Desxifrant el paper de la resposta immunitària primerenca pel control de la infecció per mers-cov en un model de camèlid
- Autores: Nigeer Te
- Directores de la Tesis: Albert Bensaid (dir. tes.), Joaquim Segalés Coma (codir. tes.), Júlia Vergara Alert (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2020
- Idioma: inglés
- ISBN: 9788449098338
- Tribunal Calificador de la Tesis: Maria Isabel Sola Gurpegui (presid.), Jordi Marquès Argilaguet (secret.), Alexandre Muller (voc.)
- Programa de doctorado: Programa de Doctorado en Medicina y Sanidad Animales por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Middle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease able to cause high mortality in humans. Severe cases associated to MERS-CoV infection are the consequence of the diffuse alveolar damage triggered by the pro-inflammatory cytokine storm and impaired interferon (IFN) responses. By contrast, camelids, the main virus reservoir, are asymptomatic MERS-CoV carriers, suggesting a crucial role for innate immune responses in controlling the infection. In study I of this dissertation, we aim to demonstrate this hypothesis by monitoring the transcription of immune response genes in the respiratory tract of MERS-CoV Qatar15/2015 (clade B strain) infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III IFNs were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.
While MERS-CoV strains from the Middle East region are subdivided into two clades (A and B), all the contemporary epidemic viruses belong to clade B. Thus, clade B MERS-CoV strains must display adaptive advantages over clade A in humans/reservoir hosts. Therefore, in study II of this dissertation, we compared an early epidemic clade A strain (EMC/2012) with a clade B strain (Jordan-1/2015) in an alpaca model monitoring virological and immunological parameters. Further, the Jordan-1/2015 strain has a partial amino acid (aa) deletion in the double stranded (ds) RNA binding motif of the open reading frame ORF 4a protein. Animals inoculated with the Jordan-1/2015 strain had higher MERS-CoV replicative capacities in the respiratory tract and larger nasal viral shedding, indicating a better fitness and transmission capability than its clade A strain counterpart. In the nasal mucosa, the Jordan-1/2015 strain provoked an early IFN response on 1-day post inoculation (dpi), confirming the role of ORF4a as an IFN antagonist in vivo. However, both strains provoked at the peak of infection (on 2 dpi) maximal transcription of ISGs correlating with decreased tissular viral loads observed on 3 dpi. Genome alignment analysis revealed several clade B specific aa substitutions occurring in the replicase and the S protein which could explain a better adaptation of clade B strains in camelid hosts.
Overall, the results exposed in the present thesis highlight the complex interactions between MERS-CoV and host factors through which camelids control the infection in a short period of time. In addition, MERS-CoV strains are still evolving acquiring enhanced replicative fitness as shown in alpacas in the present study. This is reflected in the field by the dominance of MERS-CoV clade B strains over early epidemic clade A strains in humans and camelids.
