Mitochondrial DNA stress potentiates type I interferon responses via activation of the cGAS–STING–IRF3 pathway. Accumulating evidence suggests that mitochondria, the organelles primarily responsible for cellular respiration and energy production, are also critical centres for antibacterial and antiviral innate immune responses. This study describes a link between mitochondrial stress and antiviral innate immunity. Specifically, mitochondrial DNA stress in herpes virus infected mice is shown to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance through activation of the DNA sensor cGAS and the STING–IRF3 stress pathway. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids1. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation2. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses3. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined4. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.

Autophagy is a highly conserved process that maintains homeostasis by clearing damaged organelles and long-lived proteins. The consequences of deficiency in autophagy manifest in a variety of pathological states including neurodegenerative diseases, inflammatory disorders, and cancer. Here, we studied the role of autophagy in the homeostatic regulation of innate antiviral defense. Single-stranded RNA viruses are recognized by the members of the RIG-I-like receptors (RLRs) in the cytosol. RLRs signal through IPS-1, resulting in the production of the key antiviral cytokines, type I IFNs. Autophagy-defective Atg5 ^−/− cells exhibited enhanced RLR signaling, increased IFN secretion, and resistance to infection by vesicular stomatitis virus. In the absence of autophagy, cells accumulated dysfunctional mitochondria, as well as mitochondria-associated IPS-1. Reactive oxygen species (ROS) associated with the dysfunctional mitochondria were largely responsible for the enhanced RLR signaling in Atg5 ^−/− cells, as antioxidant treatment blocked the excess RLR signaling. In addition, autophagy-independent increase in mitochondrial ROS by treatment of cells with rotenone was sufficient to amplify RLR signaling in WT cells. These data indicate that autophagy contributes to homeostatic regulation of innate antiviral defense through the clearance of dysfunctional mitochondria, and revealed that ROS associated with mitochondria play a key role in potentiating RLR signaling.

Flu immunity shows its age: As we age, our immune systems change; in many ways not for the better. For instance, the elderly account for 90% of influenza deaths annually. Pillai et al. now report that influenza-infected human monocytes, a type of immune cell, exhibit reduced antiviral activity. In influenza-infected mice, two innate immune sensing pathways work together to promote antiviral immunity to influenza. Mice lacking antiviral immunity (similar to the situation in elderly people) had elevated bacterial burdens in their lungs and increased inflammatory responses, which both contributed to their increased susceptibility to influenza. Science , this issue p. 463

Significance: This study demonstrates the efficacy of combining macrophage-checkpoint inhibition with tumor-specific antibodies for cancer immunotherapy. The combination of anti-CD47 (magrolimab) and anti-HER2 (trastuzumab) antibodies eliminated HER2⁺breast cancer cells with increased efficacy due to the enhancement of antibody-dependent cellular phagocytosis by macrophages, even when the cancer cells were tolerant to trastuzumab-induced antibody-dependent cellular cytotoxicity by natural killer cells. We believe these findings present a promising therapeutic approach for treating HER2⁺breast cancer patients whose tumors are either sensitive or resistant to trastuzumab treatment, as long as the cells harbor the HER2 trastuzumab-binding epitope. This study supports the notion that combining CD47 blockade with existing macrophage FcR-engaging tumor-specific antibodies may be an effective approach for treating a wide range of cancers.

In early 2020, a global emergency was upon us in the form of the coronavirus disease 2019 (COVID‐19) pandemic. While horrific in its health, social and economic devastation, one silver lining to this crisis has been a rapid mobilization of cross‐institute, and even cross‐country teams that shared common goals of learning as much as we could as quickly as possible about the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and how the immune system would respond to both the virus and COVID‐19 vaccines. Many of these teams were formed by women who quickly realized that the classical model of “publish first at all costs” was maladaptive for the circumstances and needed to be supplanted by a more collaborative solution‐focused approach. This review is an example of a collaboration that unfolded in separate countries, first Canada and the United States, and then also Israel. Not only did the collaboration allow us to cross‐validate our results using different hands/techniques/samples, but it also took advantage of different vaccine types and schedules that were rolled out in our respective home countries. The result of this collaboration was a new understanding of how mucosal immunity to SARS‐CoV‐2 infection vs COVID‐19 vaccination can be measured using saliva as a biofluid, what types of vaccines are best able to induce (limited) mucosal immunity, and what are potential correlates of protection against breakthrough infection. In this review, we will share what we have learned about the mucosal immune response to SARS‐CoV‐2 and to COVID‐19 vaccines and provide a perspective on what may be required for next‐generation pan‐sarbecoronavirus vaccine approaches.

Prolonged exposure of CD8⁺T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8⁺T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα⁺CD8⁺T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα⁺cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8⁺T cell-killing in vivo. SIRPα⁺CD8⁺T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8⁺T cells during chronic infection expands the cytotoxic subset of SIRPα⁺CD8⁺T cells.