IL-1beta, IL-6, and RANTES as biomarkers of Chikungunya severity.

BACKGROUND: Little is known about the immunopathogenesis of Chikungunya virus. Circulating levels of immune mediators and growth factors were analyzed from patients infected during the first Singaporean Chikungunya fever outbreak in early 2008 to establish biomarkers associated with infection and/or disease severity. METHODS AND FINDINGS: Adult patients with laboratory-confirmed Chikungunya fever infection, who were referred to the Communicable Disease Centre/Tan Tock Seng Hospital during the period from January to February 2008, were included in this retrospective study. Plasma fractions were analyzed using a multiplex-microbead immunoassay. Among the patients, the most common clinical features were fever (100%), arthralgia (90%), rash (50%) and conjunctivitis (40%). Profiles of 30 cytokines, chemokines, and growth factors were able to discriminate the clinical forms of Chikungunya from healthy controls, with patients classified as non-severe and severe disease. Levels of 8 plasma cytokines and 4 growth factors were significantly elevated. Statistical analysis showed that an increase in IL-1beta, IL-6 and a decrease in RANTES were associated with disease severity. CONCLUSIONS: This is the first comprehensive report on the production of cytokines, chemokines, and growth factors during acute Chikungunya virus infection. Using these biomarkers, we were able to distinguish between mild disease and more severe forms of Chikungunya fever, thus enabling the identification of patients with poor prognosis and monitoring of the disease.

[Epidemiological analysis of cases of TBE in 1993 in Bialystok district]. / Analiza epidemiologiczna kleszczowego zapalenia opon mózgowo-rdzeniowych i mózgu (KZM) w 1993 roku na terenie województwa bialostockiego.

111 cases of TBE was 20 times increased morbidity in comparison to 1992 in Bialystok district in 1993. Among hospitalized dominated male patients (52.35%). First cases was reported in may and last in November with a peak in July. The age of patients was from 6 to 78 years old, 63.06%, in age group from 31 to 59 years old. We established that 78.87% patients were citizens of Bialystok, spending there recreation time in forest. Despite occurrence increased cases of TBE in 1993 we conclude that among people from risk group vaccination is indicated.

Virological and immunological studies of Wesselsbron virus in experimentally infected red Sokoto (Maradi) goats.

Red Sokoto goats aged four to five months were experimentally infected with the Nigerian strain of Wesselsbron virus. Viraemia commenced 24-72 hours after infection and lasted for 3-4 days. A febrile reaction which was mostly biphasic coincided with viraemia. A 50% mortality rate was observed among infected animals. The virus was re-isolated in mice from almost every tissue (liver, spleen, lungs, brain, kidney, adrenal, lymph node and heart) obtained from dead goats. Complement fixing antigens were detected in the tissues of dead goats, the titre of which correlated positively with the infectivity titre. All infected animals developed complement-fixing and haemagglutination inhibiting antibodies to Wesselsbron virus. However, neutralizing antibody was detected only in goats that survived the infection.

Viremia in three orders of birds (Anseriformes, Galliformes and Passeriformes) inoculated with Ockelbo virus.

One-hundred six birds of 14 species were inoculated with approximately 10(2.7) plaque-forming units of Ockelbo virus and bled daily for 5 days to determine viremia levels. Virus was detected in birds of all 14 species tested (four Anseriformes, one Galliformes and nine Passeriformes). The onset of viremia occurred earlier and viral titers were higher in very young anseriforms and galliforms than in older birds. Adult passeriforms had Ockelbo viremias of higher titer and longer duration than did adult anseriforms. Viremia titers in adult birds of all three orders tested were sufficient to induce high transmission rates in enzootic mosquito vectors, and viremias in passeriforms could induce high transmission rates in bridging vectors as well. Passeriforms of the genera Turdus and Fringilla could serve as amplification hosts for Ockelbo virus based on the presently demonstrated viremia of high titer and long duration in these birds, and the previously demonstrated high prevalence of Ockelbo virus neutralizing antibodies in free-ranging individuals and great population size compared to birds of other taxa. Bird species of all three orders tested, however, could function as incidental hosts of the virus.

Macrophage function in the acute phase of lactic dehydrogenase virus-infection of mice: suppression of superoxide anion production in normal mouse peritoneal macrophages by interferon-alpha in vitro.

