Analysis of serum levels of cytokines, chemokines, growth factors, and monoamine neurotransmitters in patients with tick-borne encephalitis: Identification of novel inflammatory markers with implications for pathogenesis

Palus, Martin; Formanová, Petra; Salát, Jiřı́; Žampachová, Eva; Elsterová, Jana; Růžek, Daniel

doi:10.1002/jmv.24140

Cited by 46 publications

(38 citation statements)

References 35 publications

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“…1B). The elevated levels of IL-2, IL-12, IL-15, IFN-g, and TNF observed in the current study extend previous studies reporting increased levels of IL-6, IL-8, and IL-12 in TBE patients (28). These findings indicated that NK cells might be activated by, as well as contribute to, increased cytokine levels The Journal of Immunology and, hence, be involved in the immune response to symptomatic TBEV infection.…”

Section: Tbev Infection Induces High Levels Of Proinflammatory Cytokinessupporting

confidence: 89%

NK Cell Responses to Human Tick-Borne Encephalitis Virus Infection

Blom

Braun

Pakalnienė

et al. 2016

The Journal of Immunology

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Tick-borne encephalitis virus (TBEV) is a flavivirus that is transferred to humans by infected ticks. The virus causes tick-borne encephalitis, a severe infection of the CNS with a high risk for long-lasting sequelae. Currently, no treatment exists for the disease. Understanding the cellular immune response to this infection is important to gain further understanding into the pathogenesis, treatment, and prevention of the disease. NK cells are known to participate in the control of viral infections. We performed a longitudinal analysis of the human NK cell response to TBEV infection in a cohort of infected individuals from the onset of severe clinical symptoms to the convalescence phase. NK cell activation, as measured by expression of Ki67, was apparent at the time of hospitalization. By 3 wk after hospitalization, it decreased to levels seen in healthy controls. Concomitant with the increase in NK cell activation, augmented levels of IL-12, IL-15, IL-18, IFN-γ, and TNF were detected in patient plasma. This TBEV-induced NK cell activation was restricted predominantly to differentiated CD57(+)CD56(dim) NK cells. Functionally, CD56(dim) NK cells responded poorly to target cells at the time of hospitalization, but they recovered functional capacity to control levels during the convalescent phase. In contrast, the responsiveness of NK cells to cytokine stimulation remained intact throughout the disease. These findings demonstrate that NK cells respond to TBEV infection with characteristics that are distinct from those of other human viral infections and provide insights into the NK cell response to clinical TBEV infection.

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Section: Tbev Infection Induces High Levels Of Proinflammatory Cytokinessupporting

confidence: 89%

NK Cell Responses to Human Tick-Borne Encephalitis Virus Infection

Blom

Braun

Pakalnienė

et al. 2016

The Journal of Immunology

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“…That the interferon response, which has been associated with a greater risk of developing HSV encephalitis, was not found to be significant in our study is a potentially interesting negative, although it may be a consequence of the number of CSF samples available or the pooling of infectious aetiologies [ 40 , 50 ]. Also some mediators, which have been identified in previous studies, such as VEGFα, were not detected in significant concentrations in the majority of patients in this study [ 51 ]. Although this may be because previous studies have focused on pathogens associated with a viraemia and marked blood-brain barrier damage, rather than primary neurotropic infection, as is seen in HSV, which was the majority of infectious cases in our study [ 14 , 51 ].…”

Section: Discussioncontrasting

confidence: 64%

“…Also some mediators, which have been identified in previous studies, such as VEGFα, were not detected in significant concentrations in the majority of patients in this study [ 51 ]. Although this may be because previous studies have focused on pathogens associated with a viraemia and marked blood-brain barrier damage, rather than primary neurotropic infection, as is seen in HSV, which was the majority of infectious cases in our study [ 14 , 51 ].…”

Section: Discussioncontrasting

confidence: 64%

Characteristic Cytokine and Chemokine Profiles in Encephalitis of Infectious, Immune-Mediated, and Unknown Aetiology

et al. 2016

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BackgroundEncephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15–60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause.MethodsWe measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology.ResultsHeat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p<0.0001).ConclusionsMediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation.

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“…Recently, activation of the immune system and brain inflammatory reaction in TBE patients has been estimated by measuring the level of the corresponding cytokines, enzymes, and other factors in blood and cerebrospinal fluid (Timofeev et al, 2002; Atrasheuskaya et al, 2003; Palus et al, 2015; Grygorczuk et al, 2016). Nevertheless, experiments in laboratory animals are required for evaluation of the pathogenic potential of the virus.…”

Section: Introductionmentioning

confidence: 99%

Lethal Experimental Tick-Borne Encephalitis Infection: Influence of Two Strains with Similar Virulence on the Immune Response

et al. 2017

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Tick-borne encephalitis virus (TBEV) is a tick-transmitted arbovirus that causes serious diseases in humans in Europe and Northern Asia. About 6000–10,000 cases are registered annually, and one-third of them lead to sequela with different degrees of severity. Two TBEV strains (Absettarov and EK-328) similar in virulence rate in laboratory mice were used to study pathogenesis and immune response upon lethal infection in mice. The strains differed in the dynamics of appearance of virus, IFNs and other cytokines in blood of mice, and ability to induce a cytokine storm in the terminal stages of disease and a non-sterile immunity. Moreover, the TBEV strains differed in characteristics of their interactions with DCs: level of reproduction in these cells, virus dose triggering IFN-α production, and impact on DCs' maturation. Infection of DCs with Absettarov strain led to IFN-α induction only at high multiplicity of infection (MOI), and an increased amount of the mature DCs with high adhesion activity and low-level of MHCII positive cells. While reproduction of the EK-328 strain in DCs was less efficient, a low dose of the virus induced IFN-α production and stimulated maturation of DCs with relatively low adhesive capacity, but with the high percentage of cells expressing MHCII molecules. Thus, the studied strains differed significantly in the impact on DCs' maturation and antigen presentation to CD4+ lymphocytes. Injection of low (103 PFU) and high (106 PFU) doses of both TBEV strains caused a lethal infection in mice. At the same time, the dose of the virus in the inoculum, regardless of the strain properties, affected the following virulence characteristics: the time of virus appearance in brain (day 4–5 vs. day 1 p.i.), time of IFN-α appearance in blood (10 h vs. 5 h p.i.), concentration of IFN-α in blood, and induction of IFN-α during infection of DCs. Therefore, virulent TBEV strains during lethal infection can interact differently with the host immune system, and the infectious dose has an impact on both: virus spread in the infected organism and immune response activation.

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Analysis of serum levels of cytokines, chemokines, growth factors, and monoamine neurotransmitters in patients with tick-borne encephalitis: Identification of novel inflammatory markers with implications for pathogenesis

Cited by 46 publications

References 35 publications

NK Cell Responses to Human Tick-Borne Encephalitis Virus Infection

NK Cell Responses to Human Tick-Borne Encephalitis Virus Infection

Characteristic Cytokine and Chemokine Profiles in Encephalitis of Infectious, Immune-Mediated, and Unknown Aetiology

Lethal Experimental Tick-Borne Encephalitis Infection: Influence of Two Strains with Similar Virulence on the Immune Response

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