function.

While erasing previously known antibodies, the virus also targets non-specific naïve B cells¹³ in the bone marrow to enhance the production of antibodies specific to the MeV. These cells are ineffective antigen-presenting cells, however, when they encounter a specific antigen through B cell receptors, they become activated, proliferate, and differentiate into memory B cells and antibody-secreting plasma cells.

Dysregulation of the cytokines

Cytokines are signalling molecules that play a crucial role in the immune response, including cell communication, activation, and differentiation. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is critical for cytokine signalling.²⁰ If inhibited by MeV proteins (especially V protein) the cytokine responsiveness will be decreased.

During infection, measles disrupts the balance between Th1 (a cytokine that promotes inflammation) and Th2 (a cytokine that inhibits inflammation), in relation to T helper cell responses. The virus skews the immune response towards a Th2-dominated response, characterized by the production of IL-10 and TGF- β (mentioned later), while the Th1 response is suppressed. Th1 is involved in the production of key pro-inflammatory cytokines such as the Interferons (IFNs), Tumour Necrosis Factor (TNF-α) and Interleukin-1 (IL-1), which are essential for initiating and sustaining an effective immune response. The suppression of the IFNs-type I (IFN-α and IFN-β) and type II (IFN-γ) prohibit the activation of natural killer (NK) cells and the promotion of antigen presentation by DCs and macrophages. While the reduced secretion of TNF-α and IL-1 hampers the recruitment and activation of both the innate and adaptive immune cells to the site of the infection. This impairs the body’s ability to mount an effective antiviral response. On the other hand, the upregulation of regulatory cytokines such as Interleukin-10 (IL-10) and Transforming Growth Factor (TGF- β) inhibit the function of T cells, DCs and macrophages to contribute to further immunosuppression.^18,19

As the pathogen directly reaches and infects the DCs and Macrophages, these white blood cells will produce a reduced number of key cytokines, that are required for T-cell activation and differentiation. Moreover, antigen presentation will be dysfunctional.

Vaccination and its role in preventing measles

The increased risk after several years of recovery from measles highlights the importance of sustained public health efforts to prevent measles and its associated complications. In 1988, the measles vaccine was administered as part of the measles, mumps, and rubella (MMR) vaccine in the UK,²¹ which led to a dramatic success in reducing the incidence of the disease.

This live attenuated vaccine mimics natural infection without causing the disease by inducing the production of neutralizing antibodies and the development of memory B and T cells, hence providing a long-lasting protective response. One dose of the treatment provides about 93% protection, while a second booster dose gives 97% protection²² and would maintain optimal protection.

Individuals, who cannot be vaccinated such as immunocompromised people, can be protected by the community through herd immunity as high vaccination coverage would reduce the overall circulation of the virus among the population. So, it is crucial to have public implications and strategies to prevent outbreaks and protect public health.

Conclusion

With a high percentage mortality rate, measles is more than just a childhood illness; it is a serious disease that can affect large communities easily through respiratory droplets. The virus not only causes acute illness but also has long-lasting effects on the immune system, also known as immune amnesia. This exposes the immune system to increasing susceptibility to other infections by deleting previously known immunological memories. Although vaccination is the most effective way to induce herd immunity, challenges occur concerning insufficient access to the vaccine and vaccine hesitancy. Continued efforts in education, surveillance, and research are essential to control and ultimately eradicate measles, ensuring a healthier future for all.