Two Novel Biomarkers Associated with Clinical Outcome in Dengue

Researchers analyzed soluble forms of the B cell antigens CD27 and CD38 (sCD27 and sCD38, respectively) in the plasma of children with dengue and have suggested a role for these soluble forms as biomarkers of progression of the disease.

In a new study published in Virology, Diana M. Castañeda, RN, from South Colombian University, Neiva, Colombia, and colleagues analyzed soluble forms of the B cell antigens CD27 and CD38 (sCD27 and sCD38, respectively) in the plasma of children with dengue, as well as in cell culture, and have suggested a role for these soluble forms as biomarkers of progression of the disease.

According to the authors, sCD27, but not sCD38, can be released by activated B cells after induction either by in vitro polyclonal activation or by natural infection with dengue virus (DENV), which could indicate a new role for these cells in the pathogenesis of the disease. In addition, “[d]engue virus infection in children significantly increased the plasma levels of these two markers, which were also related to the severity of infection,” they write.

Dengue is a mosquito-borne viral infection that is a leading cause of illness and death in tropical and sub-tropical areas worldwide. The incidence of dengue has grown around the world in recent decades, and a 2013 study estimated that 390 million DENV infections occur per year, of which 96 million are associated with clinical disease.

Dengue is caused by infection with one of four closely related serotypes of DENV, and manifestations of the disease can range from asymptomatic to life-threatening hemorrhagic fever. The severity of the disease and its clinical outcome are strongly associated with the host’s immune response.

Humoral and cellular immune responses both play important roles in the pathogenesis of dengue and in protection against it. Although production of neutralizing antibodies against viral proteins is the main mechanism of protection, people who experience a secondary DENV infection with a new serotype are at increased risk of severe disease. This is because of antibody-dependent enhancement: during secondary infection, antibodies generated by the first infection bind to the new viral serotype but cannot neutralize it. Instead, the antibody—virus complex attaches to receptors on circulating monocytes, allowing the virus to more easily infect these white blood cells, leading to increased viral replication and disease severity.

DENV infection also “induces a massive increase in circulating dengue-specific plasmablasts during the acute phase, especially in secondary infections,” the authors write. Plasmablasts characteristically express high levels of the antigens CD27 (a member of the tumor necrosis factor superfamily) and CD38 (a multifunctional enzyme) on their surface. Soluble forms of both of these markers can be found in body fluids, including plasma, and are considered to originate from both activated T cells as well as activated B cells, in health and in disease. Indeed, plasma levels of both of these soluble forms have been used as biomarkers for monitoring the course of several conditions, including autoimmune diseases, malignant neoplastic diseases, and HIV infection.

With this in mind, Castañeda and colleagues therefore investigated the release of sCD27 and sCD38 by B cells that were either stimulated in vitro or naturally activated by DENV infection in children. Using plasma samples from 63 children with dengue, as well as from 15 healthy children, they also examined the levels of these markers in plasma to identify how they changed with infection and correlated with disease severity.

Using cell culture studies, the investigators showed that human B cells released sCD27 (but not sCD38) when subjected to stimuli that promote plasmablast differentiation. They also found that B cells from children with the disease released significantly higher amounts of sCD27 than did B cells from healthy children, indicating that naturally activated B cells represent one important source of plasma sCD27 in children with dengue. The levels of sCD27 also positively correlated with the frequency of plasmablasts.

The investigators also measured sCD27 and sCD38 levels in the plasma samples and showed that, compared with T and B cells from healthy children, T and B cells from children with dengue spontaneously produced higher levels of both soluble forms. Levels of both biomarkers were high during the acute phase of the disease, but significantly decreased during the convalescent phase. And while plasma sCD27 levels were higher in cases of severe dengue than in mild disease, sCD38 levels were higher in mild cases than in severe disease.

“Therefore, the increase in plasma sCD27 during the acute phase of the DENV infection is associated with severe disease, suggesting a possible role in pathogenesis,” the authors state. “For sCD38, an opposite phenomenon was observed, suggesting a contrary (possibly protective) role for this marker in dengue disease.”

Based on the results of this study, the authors therefore propose sCD27 and sCD38 as two novel, useful, and easily measurable biomarkers that reflect the degree of immune activation in pediatric patients with dengue.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.