Cytomegalovirus Promotes Intestinal Inflammation by Blocking Anti-Inflammatory Signaling in Macrophages

NEW RESEARCH

Cytomegalovirus (CMV) infection is prevalent worldwide, infecting an estimated 60% of the population in developed countries, and up to 100% of the population in developing countries.^[1] Infection can occur at any age; in the US, up to 25% of children are infected by the age of five, and more than 50% of the population is infected by age 40.^[2]

CMV persists in certain cell types, such as myeloid progenitor cells in bone marrow and circulating monocytes derived from myeloid progenitor cells. CMV infection is lifelong, although in healthy individuals, the virus mostly persists in a latent form, and is also kept in check by normal immune surveillance. The majority of infected individuals show no signs or symptoms.

CMV can become reactivated, however, when the immune system becomes compromised, or under inflammatory conditions. The colon is the most common site of CMV infection upon viral reactivation, where it may cause or further exacerbate inflammation. For example, CMV is often reactivated in inflamed colonic mucosa in ulcerative colitis patients, ^[3] who are often on immunosuppressive therapy.

Until recently, the role of CMV in promoting intestinal inflammation was unclear, but a recent study has shed new light on a potentially important mechanism.^[4] ;In the study, CMV was shown to interfere with an anti-inflammatory immune factor that normally blocks intestinal macrophages from becoming pro-inflammatory.

In healthy individuals, intestinal macrophages are usually non-inflammatory, and are regularly replenished by circulating monocytes that develop into non-inflammatory macrophages in the intestine. In CMV-infected individuals, however, reactivation of the virus can initiate a process that causes monocytes to develop into pro-inflammatory intestinal macrophages.

Within macrophages that develop from CMV-infected monocytes, the virus promotes an increase in the production of Smad7, which inhibits signaling by the transforming growth factor beta (TGFbeta), an anti-inflammatory cytokine produced in the intestinal mucosa. TGFbeta normally blocks the expression of the important pro-inflammatory factor, NFkB, in intestinal macrophages. The end result of the CMV-stimulated increase in Smad7 is increased intestinal inflammation.

It was previously known that inflammation — and NFkB in particular — is essential for replication of CMV. This new study provides a key piece of the puzzle by demonstrating that CMV not only promotes inflammation, but also its own replication, by inhibiting a critical anti-inflammatory factor that normally keeps NFkB in check in intestinal macrophages.

REFERENCES

1. Griffiths et al.,The pathogenesis of human cytomegalovirus.  J Pathol 2015; 235: 288–297
2. Centers for Disease Control and Infection (CDC), Cytomegalovirus (CMV) and Congenital CMV Infection. Article accessed on 23 Jan. 2019 from the CDC website: https://www.cdc.gov/cmv/overview.html
3. Pillet et al., Cytomegalovirus and ulcerative colitis: Place of antiviral therapy. World J Gastroenterol. 2016 Feb 14;22(6):2030-45
4. Dennis et al., Cytomegalovirus promotes intestinal macrophage-mediated mucosal inflammation through induction of Smad7. Mucosal Immunol. 2018 Nov;11(6):1694-1704