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9. Activation and evasion of the type I Interferon response by infectious bronchitis virus : roles of the accessory proteins

Author

Kint, J., Wageningen University, Geert Wiegertjes, Huub Savelkoul, and Maria Forlenza

Subjects
infectious bronchitis virus, animal structures, coronaviridae, coronavirus, viral interference, Celbiologie en Immunologie, immuniteitsreactie, immune response, fowls, quantitative methods, fowl diseases, vaccinontwikkeling, interferon, kippenziekten, pluimveeziekten, Cell Biology and Immunology, vaccine development, embryonic structures, kwantitatieve methoden, virale inmenging, WIAS, kippen, eiwit, poultry diseases, protein, infectieus bronchitisvirus
Abstract

SUMMARY Viruses are intracellular parasites that exploit the machinery of the host cell to replicate. To defend themselves against invading viruses, animal cells have evolved an anti-viral mechanism, known as the type I interferon response. Through natural selection viruses have in turn evolved mechanisms to counteract or evade the type I IFN response. Coronaviruses are a large group of positive-stranded RNA viruses that cause a range of human and veterinary diseases. Infectious bronchitis virus (IBV) is a member of the genus Gammacoronavirus and it is the causative agent of a highly contagious respiratory disease of poultry. To date, only few studies have investigated the interaction between IBV and the type I IFN response. In this thesis, we describe for the first time the activation of the type I interferon response (IFN response) by the Gammacoronavirus IBV, and the repressive role of accessory proteins therein. In Chapter 1 I provide a general introduction into coronaviruses in general and the Gammacoronavirus IBV in particular. I also introduce the IFN response, and highlight differences between the mammalian and chicken IFN response. Finally, I review current knowledge on the roles of coronavirus accessory proteins in counteraction of the IFN response. In Chapter 2 we describe our studies which demonstrated that activation of the IFN response by IBV is dependent on the intracellular double-stranded RNA sensor MDA5. We show that detection of IBV-infection by MDA5 is delayed with respect to the peak of viral replication, and demonstrate that this delay is not due to inhibition of dsRNA detection by IBV. Using mutant viruses that cannot express accessory proteins (null viruses), we found that accessory proteins 3a and 3b of IBV mediate transcription and translation of Ifnβ mRNA. The observation that IBV delays the activation of the IFN response, prompted us to investigate the sensitivity of IBV to IFN treatment in Chapter 3. Here we show that IBV is relatively resistant to treatment with type I IFN, as relatively high doses of type I IFN are required to decrease propagation of the virus. Next, we studied which viral protein(s) contribute to resistance of IBV to type I IFN and found that absence of accessory proteins 3a and 3b increased sensitivity of IBV to type I IFN, via a presently unknown mechanism. In addition, we observed that independent of accessory proteins 3a and 3b, IBV blocks signaling of IFN by inhibiting phosphorylation and translocation of the transcription factor STAT1. To explain the delayed kinetics of IFN production observed in Chapter 2, we investigated whether delayed protein production was restricted to IFN, or whether IBV, like Alpha- and Betacoronaviruses, inhibits general translation of host proteins (i.e. induces host shutoff). In Chapter 4 we demonstrate that IBV-induced transcription of Ifnβ mRNA leads to the production of relatively little IFN protein. We discovered that limited production of IFN protein by IBV-infected cells is the result of general inhibition of host translation, confirming that IBV induces a shutoff of host-protein production. This finding indicates that evasion of the innate immune system by Gammacoronaviruses may be more similar to that of Alpha- and Betacoronaviruses than previously thought. Using accessory protein null viruses we discovered that accessory protein 5b of IBV is essential for the inhibition of host-protein synthesis by IBV. In Chapter 5 and Chapter 6 we describe the methods used in this thesis to quantify the number of infectious virus particles of IBV as well as methods used to quantify the activation of the type I IFN response in chicken cells. Although the studies described in this thesis have answered several questions about the interaction of IBV with the type I IFN response of its host, they have also raised new questions to be addressed in future research. In the final Chapter of this thesis (Chapter 7), I discuss a number of remaining questions and future perspectives regarding evasion of the IFN response by IBV. Finally, I explore the possible implications of our findings on the in vivo pathogenicity of IBV and on the rational design of attenuated IBV vaccines. In conclusion, the work described in this thesis demonstrates for the first time how IBV evades, activates, and antagonises the IFN response. Also, this thesis comprises the first study that describes a function for the accessory proteins of IBV and shows that these poorly understood proteins play an important role in antagonism of the type I IFN response.

