Investigating the natural killer cell response in dengue virus infection

: a comparison between non-severe and severe disease

Abstract

Dengue is a mosquito-borne virus and a major public health issue, with half of the global population at risk of infection. It is estimated to cause 390 million annual cases, and symptoms vary from asymptomatic to severe. The mechanisms that promote the development of severe manifestations of dengue, and the involvement of the host immune response, are still not entirely understood.

Natural killer (NK) cells are a critical component of the innate immune response to dengue. Through cytotoxic functions and immunoregulatory roles, NK cells have crucial roles in initial clearance of infection, and severe dengue has previously been linked to an impairment in NK cell function. This project aimed to characterise the NK cell response in patients with dengue infection (2-5 days following development of symptoms), and compare the response between non-severe and severe cases in order to identify factors that may have a role in the development of severe dengue. This involved multiparameter flow cytometry to evaluate the NK cell phenotype, focussed on differentiation status, cytotoxic potential and expression of activating and inhibitory receptors. NK cell cytotoxic function was also investigated upon stimulation with K562 cells and IL-12/18, by assessing the resulting degranulation and cytokine production.

The results of the project indicate reduced expression of activating receptors, particularly NKG2D, as well as increased expression of several inhibitory receptors (LILRB1, LAG-3, TIGIT, PD-1 and PD-L1) by responding NK cells of severe dengue patients. This altered balance of NK cell receptors, in combination with the less mature NK cell phenotype and lower cytotoxic potential observed in severe dengue, may contribute to an impairment in NK cell function. This is further supported by the reduced degranulation response that was apparent in severe dengue patients following stimulation. Understanding the features of the immune response that may promote the development of severe dengue is necessary for development of host-directed therapies.

Date of Award	10 Dec 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Laura Rivino (Supervisor) & Christoph Wuelfing (Supervisor)