Potential global impact of the N501Y mutation on MHC-II presentation and immune escape
Summary (1 min read)
Summary
- The B.1.1.7 SARS-CoV-2 variant, characterized by the N501Y mutation, is rapidly emerging, raising concerns about its effectiveness on natural as well as vaccine-induced adaptive viral immunity at the population level.
- T cell responses are of critical importance to the antibody response, the authors examined the global effects of N501Y mutation on MHC-II presentation compared to the N501 wildtype and found poorer presentation across the majority of MHC-II alleles.
- This suggests that the N501Y mutation may not only diminish binding of antibodies to the RBD but also interfere with their production by weakening the cooperation between T and B cells, facilitating immune escape.
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Frequently Asked Questions (16)
Q2. What is the role of the MHC in the development of the RBD?
Presentation of antigen peptides complexed with the MHC initiates the expansion of T cells with direct anti-pathogen effector function, and CD4 T cells that help the activation of B cells producing anti-virus antibodies: T-B cooperation.
Q3. What is the role of the N501Y mutation in the spread of SARS?
Beside lockdown, protective masks and social distancing, the containment of community spread depends on immunity by the individual and the population.
Q4. What is the role of the MHC in the adaptive immune response?
The adaptive immune response is mediated by B and T cells and is orchestrated as a chain of events with the highly polymorphic Major Histocompatibility Complex (MHC) acting as the master regulator.
Q5. What is the key feature of the B.1.1.7 variant?
A key feature of the B.1.1.7 variant isthe mutation N501Y (asparagine to tyrosine) in the spike protein’s Receptor Binding Domain (RBD).
Q6. What is the reason for the rapid spread of the virus?
A reason for its rapid spread likely lies on the fact that mutations at residue N501 (e.g. N501F and N501T) enhance binding of SARS-CoV-2 to the ACE2 receptor (Starr et al. 2020) explaining why the N501Y variant may become the dominant strain of the pandemic in the months ahead.
Q7. What is the binding threshold for the mutated peptides?
In addition, 21.8% of all alleles and 21.9% of common alleles are no longer able to present the mutated peptides using a generous binding threshold of 20.
Q8. What is the effect of the N501Y mutation on the immune response?
Beside proving that antibodies induced by natural infection against the original unmutated virus and by current vaccines recognize and efficiently neutralize virus variants with the N501Y mutation, it will also be important to determine the effect of this mutation on the strength and specificity of neutralizing antibodies in humans.
Q9. What is the effect of the N501Y mutation on the RBD?
This suggests that the N501Y mutation may not only diminish binding of antibodies to the RBD but also interfere with their production by weakening the cooperation between T and B cells, facilitating immune escape.
Q10. What is the reason for the peptide-MHC-II presentation score?
The authors applied NetMHCIIpan-v4.0 (Reynisson et al. 2020), which uses eluted ligand mass spectrometry data, to predict peptide-MHC-II presentation affinities for all 15mers spanning the 501 position, taking the best rank out of 15 spanning peptides as a presentation score.
Q11. What is the reason for the emergence of wildtype RBD?
A first obvious possibility is that since residue N501 is embedded in the epitope recognized by numerous neutralizing antibodies isolated in convalescent patients (see (Castro et al. 2020)) antibodies to wildtype RBD may have weaker binding to virus variants, consistent with increased infectivity and virulence in a mouse model.
Q12. What is the significance of the N501Y mutation on the MHC-II?
T cell responses are of critical importance to the antibody response, the authors examined the global effects of N501Y mutation on MHC-II presentation compared to the N501 wildtype and found poorer presentation across the majority of MHC-II alleles.
Q13. What is the effect of the mutation on the immune response?
The authors found that N501Y mutant has poorer binding potential for 4786/5620 (85.2%) of all MHC-II alleles and 1580/1911 (82.7%) of common MHC-II alleles relative to N501 (Figure 1A-C).
Q14. What is the newest variant of SARS-CoV-2?
The B.1.1.7 SARS-CoV-2 variant, characterized by the N501Y mutation, is rapidly emerging, raising concerns about its effectiveness on natural as well as vaccine-induced adaptive viral immunity at the population level.
Q15. What is the reason for the eludement of the immune response?
however, the concern has been raised that virus variants may also elude the immune response (Callaway 2021; Kupferschmidt 2021b).
Q16. What is the name of the variant?
This variant has been detected in over 50 countries and is estimated to be ~50% more transmissible; the CDC has predicted B.1.1.7 will become the dominant strain by March (Corum and Zimmer 2021; Kupferschmidt 2021a).