Published
2015

16. Performance of the Coulter STKS and the Sysmex NE-1500 in a paediatric population

Author

Moreau E, jan philippé, Kint J, Benoit Y, and Leroux-Roels G

Subjects
Autoanalysis, Adolescent, Infant, Reproducibility of Results, Hematologic Diseases, Sensitivity and Specificity, Blood Cell Count, Evaluation Studies as Topic, Predictive Value of Tests, Child, Preschool, Neoplasms, Leukocytes, Humans, False Positive Reactions, Child
Abstract

The Coulter STKS and the Sysmex NE-1500 were evaluated for their performance in paediatric samples. Special attention was paid to the ability of both instruments to detect white blood cell morphology abnormalities. Therefore a population with a high frequency of pathologies was selected. The studied population included children aged between 1 month and 14 years, 45% of which suffered from oncological and/or haematological diseases. Two hundred and forty blood samples were analysed. The leukocyte differentiation results from the Coulter STKS and the Sysmex NE-1500 were compared with the manual microscopic method. The differentials compared very well for neutrophils, lymphocytes and eosinophils. Sensitivity and specificity for the detection of blasts, immature granulocytes, left shift and atypical lymphocytes were examined. While specific morphology flagging showed a rather low sensitivity, blasts and immature granulocytes were mostly detected by the two systems, taking into account white blood cell alarm flags other than the two mentioned above. The overall sensitivity for the detection of white blood cell abnormalities was better with the Coulter STKS, whereas the Sysmex NE-1500 showed a higher specificity. In an ancillary study which was performed exclusively on neonatal samples, of which 80% originated from preterm infants, we found a limited sensitivity for the detection of low percentages of nucleated red blood cells for both analysers. The high frequency of abnormalities, together with the limited sensitivity mentioned above, prompted us to review all neonatal samples in the future.

Published
1994

24. Seminal plasma α-glucosidase activity and male infertility.

Author

Mahmoud, AM, Geslevich, J, Kint, J, Depuydt, C, Huysse, L, Zalata, A, and Comhaire, FH

Abstract

Measurement of α-glucosidase (α-GLUC) activity by means of a simple colorimetric test using a commercial kit (EpiScreen®; FertiPro, Lotenhulle, Belgium) yielded results that were strongly correlated with the values obtained for the neutral iso-enzyme measured by a fluorimetric reference method (r = 0.85, P = 0.003, n = 13). The former method was characterized by a low intra- and inter-coefficient of variation (6.6 and 4.3% respectively). Vasectomized men with azoospermia (n = 27) had a significantly lower α-GLUC activity in semen than vasectomized men with residual spermatozoa present (n = 11, P < 0.01) and men with azoospermia of primary testicular origin (n = 33, P < 0.01). Receiver operating curve (ROC) analysis showed α-GLUC measurement to be reasonably accurate in differentiation between cases with obstructive versus testicular azoospermia at criterion value 13.5 U/l (sensitivity = 82%, specificity = 70%). In cases with spermatozoa present, α-GLUC activity and output per ejaculate were positively correlated with sperm concentration (r = 0.53 and 0.38, n = 472), linear velocity (r = 0.35 and 0.30, n = 224), curvilinear velocity (r = 0.32 and r = 0.29, n = 224), semen adenosine triphosphate (r = 0.35 and 0.26, n = 64), the concentration of 5α-dihydrotestosterone (r = 0.31 and 0.29, n = 74) and γ-glutamyltransferase activity (r = 0.62 and 0.32, n = 275) in seminal plasma. The activity of α-GLUC was inversely correlated with ROS generation after 12-myristate, 13-acetate phorbol ester stimulation (r = -0.27, n = 104), and both α-GLUC activity and total output were inversely correlated with the concentration of peroxidase-positive white blood cells among samples with 1x106/ml of these cells (r = -0.30 and -0.19, n = 165). It is concluded that simple photometric measurement of α-GLUC activity in seminal plasma reflects the functional state of the epididymis and may be helpful for the differential diagnosis of certain cases with azoospermia. [ABSTRACT FROM PUBLISHER]

Published
1998
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25. IgG subclass deficiency in children with recurrent bronchitis.

