Impaired NK cell activation during acute dengue virus infection: A contributing factor to disease severity

Abstract

Dengue viral (DENV) infection has a broad clinical spectrum ranging from classical febrile illness to life-threatening disease. Literature suggests that spectrum of illness could be due to differences in innate immune-responses; however, the knowledge is still at infancy. Amongst the various cells involved in innate immune responses, NK cells play a central role, particularly in anti-viral immunity. Thus in this study we have evaluated the role of NK-cells during acute-DENV infection and its influence on severity of disease, by analyzing activation, cytotoxic receptors, cytolytic granule contents and degranulation markers on NK-cells during different stages of infection. Based on the clinical manifestations and severity of the disease, DENV patients were classified into patients with dengue without warning signs (DF), dengue with warning signs (DFWS) and severe dengue (SD) patients. During acute-DENV infection, though there was no alteration in frequency of NK-cells, significant increase in frequency of CD56 bright subset in DF patients (p < 0.05) was observed, while it remained unaltered in SD patients. We also found that, CD56 dim NK-cell subset of DF patients had elevated CD69 expression, granzyme B and intracellular IFN-γ levels compared to SD patients (p < 0.05). Amongst the NK-cell cytotoxicity receptor (NCR), NKp30 receptor was significantly elevated in DF patients (p < 0.05), however in SD patients it was comparable to healthy controls. This receptor is essential for dendritic cells-NK-cells crosstalk for initiating adaptive immune response. IL-15 is known to induce NKp30 expression, which was also seen to be elevated in DF patients (p < 0.05) but unaltered in SD patients. In SD patients, even post-6 days of infection i.e. during recovery phase, CD69 and NKp30 expression did not raise, suggesting impaired NK-cell response in these patients. To summarize, our study reports, that efficient NK cell response during acute phase of DENV infection is crucial for preventing severity of the disease. This study helps in understanding the dynamics of NK cell response in immunopathogenesis of DENV infection; which is crucial for development of efficacious therapeutics as well as vaccine.

A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

“…A similar impairment in NK cell cytotoxicity was observed in hepatitis C virus-infected patients [93]. Furthermore, diminished NK responses are also observed in dengue viral infection and may play a role in the disease [94]. Thus, dysregulation of NK cells in these viral infections may be significant for peripheral NK cells and trNK cells.…”

Immuno-Haematologic Aspects of Dengue Infection: Biologic Insights and Clinical Implications

“…The CD56 bright immunoregulatory subset of NK cells was found to be increased in patients with mild disease but notably not in those with severe dengue. [79] Similarly, the cytotoxic CD56 dim NK cell subset showed increased cytolytic capability ( based on the expression of CD69, NKP30,Granzyme B and IFN) in those with mild compared to severe dengue. [79] Importantly, the impaired cytotoxic capacity of NK cells in those with severe disease persisted even up to a week after infection.…”

“…[79] Similarly, the cytotoxic CD56 dim NK cell subset showed increased cytolytic capability ( based on the expression of CD69, NKP30,Granzyme B and IFN) in those with mild compared to severe dengue. [79] Importantly, the impaired cytotoxic capacity of NK cells in those with severe disease persisted even up to a week after infection. [79] Mass cytometry by time of flight (CyTOF) analysis was able to delineate unique NK cell signatures associated with dengue infection in paediatric and adult patients, respectively.…”

“…[79] Importantly, the impaired cytotoxic capacity of NK cells in those with severe disease persisted even up to a week after infection. [79] Mass cytometry by time of flight (CyTOF) analysis was able to delineate unique NK cell signatures associated with dengue infection in paediatric and adult patients, respectively. [80] Similar studies evaluating NK cell subsets via high dimensional immune profiling at presentation and at serial time points during the disease would be of significant value, especially if NK cell phenotypes at presentation can predict severity of disease.…”

Depletion of skin bacteria by topical antibiotic treatment accelerates onset of Zika virus disease in mice

“…[42][43][44] Also for DENV, the NK cell response was identified as an important factor influencing disease severity. 45 The overall diminished antiviral immunity observed following antibiotic treatment likely contributed to the accelerated ZIKV disease progression.…”