tetano
Editor, Senior Moderator
Cell Host Microbe
. 2026 May 13:S1931-3128(26)00171-X.
doi: 10.1016/j.chom.2026.04.015. Online ahead of print.
Coronavirus protein interaction mapping in bat and human cells reveals network rewiring governing immune evasion and zoonotic potential
Jyoti Batra[SUP] 1 [/SUP], Magdalena Rutkowska[SUP] 2 [/SUP], Yuan Zhou[SUP] 1 [/SUP], Chengjin Ye[SUP] 3 [/SUP], Rithika Adavikolanu[SUP] 1 [/SUP], Janet M Young[SUP] 4 [/SUP], Durga Anand[SUP] 1 [/SUP], Sooraj Verma[SUP] 1 [/SUP], Haripriya Parthasarathy[SUP] 1 [/SUP], Martin Gordon[SUP] 1 [/SUP], Shivali Malpotra[SUP] 1 [/SUP], Anastasija Cupic[SUP] 2 [/SUP], Thomas Kehrer[SUP] 5 [/SUP], Melanie Dos Santos[SUP] 6 [/SUP], Ronald Benjamin[SUP] 1 [/SUP], Jack M Moen[SUP] 1 [/SUP], Declan M Winters[SUP] 7 [/SUP], Vincent Caval[SUP] 8 [/SUP], Ajda Rojc[SUP] 1 [/SUP], Ignacio Mena[SUP] 9 [/SUP], Sadaf Aslam[SUP] 5 [/SUP], Carles Martinez-Romero[SUP] 10 [/SUP], Isabela Conde Viñas[SUP] 11 [/SUP], Zain Khalil[SUP] 12 [/SUP], Keith Farrugia[SUP] 12 [/SUP], Fernando Villalón-Letelier[SUP] 5 [/SUP], Atoshi Banerjee[SUP] 1 [/SUP], Dafna Tussia-Cohen[SUP] 13 [/SUP], Amy Diallo[SUP] 14 [/SUP], Sourobh Maji[SUP] 14 [/SUP], Monita Muralidharan[SUP] 1 [/SUP], Helene Foussard[SUP] 1 [/SUP], Irene P Chen[SUP] 15 [/SUP], Rotem Fuchs[SUP] 13 [/SUP], C J San Felipe[SUP] 14 [/SUP], Lorena Zuliani-Alvarez[SUP] 1 [/SUP], Promisree Choudhury[SUP] 1 [/SUP], Kirsten Obernier[SUP] 1 [/SUP], Ségolène Gracias[SUP] 8 [/SUP], Rahul K Suryawanshi[SUP] 16 [/SUP], Boris Bonaventure[SUP] 5 [/SUP], Carlos Ibáñez[SUP] 17 [/SUP], Jeffrey R Johnson[SUP] 11 [/SUP], Javier Juste[SUP] 18 [/SUP], Lars Pache[SUP] 19 [/SUP], Robert M Stroud[SUP] 14 [/SUP], Kliment A Verba[SUP] 14 [/SUP], James S Fraser[SUP] 14 [/SUP], Harm van Bakel[SUP] 20 [/SUP], Taha Y Taha[SUP] 21 [/SUP], Melanie Ott[SUP] 22 [/SUP], Tzachi Hagai[SUP] 13 [/SUP], Nolwenn Jouvenet[SUP] 8 [/SUP], Caroline Demeret[SUP] 6 [/SUP], Benjamin J Polacco[SUP] 1 [/SUP], Danielle L Swaney[SUP] 1 [/SUP], Ignacia Echeverria[SUP] 23 [/SUP], Mehdi Bouhaddou[SUP] 7 [/SUP], Manon Eckhardt[SUP] 1 [/SUP], Harmit S Malik[SUP] 24 [/SUP], Luis Martinez-Sobrido[SUP] 3 [/SUP], Lisa Miorin[SUP] 25 [/SUP], Adolfo García-Sastre[SUP] 26 [/SUP], Nevan J Krogan[SUP] 27 [/SUP]
Affiliations
Coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause severe disease in humans, whereas reservoir hosts such as horseshoe bats remain asymptomatic. To investigate how host-specific protein-protein interactions (PPIs) influence infection, we generated comparative PPI maps for SARS-CoV-2 and its bat progenitor RaTG13, using affinity purification mass spectrometry (AP-MS) in human and greater horseshoe bat cells. We identify both conserved and virus- and host-specific interactions that regulate infection dynamics. Notably, SARS-CoV-2 requires a nonsynonymous mutation in the nucleocapsid to replicate in bat cells expressing human ACE2 and TMPRSS2. Strikingly, a single amino acid difference in Orf9b between viruses acts as a molecular switch that reprograms mitochondrial targeting: in human cells, enhanced translocase of outer mitochondrial membrane 70 (Tom70) binding promotes immune evasion, whereas in bat cells, strengthened interaction with the bat-enriched restriction factor mitochondrial amidoxime reducing component 2 (MTARC2) limits infection. These findings establish a general principle by which minimal sequence variation can reshape virus-host interactions and contribute to immune antagonism, host adaptation, and species barriers.
Keywords: MTARC2; RaTG13; SARS-CoV-2; Tom70; bats; coronaviruses; host-pathogen interaction; proteomics; viral reservoirs; virus-host tropism.
