Journal of Medical Microbiology (2013), 62, 441–445
DOI 10.1099/jmm.0.047589-0
The importance of myeloperoxidase enzyme activity
in the pathogenesis of Crimean–Congo
haemorrhagic fever
F. M. K. Guven,1 H. Aydin,2 G. Yildiz,3 A. Engin,4 V. K. Celik,2 D. Bakir5
and K. Deveci2
Correspondence
1
F. M. K. Guven
2
Department of Emergency Medicine, Zonguldak State Hospital, Zonguldak, Turkey
Department of Biochemistry, Zonguldak State Hospital, Zonguldak, Turkey
[email protected]
3
Nephrology Clinic, Zonguldak State Hospital, Zonguldak, Turkey
4
Department of Infectious Diseases and Clinical Microbiology, Cumhuriyet University School of
Medicine, 58140 Sivas, Turkey
5
Department of Microbiology and Clinical Microbiology, Cumhuriyet University School of Medicine,
58140 Sivas, Turkey
Received 29 May 2012
Accepted 4 November 2012
Crimean–Congo haemorrhagic fever (CCHF) is a disease with a severe course including acute
viral haemorrhagic fever, ecchymosis, thrombocytopenia, hepatic function disorder and high
mortality. Myeloperoxidase (MPO) is an enzyme located in neutrophil granulocytes and plays an
important role in the destruction of phagocytosed micro-organisms. The aim of this study was to
analyse MPO enzyme activity in CCHF cases compared with a control group. A total of 47
randomly selected CCHF patients admitted to the Department of Infectious Diseases of
Cumhuriyet University Hospital in Sivas, Turkey, were studied, and as a control group, 41 ageand sex-matched individuals without any systemic disease were included in this study. MPO
enzyme activity was measured in plasma and leukocytes for both groups by the ELISA method.
MPO plasma and MPO leukocyte values were calculated as 57.62±8.85 and 44.84±9.71 in
CCHF patients, and 0.79±0.29 and 0.49±0.11 in the controls, respectively. MPO enzyme
activity was statistically significantly higher in patients with CCHF when compared to the control
group. In conclusion, MPO enzyme activity is directly related to the activation of phagocytic
leukocytes, and increases in both the plasma and leukocytes in CCHF patients. The increase of
the MPO enzyme activity in leukocytes due to viral load leads to the destruction of the leukocyte. It
is thought that MPO enzyme activity in plasma was higher in CCHF patients due to the
destruction of leukocytes. MPO enzyme activity may be important in terms of the prognosis in
patients with CCHF; however, more extensive studies are required on this subject.
INTRODUCTION
Crimean–Congo haemorrhagic fever (CCHF) is a disease
caused by Nairovirus, from the family Bunyaviridae. It
has several symptoms including fever, ecchymosis, haemorrhage, thrombocytopenia and hepatic function disorder
(Bakir, 2004; http://www.saglik.gov.tr). The mortality rate
is very high. Transmission is usually caused by tick bites.
In our country, CCHF notifications have been made,
especially in the Middle Anatolian Region in Tokat, Sivas
and Yozgat from the Kızılırmak river basin between 2002
and 2003, and from the Eastern Black Sea Region and from
Istanbul in recent years. According to the data obtained
Abbreviations: CCHF, Crimean–Congo haemorrhagic fever; MPO,
myeloperoxidase.
047589 G 2013 SGM
from the Ministry of Health of Turkey, the number of cases
was determined as 4453 between 2002 and 2009 (http://
www.saglik.gov.tr; Mardani & Keshtkar-Jahromi, 2007;
Acar, 2006; Karti et al., 2004).
The incubation period of CCHF differs according to the
transmission type of the disease and ranges from 2 to
7 days. The disease starts suddenly and develops with fever,
trembling myalgia, headache, vomiting and abdominal
pain. Haemorrhagic incidents (petechiae, purpura, bleeding in mucosal membranes, epistaxis, haemoptysis, haematemesis, haematuria and melena) occur within the third
to fifth days. Death usually results from serious haemorrhage (Mehrabi-Tavana et al., 2002; Kara, 2006).
Mortality is high despite modern intensive care techniques,
and the death rate varies from 8 to 80 % (Acar, 2006; Lupi
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441
F. M. K. Guven and others
& Tyring, 2003). The mortality rate has been reported as 5–
6 % in Turkey (http://www.saglik.gov.tr).