The effect of interferon (IFN)-alpha on the release of superoxide anions (O2-) by normal mouse macrophages (PEM) was examined. Sera from LDV-infected mice at 1 day, but not at 7 days post-infection, suppressed the O2- release by PEM. When PEM were exposed in vitro for 24 h to IFN-alpha, their capacity to release O2- was significantly suppressed. Progressive suppression of O2- release with increasing IFN-alpha concentration was observed. These results suggest that IFN-alpha in the circulation may be one of several suppressive factors on macrophage function in the early phase of infection and IFN-alpha may play a modulatory role in inflammation and immunity.

Ecological distribution of Chikungunya haemagglutination inhibition antibodies in human and domestic animals in Nigeria.

A serological survey to detect presence of antibodies to Chikungunya virus in 477 human sera randomly sampled from four ecological zones of Nigeria was carried out employing a haemagglutination inhibition (HI) test. Similarly 220 animal sera collected mostly from the northern parts of Nigeria were screened for HI antibody to Chikungunya virus. Of the 477 human sera tested a total of 68 or 14.3% were found to possess Chikungunya HI antibodies made up of 10% in swampy forest, 20% in the rain forest, 14% in the derived savannah and 6.7% in the guinea savannah. Such sera positive for Chikungunya HI antibodies were further screened against other circulating alphaviruses of which 17 or 25% were positive to Igbo-Ora virus, 6 or 38.1% to Semliki forest virus and 36 or 52.6% were positive to Sindbis virus. Five or 2.3% of the 220 animal sera screened were found to possess Chikungunya HI antibodies.

Pestivirus infections in Norway. Epidemiological studies in goats.

During one breeding season, 2335 female goats in 39 herds in different parts of Norway were examined for pestivirus infection and for reproductive performance. Before breeding, all animals were examined for neutralizing antibodies against the NADL strain of pestivirus, 83 (3.6 per cent) positive animals in 12 herds being demonstrated. The herd prevalences ranged from 1 to 63 per cent. Antibody titres varied from 1 in 4 to 1 in 2048. Of 1816 females in 30 herds for which post-breeding information was available, a total of 178 (9.8 per cent) animals in 25 of the herds demonstrated gestation failure. Three of these goats began to produce antibodies against the NADL strain during gestation. Sera from the 83 animals with NADL antibodies were titrated for neutralizing antibodies against three additional strains of pestivirus, the highest geometrical mean titre being found for antibodies against a Norwegian bovine strain.

Pathogenicity for horses of original Sagiyama virus, a member of the Getah virus group.

Sagiyama virus is a member of the Getah virus group. Its pathogenicity for horses was examined. All the horses infected with the original 4 strains of Sagiyama virus (M6/Mag 33, Mag 121, Mag 132 and Mag 258) developed pyrexia ranging from 39.0 to 40.0 degrees C. Other clinical signs, characterized by eruptions, edema in the hind legs, enlargement of the submandibular lymph node and mild leukopenia, were also manifested. Viremia occurred 1-4 days post-inoculation (p.i.). Virus was recovered from spleen, liver, lung and various lymph nodes of a horse autopsied on Day 4 p.i. The maximum titer of virus (10(6.0) TCID50 g-1) was detected in the inguinal lymph node. Seroconversion was demonstrated in all the infected horses on Day 5 p.i. These clinical signs and virological findings were similar to those of horses infected naturally. The results indicate that Sagiyama virus has pathogenicity for horses and is similar to that of Getah virus.

Physiological relationships among stress, viruses, and cancer in experimental animals.

Anxiety-induced psychoneural stimulation, via the hypothalamic-pituitary axis, activates the adrenal cortex to release corticosteroids, which elicit various alterations of corticoid-sensitive cell-mediated immunologic processes. Stress sensitive murine tumor-host experimental models have been utilized to demonstrate various effects of stress upon aspects of tumor development. Although many of the observed anxiety-induced alterations of tumor-related parameters can be interpreted in terms of corticoid-induced modifications of immune functions, other observations are more difficult to interpret, and may be caused in part by corticosteroid-independent modulation of lymphocyte functions. In the case of tumors induced by oncogenic viruses, anxiety-induced plasma corticoid elevations may also act independently of the immune system to stimulate tumor development via hormone binding sites on proviral DNA. Rigorously controlled environmental and experimental conditions are fundamental for the demonstration and interpretation of stress-related phenomena. Technical prerequisites include protective animal facilities, special handling procedures, the use of nontraumatic stressors, and the recognition of vital psychosocial, coping and timing factors. Various biologic factors, such as sex, genetic substrain differences and common interfering viral infections, must also be controlled or taken into consideration.

