The DNA glycosylase NEIL2 plays a vital role in combating SARS-CoV-2 infection
Abstract Compromised DNA repair capacity of individuals could play a critical role in the severity of SARS-CoV-2 infection-induced COVID-19. We therefore analyzed the expression of DNA repair genes in publicly available transcriptomic datasets of COVID-19 patients and found that the level of NEIL2, an oxidized base specific mammalian DNA glycosylase, is particularly low in the lungs of COVID-19 patients displaying severe symptoms. Downregulation of pulmonary NEIL2 in CoV-2-permissive animals and postmortem COVID-19 patients validated these results. To investigate the potential roles of NEIL2 in CoV-2 pathogenesis, we infected Neil2-null (Neil2−/−) mice with a mouse-adapted CoV-2 strain and found that Neil2−/− mice suffered more severe viral infection concomitant with increased expression of proinflammatory genes, which resulted in an enhanced mortality rate of 80%, up from 20% for the age matched Neil2+/+ cohorts. We also found that infected animals accumulated a significant amount of damage in their lung DNA. Surprisingly, recombinant NEIL2 delivered into permissive A549-ACE2 cells significantly decreased viral replication. Toward better understanding the mechanistic basis of how NEIL2 plays such a protective role against CoV-2 infection, we determined that NEIL2 specifically binds to the 5’-UTR of SARS-CoV-2 genomic RNA and blocks protein synthesis. Together, our data suggest that NEIL2 plays a previously unidentified role in regulating CoV-2-induced pathogenesis, via inhibiting viral replication and preventing exacerbated proinflammatory responses, and also via its well-established role of repairing host genome damage..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
ResearchSquare.com - (2023) vom: 10. Dez. Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Hazra, Tapas [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
10.21203/rs.3.rs-1690354/v1 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XRA036124176 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XRA036124176 | ||
| 003 | DE-627 | ||
| 005 | 20231210130650.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 220528s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.21203/rs.3.rs-1690354/v1 |2 doi | |
| 035 | |a (DE-627)XRA036124176 | ||
| 035 | |a (ResearchSquare)10.21203/rs.3.rs-1690354/v1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Hazra, Tapas |e verfasserin |0 (orcid)0000-0002-4587-687X |4 aut | |
| 245 | 1 | 0 | |a The DNA glycosylase NEIL2 plays a vital role in combating SARS-CoV-2 infection |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Compromised DNA repair capacity of individuals could play a critical role in the severity of SARS-CoV-2 infection-induced COVID-19. We therefore analyzed the expression of DNA repair genes in publicly available transcriptomic datasets of COVID-19 patients and found that the level of NEIL2, an oxidized base specific mammalian DNA glycosylase, is particularly low in the lungs of COVID-19 patients displaying severe symptoms. Downregulation of pulmonary NEIL2 in CoV-2-permissive animals and postmortem COVID-19 patients validated these results. To investigate the potential roles of NEIL2 in CoV-2 pathogenesis, we infected Neil2-null (Neil2−/−) mice with a mouse-adapted CoV-2 strain and found that Neil2−/− mice suffered more severe viral infection concomitant with increased expression of proinflammatory genes, which resulted in an enhanced mortality rate of 80%, up from 20% for the age matched Neil2+/+ cohorts. We also found that infected animals accumulated a significant amount of damage in their lung DNA. Surprisingly, recombinant NEIL2 delivered into permissive A549-ACE2 cells significantly decreased viral replication. Toward better understanding the mechanistic basis of how NEIL2 plays such a protective role against CoV-2 infection, we determined that NEIL2 specifically binds to the 5’-UTR of SARS-CoV-2 genomic RNA and blocks protein synthesis. Together, our data suggest that NEIL2 plays a previously unidentified role in regulating CoV-2-induced pathogenesis, via inhibiting viral replication and preventing exacerbated proinflammatory responses, and also via its well-established role of repairing host genome damage. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Tapryal, Nisha |4 aut | |
| 700 | 1 | |a Chakraborty, Anirban |4 aut | |
| 700 | 1 | |a Rayavara, Kempaiah |0 (orcid)0000-0003-2413-1577 |4 aut | |
| 700 | 1 | |a Wakamiya, Maki |4 aut | |
| 700 | 1 | |a Islam, Azharul |4 aut | |
| 700 | 1 | |a Pan, Lang |4 aut | |
| 700 | 1 | |a Hsu, Jason |0 (orcid)0000-0002-0530-2580 |4 aut | |
| 700 | 1 | |a Tat, Vivian |4 aut | |
| 700 | 1 | |a Maruyama, Junki |0 (orcid)0000-0003-0088-4793 |4 aut | |
| 700 | 1 | |a Hosoki, Koa |4 aut | |
| 700 | 1 | |a Sayed, Ibrahim |4 aut | |
| 700 | 1 | |a Alcantara, Joshua |0 (orcid)0000-0002-7970-8970 |4 aut | |
| 700 | 1 | |a Castillo, Vanessa |4 aut | |
| 700 | 1 | |a Tindle, Courtney |4 aut | |
| 700 | 1 | |a Sarker, Altaf |0 (orcid)0000-0001-6868-8460 |4 aut | |
| 700 | 1 | |a Cardenas, Victor |4 aut | |
| 700 | 1 | |a Sharma, Gulshan |4 aut | |
| 700 | 1 | |a Alexander, Laura Crotty |4 aut | |
| 700 | 1 | |a Sur, Sanjiv |4 aut | |
| 700 | 1 | |a Ghosh, Gourisankar |4 aut | |
| 700 | 1 | |a Paessler, Slobodan |4 aut | |
| 700 | 1 | |a Sahoo, Debashis |0 (orcid)0000-0003-2329-8228 |4 aut | |
| 700 | 1 | |a Ghosh, Pradipta |0 (orcid)0000-0002-8917-3201 |4 aut | |
| 700 | 1 | |a Das, Soumita |0 (orcid)0000-0003-3895-3643 |4 aut | |
| 700 | 1 | |a Boldogh, Istvan |4 aut | |
| 700 | 1 | |a Tseng, Chien-Te |0 (orcid)0000-0001-5726-9834 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ResearchSquare.com |g (2023) vom: 10. Dez. |
| 773 | 1 | 8 | |g year:2023 |g day:10 |g month:12 |
| 856 | 4 | 0 | |u https://doi.org/10.1038/s41467-023-43938-0 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.21203/rs.3.rs-1690354/v1 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XRA | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 10 |c 12 | ||