A herpesvirus associated with female infertility

HHV-6Viruses that replicate in the male or female reproductive tract are considered to be potential causes of human infertility. Several herpesviruses have been implicated in male infertility, and now human herpesvirus 6A (HHV-6A) has been found in endometrial cells of women with unexplained infertility (paper link).

HHV-6 was only recently discovered (1986) and is now known to occur as two variants, HHV-6A and HHV-6B. The latter is a major cause of exanthem subitum, a rash of infants, but no disease has been clearly associated with HHV-6A. These viruses are transmitted to infants early in life via saliva, from mother to child, from siblings, or from other infants at day care centers. Seroprevalence studies indicate that almost all children are infected with these viruses by 2 years of age.

To determine if HHV-6 might be a cause of infertility, a study (paper link) was conducted of 30 women with unexplained primary fertility, and 36 women with at least one previous pregnancy. HHV-6B DNA was detected in PBMC from both infertile and fertile groups (25 and 28%, respectively); HHV-6A DNA was not detected. In contrast, endometrial epithelial cells from 13/30 (43%) infertile women were positive for HHV-6A DNA; this viral DNA was not detected in endometrium of fertile women. When placed in culture, endometrial epithelial cells produced viral early and late proteins, suggesting the presence of infectious virus.

Presence of HHV-6A DNA in endometrial epithelial cells was also associated with an altered hormonal and immune environment. Estradiol levels were higher in infected versus uninfected infertile women. The authors suggest that higher levels of this hormone could be involved in allowing HHV-6A infection of the endometrium.

Levels of a specific type of uterine NK cell were lower in HHV-6A positive women, and IL-10 (a Th2 cytokine) was elevated while IFN-gamma (a Th1 cytokine) was decreased. There were no differences in the levels of these cells and cytokines in peripheral blood. These changes are consistent with an increase in the ratio of Th1/Th2 responses that has been documented in female infertility.

The authors also observed enhanced endometrial NK cell responses to HHV-6A in infected but not uninfected women, together with an increase in the number of these cells that are activated when cultured with HHV-6A infected cells.

I wonder what was the source of HHV-6A in the endometrium, as the virus was not detected in blood. Was the infection recently acquired, or did it occur years before, with the virus establishing a chronic infection in the uterus?

The results suggest that HHV-6A infection of the endometrium triggers an abnormal NK cell and cytokine profile, which in turn leads to a uterine environment that is not compatible with fertility. The results need to be confirmed with studies of additional fertile and infertile women. It would also be useful to have an animal model of HHV-6A infection of the endometrium, which could lead to mechanistic work to determine how virus infection causes infertility.

Image: Electron micrograph of HHV-6 (image credit)

TWiV 214: This is your brain on polyomavirus

On episode #214 of the science show This Week in Virology, Vincent, Alan, and Kathy discuss how coagulation factor X binding to adenovirus activates the innate immune system, and a novel polyomavirus associated with brain tumors in raccoons.

You can find TWiV #214 at www.microbe.tv/twiv.

The inflammatory response

neutrophil-migrationDuring the earliest stages of a virus infection, cytokines are produced when innate immune defenses are activated. The rapid release of cytokines at the site of infection initiates new responses with far-reaching consequences that include inflammation.

One of the earliest cytokines produced is tumor necrosis factor alpha (TNF-α), which is synthesized by activated monocytes and macrophages. This cytokine changes nearby capillaries so that circulating white blood cells can be easily brought to the site of infection. TNF-α can also bind to receptors on infected cells and induce an antiviral response. Within seconds, a series of signals is initiated that leads to cell death, an attempt to prevent the spread of infection.

Inflammation is a very prominent response to TNF-α. There are four typical signs of inflammation: erythema (redness), heat, swelling, and pain. These are a consequence of increased blood flow and capillary permeability, the influx of phagocytic cells, and tissue damage. Increased blood flow is caused by constriction of the capillaries that carry blood away from the infected area, and leads to engorgement of the capillary network. Erythema and an increase in tissue temperature accompany capillary constriction. In addition, the permeability of capillaries increases, allowing cells and fluid to leave and enter the surrounding tissue. These fluids have a higher protein content than the fluids normally found in tissues, causing swelling.

Another feature of inflammation is the presence of immune cells, largely mononuclear phagocytes, which are attracted to the infected area by cytokines. Neutrophils are one of the earliest types of phagocytic cells that enter a site of infection, and are classic markers of the inflammatory response (illustrated). These cells are abundant in the blood, and usually absent from tissues. Together with infected cells, dendritic cells, and macrophages, they produce cytokines that can further shape the response to infection, and also modulate the adaptive response that may follow.

The precise nature of the inflammatory response depends upon the virus and the tissue that is infected. Viruses that do not kill cells – noncytopathic viruses – do not induce a strong inflammatory response. Because the cells and proteins of the inflammatory response come from the bloodstream, tissues with reduced access to the blood do not undergo the destruction associated with inflammation. However, the outcome of infection in such ‘privileged’ sites – the brain, for example – may be very different compared with other tissues.

As expected, the inflammatory response is highly regulated. One of the critical components is the ‘inflammasome’ – very large cytoplasmic structure with properties of pattern receptors and initiators of signaling (e.g. MDA-5 and RIG-I). Recent experimental findings demonstrate that the inflammasome is critical in innate immune response to influenza virus infection, and in moderating lung pathology in influenza pneumonia.

Thomas, P., Dash, P., Aldridge Jr., J., Ellebedy, A., Reynolds, C., Funk, A., Martin, W., Lamkanfi, M., Webby, R., & Boyd, K. (2009). The Intracellular Sensor NLRP3 Mediates Key Innate and Healing Responses to Influenza A Virus via the Regulation of Caspase-1 Immunity, 30 (4), 566-575 DOI: 10.1016/j.immuni.2009.02.006

Allen, I., Scull, M., Moore, C., Holl, E., McElvania-TeKippe, E., Taxman, D., Guthrie, E., Pickles, R., & Ting, J. (2009). The NLRP3 Inflammasome Mediates In Vivo Innate Immunity to Influenza A Virus through Recognition of Viral RNA Immunity, 30 (4), 556-565 DOI: 10.1016/j.immuni.2009.02.005