Infectious Mononucleosis

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Infectious Mononucleosis

By David Lamar

Infectious mononucleosis, also known as mono, is a disease caused by the Epstein-Barr virus (EBV). Characteristic symptoms include fever, fatigue, sore throat, and swollen glands, which can last for several weeks. Most commonly, the virus is spread through saliva (Nieves, 1998). The disease has been recognized since 1920, but the EBV was not known to be its cause until the late 60s (Omari, 1999). Infection by the virus is common to the majority of children and adolescents world wide (nearly 90% in third world countries) but actual pathology usually occurs in adolescents of high economic status from developed countries (Omari, 1999). Fatality can occur and is due to rupture of the spleen but this is very rare (Nieves, 1998). In general, the symptoms of mono are effectively eliminated by the body, but the virus can remain latent for life.

Infection by Epstein-Barr Virus
The virus enters the body via the saliva and infects B cells in the tonsils and pharyngeal epithelial tissue (Omari, 1999). This requires the virus binding to CD21, a surface receptor expressed on mature B cells (Janeway et al., 1999). Upon infection, the virus replicates and enters its lytic phase (Cohen, 1998). Infected B cells are induced to undergo significant proliferation, which in turn leads to the activation and proliferation of CD8 cytotoxic T cells specific for viral antigens expressed as MHC class I/peptide complexes on the infected B cells. This system-wide proliferation of lymphocytes is the main cause of pathology in mononucleosis (i.e. glandular swelling, tonsilitis, enlargement of the sleen) (Omari, 1999). A characteristic indication of the disease is the presence of “atypical” cytotoxic T cells, or Downey cells, in the blood (See Figure 1). Typically, the symptoms of infectious mononucleosis are cleared after several

Figure 1. Downey cells (dark purple) and erythrocytes (light purple) in blood of an individual with infectious mononucleosis (Friedlander, 2000). Permission to use requested.

weeks, when cytotoxic T cells eventually destroy the proliferating infected B cells (Nieves, 1998). Although the symptoms rarely return, the virus remains latent in resting B cells for life. Latency has been known to transform into a type of lymphoma, called Burkitt’s lymphoma, usually in individuals with a disorder effecting T cell function (Janeway et al., 1999). Normally, though, latency does not result in further problems.

The Epstein-Barr Virus
The EBV is a form of herpesvirus, which are characterized by a capsid surrounded by an envelope and glycoproteins (Omari, 1999). EBV can exist in infected individuals in a lytic and a latent phase. These phases result in the expresses of different proteins and infected cell phenotypes. Figure 2 is a map of the EBV virus genome and contains genes for proteins that will be discussed below.

Figure 2. Map of Epstein-Barr Virus Genome (Cohen, 1998). Permission to used requested.

Lytic Characteristics (Cohen, 1998): The proteins expressed by the virus in the lytic phase (see Figure 2) act to replicate the virus, induce B cell proliferation and, prevent destruction of the infected cells. ZEBRA, one the first proteins expressed, turns on the lytic cycle. Next, viral replication proteins such as DNA polymerase, capsid proteins and the envelope glycoprotein gp350 are expressed. Although a B cell protein rather than an EBV protein, infection has been shown, in vitro, to induce B cells to express CD23 which is believed to act as a growth factor receptor that mediate proliferation. Several mechanisms exist to prevent destruction of infected B cells by cytotoxic T cells. The expression and secretion of the viral protein BCRF1 inhibits release of interferon-gamma, which increases MHC class I expression in many cell types and activates natural killer cells. Experiments in vitro have shown that EBV infection can induce the expression of Fas-ligand on B cells and macrophages and Fas on T cells, a combination which leads to T cell apoptosis (Tanner, et al., 1999). Finally, the viral protein BHRF1 prevents apoptosis in infected B cells, allowing for prolonged proliferation and viral replication (Cohen, 1998).

Latent Characteristics (Cohen, 1998): Many viral proteins are involved in EBV latency. EBNA-1 has several functions. Among them are allowing the viral genome to exist as an episome in infected B cells and preventing the host proteasome from being able to process EBV proteins to be presented to T cells (Janeway et al., 1999). Many proteins act in pathways that activate trascription factors that can allow the transcription of viral proteins. These proteins include EBNA-2, LMP-1, and LMP-2 (Cohen, 1998). One of the proteins indirectly induced by LMP-1 is the host protein bcl-2 which has a similar function to EBV protein BHRF1 in that it prevents apoptosis of the infected cell, allowing the virus to continue surviving in latency (Cohen, 1998).

Diagnosis of Infectious Mononucleosis
There several methods used to diagnose a patient with mono. A firsrt step when one suspects mono is to test the white blood cell count. Because mono is characterized by proliferation of B and T cells, a high white blood cell count is a strong indication that there might be an EBV infection. Most other methods are serological tests to look for antibodies unique to mono. A common test looks for high levels of non-specific heterophile antibodies, which are expressed by infected B cells (Nieves, 1998). The presence of antibodies against EBV proteins in the patient’s serum is also an indication of the disease. Anti-VCA (Viral Capsid Antigen) antibodies are charateristic of infection as well as anti-EBNA antibodies which detect the virus in its latent phase (Omari, 1999). Tests to detect antibodies against EBV proteins are especially useful for diagnosing children, who tend to test negative for heterphile antibodies even if they have the infection.

Treatment Options
As with many viral diseases, there are few treatment options. Symptoms can be treated with basic pain killers and fever reducers (i.e. asprin, ibuprofen). Some studies have show that viral inhibitors such as acyclovir reduce replication of the EBV but symptoms continued for just as long as in non-treated patients (Nieves, 1998). Generally, patients suffering from infectious mononucleosis are encourage to remain inactive for as long as the symptoms persist, and the cytotoxic T cells eventually eliminate the disease.

References

Cohen J. (1998) Epstein-Barr Virus: An Ocogenic Human Herpesvirus. Cancer Medicine, 4 ed., Ch. 21.

Friedlander E. 2000. White Cells. <http://www.pathguy.com/lectures/sleen.htm> Accessed 2000 Apr 20.

Janeway CA, Travers P, Walport M, Capra JD. Immunobiology: the Immune System in Health and Disease. 4th ed. London: Current Biology Publication; 1999. p 602.

Nieves M. “What every pediatrician should no about Infectious Mononucleosis.” 1998. The Pediatric Bulletin. <http://home.coqui.net/myrna/mono.htm> Accessed 2000 Apr 20.

Omori M. “Mononucleosis.” 1999. E Medicine. <http://emedicine.com/EMERG/topics319.htm> Accessed 2000 Apr 20.

Tanner J and Alfieri C. (1999) Epstein-Barr virus induces Fas (CD95) in T cells and Fas ligand in B cells leading to T-cell apoptosis. Blood 94 (10): 3439-3447.

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