BATF promotes group 2 innate lymphoid cell-mediated lung tissue protection during acute respiratory virus infection.

Activated group 2 innate lymphoid cells (ILC2s) accumulate and promote inflammatory resolution and tissue repair in host defense against acute respiratory viral infections. However, the heterogeneity of ILC2s in the lung and the mechanisms by which ILC2 cells contribute to tissue repair remain elusive. Using single-cell RNA sequencing, we identify a transcriptionally distinct ILC2 subset that showed enrichment for wound healing signature genes and the transcription factor BATF. BATF promotes the proliferation and function of ILC2s and restricts their plasticity during infection with influenza virus. In the absence of BATF, ILC2s lose their immune protective properties and acquire pathogenic ILC3-like functions, leading to persistent neutrophil infiltration, tissue damage, and respiratory failure. Mechanistically, BATF directly binds to the cis-regulatory elements of wound healing genes, maintains their chromatin accessibility, and promotes their expression. Last, BATF plays an important role in an IL-33­ST2 feed-forward loop that supports ILC2 cell identity and function. Collectively, our findings shed light on a BATF-dependent ILC2 program, thereby providing a potential therapeutic target for terminating detrimental inflammation during acute viral infection.

Interferon Inducer IFI35 regulates RIG-I-mediated innate antiviral response through mutual antagonism with Influenza protein NS1.

Interferon-stimulated genes (ISGs) create multiple lines of defense against viral infection. Here we show that interferon induced protein 35 (IFI35) inhibits swine (H3N2) influenza virus replication by directly interacting with the viral protein NS1. IFI35 binds more preferentially to the effector domain of NS1 (128-207aa) than to the viral RNA sensor RIG-I. This promotes mutual antagonism between IFI35 and NS1, and frees RIG-I from IFI35-mediated K48-linked ubiquitination and degradation. However, IFI35 does not interact with the NS1 encoded by avian (H7N9) influenza virus, resulting in IFI35 playing an opposite virus enabling role during highly pathogenic H7N9 virus infection. Notably, replacing the 128-207aa region of NS1-H7N9 with the corresponding region of NS1-H3N2 results in the chimeric NS1 acquiring the ability to bind to and mutually antagonize IFI35. IFI35 deficient mice accordingly exhibit more resistance to lethal H7N9 infection than their wild-type control exhibit. Our data uncover a novel mechanism by which IFI35 regulates RIG-I-mediated anti-viral immunity through mutual antagonism with influenza protein NS1.IMPORTANCEIAV infection poses a global health threat, and is among the most common contagious pathogens to cause severe respiratory infections in humans and animals. ISGs play a key role in host defense against IAV infection. In line with others, we show IFI35-mediated ubiquitination of RIG-I to be involved in innate immunity. Moreover, we define a novel role of IFI35 in regulating the type I IFN pathway during IAV infection. We found that IFI35 regulates RIG-I mediated antiviral signaling by interacting with IAV-NS1. H3N2 NS1, but notably not H7N9 NS1, interacts with IFI35 and efficiently suppresses IFI35-dependent ubiquitination of RIG-I. IFI35 deficiency protected mice from H7N9 virus infection. Therefore, manipulation of the IFI35-NS1 provides a new approach for the development of anti-IAV treatments.