tetano
Editor, Senior Moderator
PLoS Pathog
. 2024 Dec 9;20(12):e1012755.
doi: 10.1371/journal.ppat.1012755. Online ahead of print. Emerging mutation in SARS-CoV-2 facilitates escape from NK cell recognition and associates with enhanced viral fitness
Eleni Bilev[SUP] 1 [/SUP], Nicole Wild[SUP] 2 [/SUP], Pouria Momayyezi[SUP] 1 [/SUP], Benedetta Maria Sala[SUP] 3 [/SUP], Renhua Sun[SUP] 3 [/SUP], Tatyana Sandalova[SUP] 3 [/SUP], Nicole Marquardt[SUP] 2 [/SUP], Hans-Gustaf Ljunggren[SUP] 1 [/SUP], Adnane Achour[SUP] 3 [/SUP], Quirin Hammer[SUP] 1 [/SUP]
Affiliations
In addition to adaptive immunity, natural killer (NK) cells of the innate immune system contribute to the control of viral infections. The HLA-E-restricted SARS-CoV-2 Nsp13232-240 epitope VMPLSAPTL renders infected cells susceptible to NK cells by preventing binding to the inhibitory receptor NKG2A. Here, we report that a recently emerged methionine to isoleucine substitution at position 2 (pM2I) of Nsp13232-240 impairs binding of the mutated epitope to HLA-E and diminishes HLA-E/peptide complex stability. Structural analyses revealed altered occupancy of the HLA-E B-pocket as the underlying cause for reduced presentation and stability of the mutated epitope. Functionally, the reduced presentation of the mutated epitope correlated with elevated binding to NKG2A as well as with increased NK cell inhibition. Moreover, the pM2I mutation associated with enhanced estimated viral fitness and was transmitted to descendants of the SARS-CoV-2 BQ.1 variant. Interestingly, the mutated epitope resembles sequences of related peptides found in endemic common cold-causing human coronaviruses. Altogether, these findings indicate compromised peptide presentation as a viral adaptation to evade NK cell-mediated immunosurveillance by enabling enhanced presentation of self-peptide and restoring NKG2A-dependent inhibition of NK cells.
. 2024 Dec 9;20(12):e1012755.
doi: 10.1371/journal.ppat.1012755. Online ahead of print. Emerging mutation in SARS-CoV-2 facilitates escape from NK cell recognition and associates with enhanced viral fitness
Eleni Bilev[SUP] 1 [/SUP], Nicole Wild[SUP] 2 [/SUP], Pouria Momayyezi[SUP] 1 [/SUP], Benedetta Maria Sala[SUP] 3 [/SUP], Renhua Sun[SUP] 3 [/SUP], Tatyana Sandalova[SUP] 3 [/SUP], Nicole Marquardt[SUP] 2 [/SUP], Hans-Gustaf Ljunggren[SUP] 1 [/SUP], Adnane Achour[SUP] 3 [/SUP], Quirin Hammer[SUP] 1 [/SUP]
Affiliations
- PMID: 39652590
- DOI: 10.1371/journal.ppat.1012755
In addition to adaptive immunity, natural killer (NK) cells of the innate immune system contribute to the control of viral infections. The HLA-E-restricted SARS-CoV-2 Nsp13232-240 epitope VMPLSAPTL renders infected cells susceptible to NK cells by preventing binding to the inhibitory receptor NKG2A. Here, we report that a recently emerged methionine to isoleucine substitution at position 2 (pM2I) of Nsp13232-240 impairs binding of the mutated epitope to HLA-E and diminishes HLA-E/peptide complex stability. Structural analyses revealed altered occupancy of the HLA-E B-pocket as the underlying cause for reduced presentation and stability of the mutated epitope. Functionally, the reduced presentation of the mutated epitope correlated with elevated binding to NKG2A as well as with increased NK cell inhibition. Moreover, the pM2I mutation associated with enhanced estimated viral fitness and was transmitted to descendants of the SARS-CoV-2 BQ.1 variant. Interestingly, the mutated epitope resembles sequences of related peptides found in endemic common cold-causing human coronaviruses. Altogether, these findings indicate compromised peptide presentation as a viral adaptation to evade NK cell-mediated immunosurveillance by enabling enhanced presentation of self-peptide and restoring NKG2A-dependent inhibition of NK cells.