Tuberculosis infects one quarter of the world's population and is the leading cause of death by a single infectious agent, responsible for a reported 1.3 million deaths in 2017. While Mycobacterium tuberculosis is treatable with antibiotic therapy, the increased prevalence of drug resistance, coupled with the variable efficacy of the only widely approved vaccine, has highlighted the need for creative approaches to therapeutic and vaccine development. Historically, a productive immune response to M. tuberculosis has been thought to be nearly entirely cell-mediated, with humoral immunity being largely dismissed. However, in this review, we will discuss the historical skepticism surrounding the role of the humoral immune response to M. tuberculosis , and examine more recent evidence suggesting that antibodies may play a valuable role in host defense against the pathogen. Despite the amount of data portraying antibodies in a negative light, emerging data have begun to highlight the unexpected role of antibodies in M. tuberculosis control. Specifically, it has become clear that antibody features of both the variable and constant domain (Fc) ultimately determine the extent to which antibodies modulate disease. Thus, a more precise definition of the antigen-binding and innate immune recruiting functions of antibodies that contribute to M. tuberculosis restriction, are sure to help guide the development of next-generation therapeutics and vaccines to curb this global epidemic.

Significance We report the discovery of fundamental roles for the noncanonical inflammasome molecule Caspase-4/11 in promoting pathological inflammatory and prothrombotic pathways in severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) infections. Our work demonstrates that Caspase-11 has a broader role in immune responses beyond its previously appreciated effects in bacterial infections. Further, we show that Caspase-11–deficient mice infected with SARS–CoV-2 fare significantly better in terms of overall illness, lung inflammation, and thrombosis than wild-type (WT) mice, thus implicating Caspase-11 as a new therapeutic target for preventing or treating COVID-19.

Cardiac dysfunction is a common complication of severe influenza virus infection, but whether this occurs due to direct infection of cardiac tissue or indirectly through systemic lung inflammation remains unclear. To test the etiology of this aspect of influenza disease, we generated a novel recombinant heart-attenuated influenza virus via genome incorporation of target sequences for miRNAs expressed in cardiomyocytes. Compared with control virus, mice infected with miR-targeted virus had significantly reduced heart viral titers, confirming cardiac attenuation of viral replication. However, this virus was fully replicative in the lungs and induced similar systemic inflammation and weight loss compared to control virus. The miR-targeted virus induced fewer cardiac conduction irregularities and significantly less fibrosis in mice lacking interferon-induced transmembrane protein 3 (IFITM3), which serve as a model for influenza-associated cardiac pathology. We conclude that robust virus replication in the heart is required for pathology, even when lung inflammation is severe.

Interferon-induced transmembrane protein 3 (IFITM3) is an antiviral protein that alters cell membranes to block fusion of viruses. Conflicting reports identified opposing effects of IFITM3 on SARS-CoV-2 infection of cells, and its impact on viral pathogenesis in vivo remains unclear. Here, we show that IFITM3 knockout (KO) mice infected with SARS-CoV-2 experience extreme weight loss and lethality compared to mild infection in wild-type (WT) mice. KO mice have higher lung viral titers and increases in inflammatory cytokine levels, immune cell infiltration, and histopathology. Mechanistically, we observe disseminated viral antigen staining throughout the lung and pulmonary vasculature in KO mice, as well as increased heart infection, indicating that IFITM3 constrains dissemination of SARS-CoV-2. Global transcriptomic analysis of infected lungs shows upregulation of gene signatures associated with interferons, inflammation, and angiogenesis in KO versus WT animals, highlighting changes in lung gene expression programs that precede severe lung pathology and fatality. Our results establish IFITM3 KO mice as a new animal model for studying severe SARS-CoV-2 infection and overall demonstrate that IFITM3 is protective in SARS-CoV-2 infections in vivo.