Diseño de una vacuna para prevenir la infección por el coronavirus causante del síndrome respiratorio agudo y grave
Author
Regla Nava, José ÁngelEntity
UAM. Departamento de Biología Molecular; CSIC. Centro Nacional de Biotecnología (CNB)Date
2015-07-24Subjects
Virus - Tesis doctorales; Aparato respiratorio - Enfermedades - Tesis doctorales; Infecciones por coronavirus - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 24-07-2015Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Coronavirus such as the severe acute respiratory syndrome coronavirus (SARSCoV)
and the Middle East respiratory syndome virus (MERS-CoV) cause high case
fatality rates and remain as major human public health threats. No specific therapy
for any human coronavirus is available, making vaccine development critical for
protection against these viruses. Previously, we demonstrated that a mouseadapted
SARS-CoV (SARS-CoV-MA15) lacking the envelope (E) protein (rSARSCoV-MA15-ΔE)
is attenuated in vivo. To identify E protein regions and host
responses that contribute to rSARS-CoV-MA15-ΔE attenuation, several mutants
(rSARS-CoV-MA15-E*) containing point mutations or deletions in the aminoterminal
or the carboxy-terminal regions of the E protein were generated. We
showed that small deletions and modifications within E protein led to virus
attenuation, causing minimal lung injury, limited neutrophil influx to the lungs,
reduced expression of proinflammatory cytokines, increased anti-inflammatory
cytokine levels, and enhanced CD4+ and CD8+ T cell counts in vivo. These data
suggests that the described mutant phenotype contributed to virus attenuation.
The attenuated mutants fully protected mice from challenge with virulent virus. A
major problem of using live attenuated viruses as vaccines is the possibility of
reversion to virulence. To overcome this limitation, we introduced additional
attenuating mutations into the nsp1 protein to generate a safer vaccine candidate.
Nsp1 gene was selected as a target because it is located at a distal position (>20kb)
from that of E gene in the viral genome, making the generation of a virulent virus
through a single recombination event with circulating coronaviruses highly
unlikely. To identify nsp1 protein regions that contribute to rSARS-CoV-MA15
attenuation, several mutants (rSARS-CoV-MA15-nsp1*) containing small deletions
in of the nsp1 protein were generated. Deletion of 121 to 129 and 154 to 165
aminoacids in the carboxy terminal region of nsp1 protein led to virus attenuation.
Immunization with single SARS-CoV mutants protected mice against challenge
with the lethal parental virus. A recombinat virus including safety guards in E and
nsp1 genes was generated. This mutant virus was in general genetically stable in
vitro and in vivo, completely attenuated, and protected mice against challenge with
the lethal parental virus, indicating that this virus is promising vaccine candidate.
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