Author

DeBaets, F, Kint, J, Pauwels, R, and Leroy, J

Subjects
BRONCHITIS, IMMUNOGLOBULINS, IMMUNOLOGICAL deficiency syndromes, REFERENCE values, DISEASE relapse
Abstract

We studied the incidence of IgG subclass deficiency in children with recurrent bronchitis. Recurrent bronchitis was defined as three or more episodes a year during at least 2 consecutive years, of bronchopulmonary infection, productive cough with or without fever and/or diffuse râles by physical examination in the absence of asthma or atopy. Fifty three children were selected, of whom 30 (57%) were deficient in one of the IgG subclasses. None had an IgG1 deficiency. Nine (17%) were deficient in IgG2, 9 (17%) in IgG3 and 20 (38%) in IgG4. Isolated IgG subclass deficiencies were most frequently seen for IgG4 (14, 26%), less for IgG3 (6, 12%) and even less for IgG2 (4, 7%). Nine (17%) children were IgA deficient and 8 (15%) IgG deficient with a combined IgG subclass deficiency in 8 and 7 of them respectively. By subdivision into different age groups most patients were encountered in the youngest group. The mean content of IgG2, IgG3 and IgG4 in 3- to 4-year-old children with recurrent bronchitis was significantly lower than in the age matched controls. The mean value for IgG4 in the 5- to 6-year-olds was significantly lower than in the control group. This study demonstrates the correlation between recurrent bronchitis in childhood and IgG subclass deficiency. IgG subclass deficiency and recurrent bronchitis are both quite prominent phenomena in young children but rare in older children, suggesting a transient immaturity of the immune system as one of the possible pathogenetic factors. An IgA or an IgG deficiency is highly suggestive for the existence of a combined IgG subclass deficiency. [ABSTRACT FROM AUTHOR]

Published
1992

26. IgG subclass deficiency in children with recurrent bronchitis.

Author

Baets, F., Kint, J., Pauwels, R., and Leroy, J.

Abstract

We studied the incidence of IgG subclass deficiency in children with recurrent bronchitis. Recurrent bronchitis was defined as three or more episodes a year during at least 2 consecutive years, of bronchopulmonary infection, productive cough with or without fever and/or diffuse râles by physical examination in the absence of asthma or atopy. Fifty three children were selected, of whom 30 (57%) were deficient in one of the IgG subclasses. None had an IgG1 deficiency. Nine (17%) were deficient in IgG2, 9 (17%) in IgG3 and 20 (38%) in IgG4. Isolated IgG subclass deficiencies were most frequently seen for IgG4 (14, 26%), less for IgG3 (6, 12%) and even less for IgG2 (4, 7%). Nine (17%) children were IgA deficient and 8 (15%) IgG deficient with a combined IgG subclass deficiency in 8 and 7 of them respectively. By subdivision into different age groups most patients were encountered in the youngest group. The mean content of IgG2, IgG3 and IgG4 in 3- to 4-year-old children with recurrent bronchitis was significantly lower than in the age matched controls. The mean value for IgG4 in the 5- to 6-year-olds was significantly lower than in the control group. This study demonstrates the correlation between recurrent bronchitis in childhood and IgG subclass deficiency. IgG subclass deficiency and recurrent bronchitis are both quite prominent phenomena in young children but rare in older children, suggesting a transient immaturity of the immune system as one of the possible pathogenetic factors. An IgA or an IgG deficiency is highly suggestive for the existence of a combined IgG subclass deficiency. [ABSTRACT FROM AUTHOR]

Published
1992
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29. HIV prevalence and risk behaviour among prostitutes and clients in Amsterdam: migrants at increased risk for HIV infection.

