tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2026 Mar 24;123(12):e2519903123.
doi: 10.1073/pnas.2519903123. Epub 2026 Mar 18.
An autoimmunity-associated allele of PTPN22 enhances innate antiviral immunity to protect against acute coronavirus infection
Alec M Bevis[SUP] 1 [/SUP], Kathryn J L H Rosa[SUP] 1 [/SUP], Nancy Schwarting[SUP] 1 [/SUP], Tammy R Cockerham[SUP] 1 [/SUP], Catherine M Kerr[SUP] 1 [/SUP], Sunil More[SUP] 2 [/SUP], Anthony R Fehr[SUP] 1 [/SUP], Robin C Orozco[SUP] 1 [/SUP]
Affiliations
Allelic variation can impact viral clearance and disease severity. Still, our understanding of the effect of the autoimmunity-associated allelic variant of Ptpn22 (PEP-R619W) on antiviral immunity remains incomplete, as previous reports have only focused on chronic lymphocytic choriomeningitis virus infection. This research defines how the loss of Ptpn22 (PEP-null) and PEP-R619W changes antiviral immunity during an acute coronavirus infection. We address the hypothesis that CRISPR/Cas9-generated PEP-null and PEP-R619W mice have enhanced antiviral immunity over PEP-wild-type (WT) mice during coronavirus infection. Following mouse hepatitis virus A59 infection, we interrogated pathology, cytokine production, and cellular responses in the blood, spleen, and liver of PEP-WT, PEP-null, and PEP-R619W mice. Key findings show that PEP-R619W mice have reduced viral titer and weight loss, increased survival, and more mature natural killer (NK) cells in the liver and spleen compared to PEP-WT mice. Interestingly, protection against disease in PEP-null mice was inoculation dose dependent, whereas PEP-R619W conferred immunity regardless of infection dose. Further, Rag1[SUP]-/-[/SUP] PEP-R619W mice had increased survival and reduced viral titer over Rag1[SUP]-/-[/SUP] PEP-WT mice. PEP-R619W mice also had higher concentrations of interferon-gamma (IFNγ) and enhanced IFNγ production by mature NK cells in the liver at 3 d postinfection. Finally, NK cell depletion elevated PEP-R619W viral titer to similar levels as PEP-WT mice. This study investigates the role of Ptpn22 within NK cells and demonstrates that the Ptpn22 allelic variant augments NK cell function and is beneficial during coronavirus infection.
Keywords: PTPN22; coronavirus; natural killer (NK) cells.
. 2026 Mar 24;123(12):e2519903123.
doi: 10.1073/pnas.2519903123. Epub 2026 Mar 18.
An autoimmunity-associated allele of PTPN22 enhances innate antiviral immunity to protect against acute coronavirus infection
Alec M Bevis[SUP] 1 [/SUP], Kathryn J L H Rosa[SUP] 1 [/SUP], Nancy Schwarting[SUP] 1 [/SUP], Tammy R Cockerham[SUP] 1 [/SUP], Catherine M Kerr[SUP] 1 [/SUP], Sunil More[SUP] 2 [/SUP], Anthony R Fehr[SUP] 1 [/SUP], Robin C Orozco[SUP] 1 [/SUP]
Affiliations
- PMID: 41849391
- DOI: 10.1073/pnas.2519903123
Allelic variation can impact viral clearance and disease severity. Still, our understanding of the effect of the autoimmunity-associated allelic variant of Ptpn22 (PEP-R619W) on antiviral immunity remains incomplete, as previous reports have only focused on chronic lymphocytic choriomeningitis virus infection. This research defines how the loss of Ptpn22 (PEP-null) and PEP-R619W changes antiviral immunity during an acute coronavirus infection. We address the hypothesis that CRISPR/Cas9-generated PEP-null and PEP-R619W mice have enhanced antiviral immunity over PEP-wild-type (WT) mice during coronavirus infection. Following mouse hepatitis virus A59 infection, we interrogated pathology, cytokine production, and cellular responses in the blood, spleen, and liver of PEP-WT, PEP-null, and PEP-R619W mice. Key findings show that PEP-R619W mice have reduced viral titer and weight loss, increased survival, and more mature natural killer (NK) cells in the liver and spleen compared to PEP-WT mice. Interestingly, protection against disease in PEP-null mice was inoculation dose dependent, whereas PEP-R619W conferred immunity regardless of infection dose. Further, Rag1[SUP]-/-[/SUP] PEP-R619W mice had increased survival and reduced viral titer over Rag1[SUP]-/-[/SUP] PEP-WT mice. PEP-R619W mice also had higher concentrations of interferon-gamma (IFNγ) and enhanced IFNγ production by mature NK cells in the liver at 3 d postinfection. Finally, NK cell depletion elevated PEP-R619W viral titer to similar levels as PEP-WT mice. This study investigates the role of Ptpn22 within NK cells and demonstrates that the Ptpn22 allelic variant augments NK cell function and is beneficial during coronavirus infection.
Keywords: PTPN22; coronavirus; natural killer (NK) cells.