The pathogenesis of measles virus infection

Introduction

Measles is one of the most important contagious diseases of mankind. It remains one of the leading causes of infant deaths in developing countries. In 1998 the world health organization (WHO) estimated that despite all the efforts to eradicate measles it still accounted for more than 30 million infections and 1 million deaths every year. Most the infections, it is believed are from countries where vaccination has not been taken up properly and developing countries where vaccination programs are not that robust.

Measles is very infections with an infection rate of 90% when susceptible individuals are exposed to the organism that causes measles. This organism is an RNA virus of the genus morbillivirus, hence measles sometimes being referred to as morbilli. This virus belongs to the virus family of the Paramyxoviridae. The measles virus is transmitted through bodily fluids mainly as aerosols (airborne exposure) or droplets. It enters the host through the respiratory tract and immediately starts to replicate in the epithelial cells of the respiratory tract, from here the virus start to invade some cells of the immune system in the lymph nodes particularly the monocytes through which it then spreads to rest of the host body.

Measles is a self-limiting disease, which means it will normally resolve itself after a few weeks, but because measles also induces transient profound immunosuppression, most of its victims succumb to fatal opportunistic infections. Without these infections, the host will normally clear the virus from its system as illustrated by the graph below.

It should be noted that in very rare cases the measles virus cannot be cleared from the host and persist in the host system in what is termed persistent measles virus (PMV). This is the cause of most measles complications which includes subacute sclerosing pan encephalitis (SSPE) which may occur in about 1:10 000 measles cases and inclusion encephalitis which may occur if the host does not have adequate cellular response to the infection.

Infection and Spread

Clinical symptoms of measles include fever, malaise, coryza (runny nose), conjunctivitis, and tracheobronchitis. Other symptoms that appear at a later stage during infection are the Koplik’s spots, 10-12 days post-exposure, and erythematous maculopapular rash which appears at around day 14. Symptoms like diarrhea and pneumonia, which are from opportunistic infections, will not be discussed here as they are not a direct result of the measles virus. The direct results will be discussed later in this essay after discussing how the virus infects and spread around the host body. To fully understand the mechanism of measles virus infection, one has to understand the measles virus structure.

The Virus

As a morbillivirus in the paramyxoviridae family, the measles virus is a negative, single-strand enveloped RNA virus. It is about 150-300 nm in diameter and has a lipid bilayer surrounding the RNA forming the envelope. Protruding from this envelope are two glycoprotein ligands called haemagglutinin (H) and fusion (F), necessary for virus attachment to host cells. The RNA is enclosed in a nucleoprotein (N) and associated with two proteins called phosphoprotein (P) and large protein (L).

The lipid envelope on the outside of the virus is acquired from the host cell during budding, because this outer layer is made up of host material it becomes difficult for the body’s immune system to detect the virus as non-self in the initial stages of infection enabling the virus to gain a foothold.

Directly beneath the lipid envelop is the matrix (M), a protein that is important in virus replication as it facilitates the assembly of virus particles to the cell surface membrane during budding.

The nucleoprotein (N) forms a protective sheath around the virus RNA called the nucleocapsid. The associated proteins P and L have been suggested to act as virus polymerase by some studies, helping in RNA replication.

Then there are the two glycoproteins H and F. As their names suggest, they are responsible for anchoring the virus to the host cell and penetration of the cell membrane. The haemagglutinin binds (agglutinates) the virus to the host cell receptor (CD46, to be discussed later) and the fusion protein fuses the virus envelope with the cell membrane.

Infection

The infective process occurs in two key stages of attachment and fusion. In order for the virus genome to gain entry into the host cell and start replicating it needs to “catch” and “inject” host cells with its genome.

The “catching” of host cells occurs when the virus haemagglutinin protein (H) attaches to the host cell receptor CD46. CD46 in the human cell act as a co-factor for serine protease degradation of C3b and C4b, these are the complement proteins of the immune system hence immunosuppression by the measles virus. Studies suggest that there exist more undefined virus receptors that enable the virus to attach to its host cells. The formation of syncytiae, cell-to-cell contact, also allows virus to spread to other cells.

The “injecting” of host cells with the virus genome occurs during fusion, and the processes are less understood. It is thought that the same fusion processes occur for all enveloped virus, and studies on human immune-deficiency virus (HIV) has shed some light into this. Two glycoproteins are involved, gp41 and gp120. gp41 is anchored onto the virus envelope and gp120 attaches to the host cell CD4 receptor next to the CCR5 co-receptor. Structural changes then occur whereby the gp41 is driven into the membrane of the host cell thereby linking the two cells (virus and host). The whole structure of gp41, gp120, co-rector CCR5 and CD4 receptor then collapses leaving the two membranes in apposition for fusion.

Spread

As discussed earlier, the virus enters the host through the respiratory tract, where it replicated in the epithelial cells. Then it infects cells of the immune system, monocytes are the most affected cells. B and T lymphocytes are also infected but at less proportions as compared to monocytes. This amplification of the virus occurs in the lymph nodes of the host. Monocytes, B and T lymphocytes are cell of the peripheral blood and therefore circulate around the body, carrying with them the virus and spreading the infection to other parts of the body including the skin, gastrointestinal tract, liver and the central nervous system. Disseminated virus proliferation occurs in the epithelial and endothelial cells of the blood vessels and other infected organs. Another mode of spread (mentioned earlier) is the formation of syncytia, not only do infected cells aggregate together, but they can also form syncytia with noninfected cells, therefore, infecting them in the process.