Immune complexes and Ross River virus disease (epidemic polyarthritis).

Immune complexes were sought in serum and synovial fluid in Ross River virus disease (epidemic polyarthritis). Multiple samples from 15 patients showing varied degrees of disease activity over a 3 month period were analysed for their content of complement components C3 and C4, and for C1q solid-phase and Raji cell binding activity. Levels of C3 and C1q binding activity were normal. C4 and Raji cell binding activity were normal except for three high levels of Raji cell binding, of which two were accompanied by low levels of C4, with normal C3 and C1q binding. Synovial fluid showed anomalous Raji cell reactivity of uncertain significance. Conglutinin solid-phase binding activity and IgG rheumatoid factor were compared in the serum of 20 patients during active disease and after recovery. The results were identical and within the normal range in both phases. One patient developed IgM rheumatoid factor in a low titre late in his illness. Although these findings do not entirely exclude a role for immune complexes formed at the onset in the circulation or tissues, it is concluded from this and other evidence that circulating complexes are not commonly responsible for the persistence of syndromes in this disease.

Natural immunity to Sindbis virus is influenced by host tissue sialic acid content.

Recent studies have shown that the sialic acid content of Sindbis virus influences both its ability to active the alternative pathway in vitro and its susceptibility to complement dependent clearance from the bloodstream in vivo. Other studies have shown that the sialic acid content of Sindbis virus is determined by the host in which it is propagated. Because individuals vary in their cell surface sialic acid content, it is possible they also vary in their ability to defend themselves against Sindbis virus infection by virtue of their ability to modify the virus sialic acid content and thereby the capacity of the virus to activate the alternative pathway. To test this hypothesis, outbred Swiss mice were injected subcutaneously with Sindbis virus. There was a significant positive correlation between the level of viremia 18 hr after infection and the sialic acid content of the host's erythrocytes. In addition, animals with erythrocyte sialic acid levels equal to or greater than the mean had a higher level of viremia than animals with erythrocyte sialic acid levels less than the mean. Finally, animals that had muscle sialic acid levels equal to or greater than the mean had a higher incidence of viremia than animals with muscle sialic acid levels less than the mean. These studies suggest that the amount of tissue sialic acid in an individual host influences its ability to resist Sindbis virus infection.

Comparison of (2'-5') oligo-adenylate synthetase and interferon blood-levels in mice early after viral infection.

The level of the IFN-induced enzyme (2'-5') oligo A synthetase in the peripheral blood mononuclear cells (PBMC) was determined in mice at different times following virus infection. There was a significant increase (4-7-fold) of the enzyme level within less than 12 h after i.p. injection of either VSV (10(7) pfu) or Sindbis virus (2.10(4) pfu). The elevated level was maintained for about a week and then the activity returned to normal. There was, however, a marked difference in the pattern of serum level of IFN during infection by the two viruses; while in the mice infected by VSV, serum IFN was very high on the first day and declined to an undetectable level by the fourth day, in the mice infected with Sindbis virus, serum IFN was barely detectable at the first day and then increased towards the fourth day of infection. Antiviral antibodies could be detected in the serum only about a week after infection. We conclude that viral infection can result in a rapid elevation of (2'-5') oligo A synthetase in the PBMC, even when serum IFN remains low. Thus, quantitation of the enzyme level can be a useful diagnostic aid in viral infection particularly in the early stages and in cases in which antiviral antibodies and IFN can not be detected.

Development of age-dependent resistance to sindbis virus encephalitis: correlation with inactivation of virus within the blood stream.

The clearance of Sindbis virus from the blood stream and its localization in the reticuloendothelial system (RES) was studied in mice susceptible (2 weeks old) and resistant (6 weeks old) to fatal Sindbis virus encephalitis. No significant differences in the relative capacity of 2-week-old and 6-week-old mice to remove 125I-labelled virus from the blood stream and to localize virus within the liver were observed. However, the decline of infectious virus was more rapid in the blood of adult mice. These studies suggest that, in addition to physical removal of virus by the RES, inactivation of virus in the blood serum stream plays an important role in limiting viremia during infections with Sindbis virus.