. 2026 May 13:S1931-3128(26)00171-X.
doi: 10.1016/j.chom.2026.04.015. Online ahead of print.
Coronavirus protein interaction mapping in bat and human cells reveals network rewiring governing immune evasion and zoonotic potential
Jyoti Batra[SUP] 1 [/SUP], Magdalena Rutkowska[SUP] 2 [/SUP], Yuan Zhou[SUP] 1 [/SUP], Chengjin Ye[SUP] 3 [/SUP], Rithika Adavikolanu[SUP] 1 [/SUP], Janet M Young[SUP] 4 [/SUP], Durga Anand[SUP] 1 [/SUP], Sooraj Verma[SUP] 1 [/SUP], Haripriya Parthasarathy[SUP] 1 [/SUP], Martin Gordon[SUP] 1 [/SUP], Shivali Malpotra[SUP] 1 [/SUP], Anastasija Cupic[SUP] 2 [/SUP], Thomas Kehrer[SUP] 5 [/SUP], Melanie Dos Santos[SUP] 6 [/SUP], Ronald Benjamin[SUP] 1 [/SUP], Jack M Moen[SUP] 1 [/SUP], Declan M Winters[SUP] 7 [/SUP], Vincent Caval[SUP] 8 [/SUP], Ajda Rojc[SUP] 1 [/SUP], Ignacio Mena[SUP] 9 [/SUP], Sadaf Aslam[SUP] 5 [/SUP], Carles Martinez-Romero[SUP] 10 [/SUP], Isabela Conde Viñas[SUP] 11 [/SUP], Zain Khalil[SUP] 12 [/SUP], Keith Farrugia[SUP] 12 [/SUP], Fernando Villalón-Letelier[SUP] 5 [/SUP], Atoshi Banerjee[SUP] 1 [/SUP], Dafna Tussia-Cohen[SUP] 13 [/SUP], Amy Diallo[SUP] 14 [/SUP], Sourobh Maji[SUP] 14 [/SUP], Monita Muralidharan[SUP] 1 [/SUP], Helene Foussard[SUP] 1 [/SUP], Irene P Chen[SUP] 15 [/SUP], Rotem Fuchs[SUP] 13 [/SUP], C J San Felipe[SUP] 14 [/SUP], Lorena Zuliani-Alvarez[SUP] 1 [/SUP], Promisree Choudhury[SUP] 1 [/SUP], Kirsten Obernier[SUP] 1 [/SUP], Ségolène Gracias[SUP] 8 [/SUP], Rahul K Suryawanshi[SUP] 16 [/SUP], Boris Bonaventure[SUP] 5 [/SUP], Carlos Ibáñez[SUP] 17 [/SUP], Jeffrey R Johnson[SUP] 11 [/SUP], Javier Juste[SUP] 18 [/SUP], Lars Pache[SUP] 19 [/SUP], Robert M Stroud[SUP] 14 [/SUP], Kliment A Verba[SUP] 14 [/SUP], James S Fraser[SUP] 14 [/SUP], Harm van Bakel[SUP] 20 [/SUP], Taha Y Taha[SUP] 21 [/SUP], Melanie Ott[SUP] 22 [/SUP], Tzachi Hagai[SUP] 13 [/SUP], Nolwenn Jouvenet[SUP] 8 [/SUP], Caroline Demeret[SUP] 6 [/SUP], Benjamin J Polacco[SUP] 1 [/SUP], Danielle L Swaney[SUP] 1 [/SUP], Ignacia Echeverria[SUP] 23 [/SUP], Mehdi Bouhaddou[SUP] 7 [/SUP], Manon Eckhardt[SUP] 1 [/SUP], Harmit S Malik[SUP] 24 [/SUP], Luis Martinez-Sobrido[SUP] 3 [/SUP], Lisa Miorin[SUP] 25 [/SUP], Adolfo García-Sastre[SUP] 26 [/SUP], Nevan J Krogan[SUP] 27 [/SUP]
Affiliations
- PMID: 42134328
- DOI: 10.1016/j.chom.2026.04.015
Coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause severe disease in humans, whereas reservoir hosts such as horseshoe bats remain asymptomatic. To investigate how host-specific protein-protein interactions (PPIs) influence infection, we generated comparative PPI maps for SARS-CoV-2 and its bat progenitor RaTG13, using affinity purification mass spectrometry (AP-MS) in human and greater horseshoe bat cells. We identify both conserved and virus- and host-specific interactions that regulate infection dynamics. Notably, SARS-CoV-2 requires a nonsynonymous mutation in the nucleocapsid to replicate in bat cells expressing human ACE2 and TMPRSS2. Strikingly, a single amino acid difference in Orf9b between viruses acts as a molecular switch that reprograms mitochondrial targeting: in human cells, enhanced translocase of outer mitochondrial membrane 70 (Tom70) binding promotes immune evasion, whereas in bat cells, strengthened interaction with the bat-enriched restriction factor mitochondrial amidoxime reducing component 2 (MTARC2) limits infection. These findings establish a general principle by which minimal sequence variation can reshape virus-host interactions and contribute to immune antagonism, host adaptation, and species barriers.
Keywords: MTARC2; RaTG13; SARS-CoV-2; Tom70; bats; coronaviruses; host-pathogen interaction; proteomics; viral reservoirs; virus-host tropism.