Symptoms

The symptoms of measles infections as mentioned earlier are fever, malaise, coryza, conjunctivitis, cough, and Koplik’s spots in the oral cavity, later on, the erythmatous maculopapular rash appears. These symptoms are tied with the immune response as the virus infection progresses. From day 0 when the virus first enters the host to around day 8, the first response from the immune system is the innate one, which is characterized by inflammation, giving rise to fever and general body malaise. As the virus continues to replicate in the epithelial cell of the host especially the nasal cavity (causing coryza), the trachea and bronchus (causing coughs), the nasolacrimal duct (causing conjunctivitis) and the oral epithelial cells (causing Koplik’s spots), it irritates these mucosal surfaces and causes their inflammation. The appearance of Koplik’s spots is diagnostic of measles and it signals the appearance of early symptoms and viral load start to peak in the blood (refer to fig 1 for the measles timeline in-host infection). These spots are transient and last for only about 3 to 4 days; also it is about this time that the adaptive immune response starts to kick in. At day 14 the viral load is at its peak and the adaptive immune response is fully operational and is clearing the pathogen from the system, the formation of the immune complex on the skin as the virus gets cleared result in the measles rash signaling cytotoxic T cell clearance of virus-infected cells. After peak levels of the virus, following successful adaptive immune response, the virus levels drop and the immunological memory begins. In rare circumstances the virus can persist in the host, causing complications. One of these complications is subacute sclerosing panencephalitis (SSPE), discussed below.

Subacute Sclerosing Panencephalitis

This is one of the complications of persistent measles virus infection; it affects the central nervous system of children who are infected by measles virus at a very early age. These children normally lack the maternal antibodies in their circulation to help combat the infection at its early stages. Studies found that 50-75% of children who develop SSPE had measles infection before the age of two and also the prevalence rates of SSPE are 1:10 000 cases. This complication can take a very long time to manifest itself, with an average time of 8 years before SSPE symptoms appear and the reported range is between 9 months and 30 years. The disease leads to neurological deficits and eventually the patient dies. The other two measles complication worth mentioning are progressive measles inclusion body encephalitis (MIBE) which can occur in patients who are immunocompromised, and the post-infection encephalomyelitis which is an autoimmune disorder that attacks the myelin sheath covering neurons.

Recovery from measles (assuming opportunistic infections have not prompted medical intervention) requires both the humoral and cell-mediated immune response. Cytotoxic T lymphocytes clear infected host cells and measles antibodies reduce free viral load by serum neutralisation these antibodies can also be directed directly against the virus. The humoral response as usual is mostly for preventing re-infection and is involved in building immunity, a process taken advantage of by vaccine developers. After cytotoxic clearance of infected cells; there follows an immunologic type 2dominance where cytokines IL4, IL5, and IL10 are secreted by type 2 CD4+ T cells.

Vaccination

Many virus infections are untreatable, they are either self limiting, maim, or kill the host, so the only intervention that is available is to prevent infection in the first place. As noted from fig 1, after day 21 when the pathogen has been cleared, immunological memory is activated. This activation of immunological memory can only happen after the host has encountered the measles virus. Subsequent infections are met with a robust humoral response and the virus does not progress to cause infection. This is the basis of immunisation, the host immune system has to be introduced to the virus first, and as there is a risk of the virus overwhelming the immune system most virus used in vaccines are “controlled”.

Attenuated Virus Vaccine

Once the measles virus was isolated and cultivated by Enders and Peebles it was then able to be manipulated. They found that the virus once cultured in chick embryos was attenuated in virulence and immunogenic enough to stimulate the host immune system to produce antibodies against it and remembering it.

Work to produce a licensed measles vaccine begun in 1958 and by 1963 the first licensed measles vaccine, RUBEOVAX®, was available. In 1968 a more attenuated vaccine ATTENUVAX® was licensed. As more vaccines for viruses e.g. mumps and rubella were developed there was a need to combine the doses into one single shot. In 1971 a trivalent vaccine with all three vaccines, measles-mumps-rubella was licensed. In recent times a fourth vaccine has been added to the MMR vaccine, resulting in a tetravalent vaccine MMRV. The fourth vaccine is a chicken pox vaccine, varicella.

Other Virus Vaccines

Other less favourable virus vaccines exist. Experiments were done on high titre vaccines by Sabin et al. These were aimed at infants who are at risk because they have circulating maternal measles antibodies which prevent vaccine uptake by neutralising it. The other vaccine, an inactivated measles virus vaccine produced by killing the virus in formalin was produced and licensed in 1963. It fell out of favour because the immunity if offered lasted for only one year and it had to be taken in three doses.

With vaccination and great knowledge gained from studying measles it can be said that total eradication of the virus is possible. It is the beliefs and cultures of people that are slowing this up because they are not taking up vaccination.

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