Myeloperoxidase (MPO) enzyme is a member of the
mammalian peroxidase family, which also includes lactoperoxidase, eosinophil peroxidase and thyroid peroxidase. MPO
has three isoenzymes: MPO I, II and III, and plays an
important role in the defence mechanism against microorganisms (Wright et al., 1990; Miyasaki et al., 1987; Rocha
et al., 2002). This enzyme, purified for the first time by Agner
(1941), is one of the important proteins of azurophilic granular
leukocytes, is found in their cytoplasm with other antimicrobial proteins and is effective on many micro-organisms,
especially viruses (Olsson et al., 2004; Chochola et al., 1994).
The anti-microbial functions of leukocytes occur as part of
the phagocytosis process. Respiratory burst occurs via
nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase, which is localized in the phagosome membrane. In
this process, oxygen consumption increases and superoxide
radicals (superoxide anions and hydrogen peroxide) occur
rapidly (Hampton et al. 1998). The MPO enzyme catalyses
H2O2 and halides (CI2, F2, Br2 and I2), creating
hypohalous forms. These materials are very toxic against
bacteria, fungus and mammalian cells. The biochemical
reactions occurring during the phagocytosis of microorganisms in the activated neutrophils and the location of
MPO are shown in Fig. 1 (Inal, 2007).
Generally, MPO activity increases in viral infections (Kulander
et al., 2001). The objective of this study was to find out
whether MPO enzyme activity is a useful diagnostic and
treatment method by the comparison of the MPO enzyme
activity level between controls and CCHF patients.
METHODS
This study was conducted in the Department of Emergency Medicine
and Infectious Diseases, Cumhuriyet University Hospital, Sivas,
Turkey, in 2007. Of the samples, 47 cases with a positive diagnosis
of CCHF according to the PCR/ELISA result from the Refik Saydam
National Public Health Agency Virology Reference and Research
Laboratory (Ankara, Turkey) were selected for the study. Forty-one
age and gender matched volunteers, who had not any viral or
metabolic disease, were enrolled as the control group. Samples were
collected into tubes containing EDTA.
Purification of leukocytes. Samples were centrifuged at 1000 r.p.m.
for 10 min at +4 uC and the upper plasma portion was extracted.
The precipitate was centrifuged at 3000 r.p.m. for 5 min at +4 uC.
The white layer of leukocytes that occurred in the upper portion was
aspirated with a Pasteur pipette and extracted as a leukocyte
suspension. Turk solution (2 ml) prepared with 2 ml glacial acetic
acid and 98 ml distilled water was added to the leukocyte suspension
to fragment the erythrocytes present. This mixture was centrifuged,
and the supernatant portion was removed and the precipitate was
retrieved. Isotonic solution (0.9 % NaCl) (2 ml) was added to this
precipitate, and the mixture was centrifuged at 1000 r.p.m. for
10 min at +4 uC. This washing process was repeated four times.
Distilled water (1 ml) was added on this mixture, resulting in
fragmentation of the leukocytes. Plasma and leukocytes were obtained
from these samples. A microscopic view of the fragmented and
unfragmented leukocytes is given in Fig. 2(a, b). Plasma and leukocyte
MPO enzyme activity was measured using the Rayto 2100 C ELISA
reader and MPO ELISA kit (Northwest Life Science Specialties)
according to the ELISA method.
Statistical analysis. Statistical Package for the Social Sciences,
version 14.0, was used for statistical analysis. Inter-group differences
were tested with independent-samples t-test, Mann–Whitney U test
and Kruskall Wallis test. Data were expressed as arithmetical
mean±SD and P,0.05 values were considered significant.
RESULTS
MPO enzyme activity was measured both in the plasma and
leukocytes of the patient and control group. The patient
group included 47 CCHF patients who had a definite
diagnosis by the PCR/ELISA method. The control group
consisted of 41 individuals who did not have systemic
diseases. The difference between the groups in terms of age
and gender was statistically insignificant (P.0.05).
The MPOplasma and MPOleukocyte enzyme activities of
CCHF patients were found to be higher than those of the
NADPH
NADPH oxidase
NADP+
Bacteria
HOCl
Myeloperoxidase
Bacteria
Inside the neutrophil phagocytosis
pseudopodium
Fig. 1. MPO in activated neutrophils.
