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There is a desperate need for effective therapies and vaccines for SARS-CoV-2 to mitigate the growing economic crisis that has ensued from societal lockdown. Vaccines are being developed at an unprecedented speed and are already in clinical trials, without preclinical testing for safety and efficacy. Yet, safety evaluation of candidate vaccines must not be overlooked.Here, Iwasaki and Yang highlight the potential dangers of inducing suboptimal antibody responses to SARS-CoV-2. They stress the need for proper safety evaluation of candidate vaccines for COVID-19.

Since the initial reports of a cluster of pneumonia cases of unidentified origin in Wuhan, China, in December 2019, the novel coronavirus that causes this disease — severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — has spread throughout the world, igniting the twenty-first century’s deadliest pandemic. Over the past 12 months, a dizzying array of information has emerged from numerous laboratories, covering everything from the putative origin of SARS-CoV-2 to the development of numerous candidate vaccines. Many immunologists quickly pivoted from their existing research to focus on coronavirus disease 2019 (COVID-19) and, owing to this unprecedented convergence of efforts on one viral infection, a remarkable body of work has been produced and disseminated, through both preprint servers and peer-reviewed journals. Here, we take readers through the timeline of key discoveries during the first year of the pandemic, which showcases the extraordinary leaps in our understanding of the immune response to SARS-CoV-2 and highlights gaps in our knowledge as well as areas for future investigations.A timeline of the major scientific discoveries during the first year of the COVID-19 pandemic showcases the collaborative efforts that enabled the key aspects of the immune response to SARS-CoV-2 to be reported at unprecedented speed.

Iwasaki and Mezhitov provide an update of their classic 2004 Review looking at the control of adaptive immunity by the innate immune system Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity.

The immunology research community lacks diversity, particularly at the top. Here I discuss diversity, inclusion and equity and their benefit to science. I suggest steps we can take to achieve a more diverse and inclusive community.

There is a pervasive problem in academia of principal investigators who abuse their powers and mistreat their trainees. Here I share suggestions that would help protect the trainees and ultimately reduce the number of toxic supervisors.

Twenty years after the proposal that pattern recognition receptors detect invasion by microbial pathogens, the field of immunology has witnessed several discoveries that have elucidated receptors and signaling pathways of microbial recognition systems and how they control the generation of T and B lymphocyte-mediated immune responses. However, there are still many fundamental questions that remain poorly understood, even though sometimes the answers are assumed to be known. Here, we discuss some of these questions, including the mechanisms by which pathogen-specific innate immune recognition activates antigen-specific adaptive immune responses and the roles of different types of innate immune recognition in host defense from infection and injury.

Graphical Abstract The COVID‐19 pandemic has spread to many countries around the world, but the infection and death rates vary widely. One country that appeared to have kept the infection under control despite limited societal restrictions is Japan. This commentary explores why Japan may have, up to now, been spared an escalation of the SARS‐CoV‐2 infections.

Endogenous retroviruses (ERVs) are integrated retroviral elements that make up 8% of the human genome. However, the impact of ERVs on human health and disease is not well understood. While select ERVs have been implicated in diseases, including autoimmune disease and cancer, the lack of tools to analyze genome-wide, locus-specific expression of proviral autonomous ERVs has hampered the progress in the field. Here we describe a method called ERVmap, consisting of an annotated database of 3,220 human proviral ERVs and a pipeline that allows for locus-specific genome-wide identification of proviral ERVs that are transcribed based on RNA-sequencing data, and provide examples of the utility of this tool. Using ERVmap, we revealed cell-type–specific ERV expression patterns in commonly used cell lines as well as in primary cells. We identified 124 unique ERV loci that are significantly elevated in the peripheral blood mononuclear cells of patients with systemic lupus erythematosus that represent an IFN-independent signature. Finally, we identified additional tumor-associated ERVs that correlate with cytolytic activity represented by granzyme and perforin expression in breast cancer tissue samples. The open-source code of ERVmap and the accompanied web tool are made publicly available to quantify proviral ERVs in RNA-sequencing data with ease. Use of ERVmap across a range of diseases and experimental conditions has the potential to uncover novel diseaseassociated antigens and effectors involved in human health that is currently missed by focusing on protein-coding sequences.

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA and a sustained interferon (IFN) response, all of which are recapitulated and required for pathology in the SARS-CoV-2-infected MISTRG6-hACE2 humanized mouse model of COVID-19, which has a human immune system 1 – 20 . Blocking either viral replication with remdesivir 21 – 23 or the downstream IFN-stimulated cascade with anti-IFNAR2 antibodies in vivo in the chronic stages of disease attenuates the overactive immune inflammatory response, especially inflammatory macrophages. Here we show that SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release interleukin 1 (IL-1) and IL-18, and undergo pyroptosis, thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and the accompanying inflammatory response are necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Notably, this blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 through the production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle. A new humanized mouse model for COVID-19 demonstrates SARS-CoV-2 infection and subsequent activation of inflammasomes in human macrophages as a critical driver of disease.