Immune Response to Dengue Virus Infection in Pediatric Patients in New Delhi, India—Association of Viremia, Inflammatory Mediators and Monocytes with Disease Severity

Abstract

Dengue virus, a mosquito-borne flavivirus, is a causative agent for dengue infection, which manifests with symptoms ranging from mild fever to fatal dengue shock syndrome. The presence of four serotypes, against which immune cross-protection is short-lived and serotype cross-reactive antibodies that might enhance infection, pose a challenge to further investigate the role of virus and immune response in pathogenesis. We evaluated the viral and immunological factors that correlate with severe dengue disease in a cohort of pediatric dengue patients in New Delhi. Severe dengue disease was observed in both primary and secondary infections. Viral load had no association with disease severity but high viral load correlated with prolonged thrombocytopenia and delayed recovery. Severe dengue cases had low Th1 cytokines and a concurrent increase in the inflammatory mediators such as IL-6, IL-8 and IL-10. A transient increase in CD14+CD16+ intermediate monocytes was observed early in infection. Sorting of monocytes from dengue patient peripheral blood mononuclear cells revealed that it is the CD14+ cells, but not the CD16+ or the T or B cells, that were infected with dengue virus and were major producers of IL-10. Using the Boruta algorithm, reduced interferon-α levels and enhanced aforementioned pro-inflammatory cytokines were identified as some of the distinctive markers of severe dengue. Furthermore, the reduction in the levels of IL-8 and IL-10 were identified as the most significant markers of recovery from severe disease. Our results provide further insights into the immune response of children to primary and secondary dengue infection and help us to understand the complex interplay between the intrinsic factors in dengue pathogenesis.

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

“…3A and B). Viral loads were not significantly different between the two groups, as shown in our previous study (28). From these data, we conclude that both HLA-DR + CD38 + and HLA-DR − CD38 + CD8 T cell subsets proliferate and expand massively in dengue patients.…”

“…Indeed, most dengue cases from studies performed in other parts of the world (42) and our Indian cohort had some IFN-γ in the plasma (28). This suggests that, perhaps, these cells and/or other immune cells were making IFN-γ in vivo prior to the arrival of the patient at the clinic, but a vast majority of them may have lost the in vitro IFN-γ production capacity by the time the patient experienced clinical symptoms and presented to the clinic.…”

Protective Capacity of the Human Anamnestic Antibody Response during Acute Dengue Virus Infection

“…The readout of that study was viremia, which is often a good indicator of the in vivo protective capacity of an antibody. In patients, however, viremia is not always associated with disease severity (33, 34). Secondary infection is associated with a higher risk of severe disease.…”

Interleukin-6: A promising disease severity index for dengue virus infection

“…A close connection between IL-6 up-regulation and severe dengue infection can be established because high plasma level of IL-6 is not only working as activation marker of coagulation and fibrinolysis in severe DV infections, but also involved in the onset and regulation of hemostasis [25,26]. Severe dengue infection also holds the virulence of DV as a devastating phenomenon for hemorrhage being a virologic factor.…”