Central role of Caspase-8 in control of host tolerance and resistance mechanisms in pulmonary macrophage populations during severe respiratory infections

Brown University, Providence RI

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Abstract

Parent grant: R01 HL165259 Title: Central role of Caspase-8 in control of host tolerance and resistance mechanisms in pulmonary macrophage populations during severe respiratory infections PI: Amanda Jamieson A. Abstract of the parent grant: Pneumonia is an important global health problem1. Influenza A virus (IAV) leads to an estimated 500,000 deaths annually, and these numbers can be even higher during IAV pandemic years 2. A complication following infection with IAV is bacterial pneumonia, and this can lead to a more severe disease 3–21. To survive a given infection hosts must be able to not only clear the pathogen, but also tolerate to the effects of the pathogen or the host response. The latter processes are referred to as disease tolerance. Normally, a balance between these two processes is reached, and the infection resolves22,23. My research lab has been at the forefront of exploring the concept of host disease tolerance in deadly complex respiratory infections22–26. We have shown that during pulmonary IAV/bacterial coinfection this balance between resistance and tolerance is disrupted causing increased lethality23,26. Regulated cell death (RCD) plays important roles in both resistance and tolerance to infection. Cell death can be broadly categorized as membrane permeable (e.g. necroptosis and pyroptosis) or membrane impermeable (e.g. apoptosis). During infection several different types of cell death can be induced each inducing a unique response. Macrophages are responsible for both resistance mechanisms such as coordination of the immune response, and they contribute to tolerance in the form of the tissue repair responses after damage. This proposal aims to bridge gaps in our current understanding of complex respiratory infections by investigating the role of Caspase-8, a key regulator of RCD, in relevant in vitro and in vivo models of IAV/bacterial coinfection. We will focus on understanding how Caspase-8 pathways in lung macrophages during IAV/bacterial coinfection contributes to resistance and tolerance. Our preliminary data has demonstrated that Caspase-8 deficiency in macrophages leads to increased host resistance at the expense of host tolerance in the early stages of coinfection. This is most likely due to increased necroptosis and anti-microbial responses. We hypothesize that during severe lung infections such as those that occur with bacterial infection following IAV infection macrophage cell death controlled by Caspase-8 plays an important role in regulating the balance between resistance and tolerance. In this study we will determine the role that Caspase-8 in macrophages plays throughout the course of infection. We will use relevant in vitro models using human primary macrophages, as well as in vivo models. These studies will lay the foundation for future studies on understanding the impact of RCD in macrophages during complex pulmonary infections, which may ultimately lead to improved treatment options for patients with complex and severe lung infections. B. Specific Aims of the parent grant Aim 1: Determine the role for Caspase-8 in resistance and tolerance functions using in vitro models of coinfected alveolar macrophages. Aim 1a: Determine the impact of Caspase-8 on the role of mouse macrophages in coinfection by using pharmacologic inhibitors and genetic models. Aim 1b: Determine the impact of Caspase-8 on the role of human macrophages in coinfection by using pharmacologic inhibitors and genetic manipulation. Aim 1c: Determine the role of direct infection and bystander effect on Caspase-8 dependent cell death modalities in macrophages Aim 2: Using in vivo systems, determine the role of Caspase-8 in clearing pathogens while maintaining host tolerance to lung infection. Aim 2a: In the context of a whole lung we will test the hypothesis that Caspase-8 plays an essential role in controlling cell death modalities that influence resistance and tolerance responses by macrophages to pulmonary IAV/bacterial coinfection. Aim 2b Determine the impact of Caspase-8 on host resistance and tolerance mechanisms in macrophage subsets during lung infection and coinfection Aim 2c Determine impact of Caspase-8 in macrophages over the course of pulmonary infection and coinfection C. Research Plan for Supplement This is in response to: Notice of Special Interest (NOSI): Availability of Administrative Supplements for the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project Notice Number: NOT-OD-22-137 Title: Excessive Type I Interferon Signaling in Down Syndrome Promotes Macrophage Dysfunction and Cell Death, Increasing Susceptibility to Bacterial Pneumonia following influenza A virus infection Abstract Individuals with Down Syndrome (DS, Trisomy 21) face a significantly elevated risk of severe respiratory infections, particularly bacterial pneumonia. We propose that this susceptibility is driven in part by chronic overactivation of Type I interferons (IFN-I), a consequence of gene dosage effects on chromosome 21, which harbors four of the six IFNR genes. While IFN-Is are essential for antiviral immunity, their dysregulation is associated with immune exhaustion and impaired antibacterial responses. This has been shown in several studies where respiratory bacterial infection follows pulmonary viral infection. Macrophages, critical first responders in lung infection, are particularly sensitive to cytokine environment and are central to host defense against bacterial pneumonia. We hypothesize that heightened IFN-I signaling in DS drives macrophage dysfunction and death, impairing bacterial clearance and promoting pneumonia severity. This proposal aims to delineate the mechanisms by which IFN-I overactivation impairs macrophage viability and function in the context of DS, identifying potential therapeutic targets to reduce infection-related morbidity. This supports the National Heart, Lung, and Blood Institute (NHLBI) goals of “providing global leadership for a research, training, and education program to promote the prevention and treatment of heart, lung, and blood disorders and enhance the health of all individuals so that they can live longer and more fulfilling lives”. The INCLUDE (INvestigation of Co- occurring conditions across the Lifespan to Understand Down syndromE) contribution from NHLBI contributes by focusing on pulmonary function specifically other respiratory complications associated with DS. This supplement will fulfill component 1: Targeted high risk - high reward basic science studies in areas highly relevant to Down syndrome Co-occuring conditions that also impact the general population.