Atopic disease and the herpes microbiome

Unlike bacteria or fungi, herpes viruses establish life-long infection in the human host through latent genomic persistence within the host cells nuclei and are thus considered part of the human microbiome. The ability of the virus to interact with the human genome influences allergic and atopic disease due to the bias these patients have towards a Th2 profile. Dr. David Dreyfus examined the role of common human herpes viruses on the microbiome of atopic patients, who have more severe and atypical disease when infected (J Allergy Clin Immunol 2013; 132(6): 1278-1286).

The herpes virus Epstein Barr (EBV or mononucleosis) expresses latency in lymphocytes and has co-evolved with humans long enough to encode for a protein that resembles the cytokine IL-10, as well as other cytokines by activating host transcription factors. The author explains that EBV and other herpes viruses encode for microRNAs that cause immunomodulation of distant cells. This lead to studies suggesting that EBV infection early in life is protective against atopic disease compared to infection later in life, where there is a predisposition to atopic disease. Atopic patients that have a primary infection of EBV can have a more severe non-specific rash that can be mistaken for allergic diseases or other infectious diseases and can be misdiagnosed.

Another ubiquitous herpes virus, VZV or shingles, becomes latent in neuronal cells and reactivation risk increases with age as the natural antibodies decline over time. The current VZV vaccine has been successful for a decade, reducing the VZV associated morbidity and mortality especially in the elderly. However, studies suggest that children who receive the vaccine have an increased incidence for atopic disease compared to children that are infected naturally with the virus, suggesting there could be a protective benefit to natural infection. Like VZV, Human Simplex Virus 1 and 2 (HSV1 and HSV 2) become latent in the neuron after primary infection of subcutaneous and pulmonary epithelial cells. The author explains that infants and others that are immunodeficient are at high risk of pulmonary syndromes such as bronchitis and pneumonia, and neurologic syndromes such as encephalitis. The most common atypical presentation of the virus is a severe skin rash called eczema herpeticum among atopic patients. This is similar to the severe drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) seen with the reactivation of HSV6, also referred to as roseola, which is present in both atopic and non-atopic patients. Furthermore, another related herpes virus, cytomegalovirus (CMV) can cause cutaneous symptoms similar to EBV, as well as chronic inflammation and cardiovascular disease due to its latency in macrophages that are associated with vascular inflammation by directly inducing Th2 cytokines.

Molecular evidence suggests that herpes viruses have been co-evolving with the human immune system since before the origin of the adaptive immune system. The herpes microbiome along with environmental factors such as improved global hygiene that prevents the exposure to a variety of components interact with each other to create the atopic phenotype. Dr. Dreyfus emphasizes that this information can positively impact the care for the allergic and atopic patient populations. Clinicians must have a heightened awareness of the various presentations of herpes viruses to avoid unnecessary testing and treatments for drug allergy or autoimmune disease. 

Questions for the author:

What are the effects of the herpes microbiome on other allergic diseases?  Is there an increase in Th2 dependent disease in patients who express viral lesions and reactivation of herpes viruses? 

Regarding the question of effects of herpes on atopic disease, in addition to the references cited in my article particularly regarding an increase in atopic disease in pediatric patients who receive the varicella vaccine vs wild type virus there is a more recent article just published with some more experimental observations on this question:

Sohlberg, E. et al (2013) Cytomegalovirus-Seropositive Children Show Inhibition of an In Vitro EBV infection That Is Associated with CD8+ CD57+ T-cell Enrichment and IFN-gamma. Journal of Immunology 191:5669