Author

van Haastrecht, H J, Fennema, J S, Coutinho, R A, van der Helm, T C, Kint, J A, and van den Hoek, J A

Abstract

OBJECTIVES--To study groups of prostitutes and clients of prostitutes in order (i) to determine HIV prevalence and sexual risk behaviour, (ii) to determine differences between samples recruited within and outside a clinic for sexually transmitted diseases (STD) and (iii) to determine correlates of inconsistent condom use (ICU) among both groups. DESIGN--Participants were interviewed and anonymously tested for HIV-antibody; approximately half were recruited at a clinic for sexually transmitted diseases (STD) and half at prostitute working places. SETTING--An STD clinic and prostitute working places in Amsterdam in 1991. SUBJECTS--201 female prostitutes without a history of injecting drugs and 213 male clients of female prostitutes. MAIN OUTCOME MEASURES--antibodies to HIV, consistency of condom use in commercial vaginal contacts in the preceding 6 months. RESULTS--HIV prevalence was low: three prostitutes (1.5%; 95% CI 0.5-4.6%) and one client (0.5%; 95% CI 0.1-3.3%) were infected. All three HIV positive prostitutes originated from AIDS-endemic countries, came to the Netherlands only recently and were recruited outside the STD clinic. Large differences between subgroups resulted from the two recruitment methods: while clients of prostitutes with relatively high risk behaviour were strongly represented among the STD clinic sample, high risk prostitutes were underrepresented in this sample. Consistent condom use (with 100% of contacts) was reported by 66% of prostitutes and 56% of clients of prostitutes. Inconsistent condom use was found to be high among prostitutes who had migrated from Latin America and among migrant clients of prostitutes. CONCLUSIONS--When monitoring HIV infection one must take into account imported cases. HIV prevention efforts should be particularly focused at prostitutes from Latin America and at clients of prostitutes who migrated to the Netherlands. [ABSTRACT FROM PUBLISHER]

Published
1993
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33. Nextdoor quartier: Teaching young designers social conscience

Author

Oscar Tomico, Kint, J. M. L., and Ferwerda, I.

Abstract

The NextDoor Quartier project gave the opportunity to students of communication design and product design to experience the societal relevance of their work. They had to dive into the implications of trying to deal with cultural differences knowing that their decisions will have an impact and can't be pulled back. Results from the two groups of 8 students (4 industrial design, 4 communication design), showed the importance of learning by doing as the main driving force for social understanding. By confronting young designers with their own beliefs as a person, they were able to improve their social conscience at the same time that they design for a specific social group. Involving the community in Brussels North proved to be key to develop this project. The active participation of the inhabitants worked as a catalyst to create synergies between content, context and locality that define a specific intercultural context. The results of the project were delivered by means of installations or experiential prototypes. They publicly were displayed in the city of Brussels (Brabantwijk).

43. Incidence, risk factors and treatment of diarrhoea among Dutch travellers: reasons not to routinely prescribe antibiotics

Author

Belderok Sanne-Meike, van den Hoek Anneke, Kint Joan A, Schim van der Loeff Maarten F, and Sonder Gerard JB

Subjects
Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Travellers' diarrhoea (TD) is the most common infectious disease among travellers. In the Netherlands, stand-by or prophylactic antibiotics are not routinely prescribed to travellers. This study prospectively assessed the incidence rate, risk factors, and treatment of TD among immunocompetent travellers. Methods Persons who attended the travel clinic of the Public Health Service Amsterdam in 2006-2007 before short-term travel to tropical and subtropical countries were invited to answer a questionnaire regarding sociodemographics and travel purpose; they were also asked to keep a daily structured travel diary, recording their itinerary, symptoms, and self-medication or consultation with a doctor. Diarrhoea episodes containing blood or mucous were considered severe. Results Of 1202 travellers, the median age was 38 years, and the median travel duration 3 weeks. Of all episodes, 96% were mild. The median duration of TD was 2 days and significantly shorter in subsequent episodes compared to first episodes (p < 0.0005). Of first episodes 38% started in the first travel week. The incidence rate (IR) for first episodes was 2.49 (95% confidence interval [CI], 2.30-2.70) per 100 travel days, with the highest IR among travellers to South-Central and West Asia. The IR for first and subsequent episodes was comparable. Risk factors for first episodes included female sex, a Western country of birth, and tourism as the purpose of travel. The lowest risk was in travellers to South America. An independent risk factor for subsequent episodes was female sex. In total, 5% of travellers used antibiotics; of those, 92% had mild diarrhoea, and 53% received antibiotics over the counter. Conclusions TD is common among travellers, but the overall course is mild, not requiring treatment. The incidence rates for first and second episodes are comparable. Female sex is a risk factor for the first episode, as well as subsequent ones. Prescription antibiotics are not needed in short-term healthy travellers.