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Journal of Medical Microbiology 62
Myeloperoxidase enzyme activity in CCHF patients
(a)
between the males and females in the patient group was
not statistically significant (P.0.05), and there was an
insignificant difference in the control group (P.0.05)
(Table 2). When MPOplasma and MPOleukocyte for the males
and females in the patient and control groups were
compared, the difference between the groups was found
to be significant (P,0.05).
DISCUSSION
The aim of the study was to analyse the MPO enzyme activity
in CCHF patients. CCHF disease is seen in nearly 30 countries
in the world, including our country where it is especially seen in
and around the provinces of Sivas. In our study, the leukocyte
and plasma MPO enzyme activity of CCHF patients was found
to be higher than in the control group. Currently, there is no
information about the MPO enzyme activity measurement of
CCHF patients in the literature. Therefore, the data obtained
from this study were compared with other clinical research.
(b)
Fig. 2. Microscopic view before (a) and after (b) destruction of
leukocytes.
controls (P,0.05) (Table 1). In terms of MPO enzyme
activity, according to the age groups in the control group
the difference was statistically significant (P,0.05). When
the MPO values were compared according to the age
groups, the difference was statistically significant between
14 years and under and 40–49 years, 50–59 years and 60
years and over; and between 20–29 years, 30–39 years, 40–
49 years, 50–59 years and 60 years and over (P,0.05).
In terms of MPO enzyme activity, according to the age
groups in the patient group the difference was not
statistically significant (P.0.05). Similarly, the difference
Table 1. Enzyme activity values of MPOplasma, MPOleukocyte,
CCHF groups and controls
The data are presented as means±SD.
MPOplasma (ng ml21)
MPOleukocyte (ng ml21 per
leukocyte)
CCHF group
(n547)
Control group
(n541)
57.62±8.85*
0.79±0.29*
44.84±9.71
0.49±0.11
*Higher when compared to the control group (P,0.05).
http://jmm.sgmjournals.org
Generally, in viral infections, MPO activity increases (Kulander
et al., 2001). The MPO enzyme found abundantly in
phagocytic leukocytes is one of the most important producers
of oxidants. The MPO enzyme catalyses H2O2 and halides
(CI2, F2, Br2 and I2), creating hypohalous forms. These
materials are very toxic against bacteria, fungus and mammal
cells. When the immune system is stimulated by bacteria or
viruses, the chemotactic and phagocytic activities of leukocytes
increase. After phagocytosis, the leukocytes lead to increased
reactive oxygen species through MPO and NADPH oxidase
(Altınyazar et al., 2006). The leakage or secretion of the toxic
agents from the neutrophils damages the nearby cells.
Phagocyte-derived oxidants show toxic, immunosuppressive
and mutagenic effects (Valenzuela, 1991). Therefore, the
activity level of MPO is directly related to the activation of
phagocytic leukocytes. MPO activity is expected to increase
with the number of active phagocytic leukocytes. Altınyazar
et al. (2006) did not find a significant difference compared with
the control group in the neutrophil MPO enzyme activity of
patients with recurrent aphthous stomatitis (RAS) disease and
they stated that the MPO enzyme activity is at normal levels in
the disease cases because the phagocytic active leukocyte
number is also at normal levels. Although in our study patients
had leukopenia, we found the level of MPO high both in
leukocytes and plasma in these patients. The MPO level in the
leukocytes suggested increased MPO expression in leukocytes
stimulated by viral infection and the plasma level of MPO
suggested leukocytes were lysed. Therefore, this was suggestive
that leukopenia in CCHF patients might be attributed to lysis.
Işeri et al. (2005) reported that the colon and hepatic MPO
enzyme activity increases in rats that have developed sepsis
(P,0.05 and P,0.01, respectively). In sepsis patients,
plasma MPO enzyme activity was shown to be significantly
higher (Kothari et al., 2011). Bekheet et al. (2009) reported
that a high level of plasma MPO, associated with increased
hepatic tissue MPO immunoreactivity, is important and
plays a critical role in the development of hepatic cirrhosis
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F. M. K. Guven and others
Table 2. Comparison of males and females according to parameters measured for the patient and control groups
21
MPOplasma (ng ml )
MPOleukocyte (ng ml21 per leukocyte)
Patient
Control
Patient
Control
Male*
Female*
Result
58.22±9.08
44.31±8.71
0.83±0.33
0.46±0.10
56.82±8.68
45.17±10.46
0.74±0.23
0.50±0.12
P50.505
P50.748
P50.511
P50.329
P.0.05
P.0.05
P.0.05
P.0.05
*Mean±SD.
in hepatitis C virus infection. Zelzer et al. (2009)
determined that MPO levels increase in patients with
transplants before infection or rejection rather than in
patients without any complication. They stated that the
high MPO levels can be a determinant of the complications
in patients who have an organ transplantation.
In a study conducted in vitro it was determined that the oxidant
types produced by MPO cause tissue and cell damage, and
contribute to many inflammatory diseases including respiration disorder syndrome, glomerulonephritis, arthritis, peptic
ulcer and gastric cancer (Winterbourn et al., 2000). Clinical
features such as haemorrhage and increased vascular permeability indicate that infection of the endothelium is a major target
in CCHF pathogenesis (Swanepoel et al., 1987). CCHF virus
targets endothelial cells in two ways. Directly via virus infection
and replication in endothelial cells, and/or indirectly via viral
factors or infected leukocytes releasing soluble mediators
causing endothelial activation and dysfunction (Schnittler &
Feldmann, 2003). The involvement of endothelial cells by
CCHF virus increases vascular permeability and initiates
inflammatory responses (Vestweber, 2007).
The MPO level is an indicator of endothelial dysfunction,
inflammation, atherosclerosis and oxidative stress (Michowitz
et al., 2008). This enzyme converts the low density lipoprotein
into the atherogenic form, many reactive oxidants and free
radicals occur and contribute to endothelial dysfunction by
decreasing the nitric oxide level. MPO and MPO oxidant
products can be a biomarker for the complications occurring
during coronary heart disease and chronic heart failure (Tang
et al., 2007; Morrow et al., 2008).
Ronald et al. (2009) determined that MPO activity is high
in biochemical experiments comparing atherosclerotic
plaques to normal arterial walls. They also determined
that in vivo MPO activity is related to atherosclerotic
plaque development and progression. The MPO enzyme is
a rising determinant in acute cases, and plaque instability
and plasma MPO levels have been found to be high in
patients with stroke (Re et al., 1997).
In unstable angina and acute myocardial infarction, MPO
is secreted into coronary circulation, thus the plasma levels
of MPO increase (Buffon et al., 2002; Deby-Dupont et al.,
1999). There is a strong relationship between high
leukocyte and blood MPO levels and coronary artery
disease (Baldus et al., 2003; Zhang et al., 2001).
444
Baldus et al. (2003) found that the MPO is significant in
patients with a negative troponin test. Kaya et al. (2005)
compared plasma levels of MPO enzyme activity and
coronary angiography results, and stated that 50 % of the
patients with a high MPO have coronary artery diseases,
but coronary artery disease was not found in patients with
normal plasma MPO levels.
In our study, plasma MPO enzyme activity was higher in the
CCHF patient group than the control group. Therefore,
increased MPO activity and related oxidant products are
thought to contribute to endothelial dysfunction in CCHF
patients. However, the presence of vascular disease is
unknown in the CCHF patients included in our study.
Increased levels of MPO suggested that CCHF disease
contributed to the pathogenesis of vascular disorder.
Extensive studies on this subject will provide further
contribution. In this respect, if CCHF patients have a
vascular disease history, during the period from the onset of
the infection of the virus to the occurrence of symptoms,
MPO enzyme activity levels may contribute to the prognosis.
Conclusion
Increased levels of MPO in leukocytes found in the
cytoplasm of azurophilic granular leukocytes suggested
synthesis related to viral infection, and an increased plasma
level of MPO is suggested to be the result of lysis of the
leukocytes. Leukopenia in CCHF patients is suggested to be
correlated with lysis and not due to the involvement of
bone marrow. We concluded that a high level of MPO
affects pathogenesis and contributes to increasing oxidative
stress. However, further studies are required to determine
the significance of MPO in patients with CCHF.
ACKNOWLEDGEMENTS
Informed consent forms were taken for this study. Ethical approval
(2007-10/5) was obtained from the Clinical Research Ethics
Committee of Cumhuriyet University School of Medicine.
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