Published
2011
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44. Travel-related schistosomiasis, strongyloidiasis, filariasis, and toxocariasis: the risk of infection and the diagnostic relevance of blood eosinophilia

Author

Sonder Gerard J, Baaten Gijs G, van Gool Tom, Kint Joan A, and van den Hoek Anneke

Subjects
helminth infection, eosinophilia, travel, prospective study, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background This study prospectively assessed the occurrence of clinical and subclinical schistosomiasis, strongyloidiasis, filariasis, and toxocariasis, and the screening value of eosinophilia in adult short-term travelers to helminth-endemic countries. Methods Visitors of a pre-travel health advice centre donated blood samples for serology and blood cell count before and after travel. Samples were tested for eosinophilia, and for antibodies against schistosomiasis, strongyloidiasis, filariasis, and toxocariasis. Previous infection was defined as seropositivity in pre- and post-travel samples. Recent infection was defined as a seroconversion. Symptoms of parasitic disease were recorded in a structured diary. Results Previous infection was found in 112 of 1207 subjects: schistosomiasis in 2.7%, strongyloidiasis in 2.4%, filariasis in 3.4%, and toxocariasis in 1.8%. Recent schistosomiasis was found in 0.51% of susceptible subjects at risk, strongyloidiasis in 0.25%, filariasis in 0.09%, and toxocariasis in 0.08%. The incidence rate per 1000 person-months was 6.4, 3.2, 1.1, and 1.1, respectively. Recent infections were largely contracted in Asia. The positive predictive value of eosinophilia for diagnosis was 15% for previous infection and 0% for recent infection. None of the symptoms studied had any positive predictive value. Conclusion The chance of infection with schistosomiasis, strongyloidiasis, filariasis, and toxocariasis during one short-term journey to an endemic area is low. However, previous stay leads to a cumulative risk of infection. Testing for eosinophilia appeared to be of no value in routine screening of asymptomatic travelers for the four helminthic infections. Findings need to be replicated in larger prospective studies.

Published
2011
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50. Dermal Delivery of a SARS-CoV-2 Subunit Vaccine Induces Immunogenicity against Variants of Concern.

Author

McMillan CLD, Azuar A, Choo JJY, Modhiran N, Amarilla AA, Isaacs A, Honeyman KE, Cheung STM, Liang B, Wurm MJ, Pino P, Kint J, Fernando GJP, Landsberg MJ, Khromykh AA, Hobson-Peters J, Watterson D, Young PR, and Muller DA

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic continues to disrupt essential health services in 90 percent of countries today. The spike (S) protein found on the surface of the causative agent, the SARS-CoV-2 virus, has been the prime target for current vaccine research since antibodies directed against the S protein were found to neutralize the virus. However, as new variants emerge, mutations within the spike protein have given rise to potential immune evasion of the response generated by the current generation of SARS-CoV-2 vaccines. In this study, a modified, HexaPro S protein subunit vaccine, delivered using a needle-free high-density microarray patch (HD-MAP), was investigated for its immunogenicity and virus-neutralizing abilities. Mice given two doses of the vaccine candidate generated potent antibody responses capable of neutralizing the parental SARS-CoV-2 virus as well as the variants of concern, Alpha and Delta. These results demonstrate that this alternative vaccination strategy has the potential to mitigate the effect of emerging viral variants.

Published
2022
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