Fluoxetine promotes immunometabolic defenses to mediate host-pathogen cooperation during sepsis.

Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19, however the mechanisms underlying this protection are largely unknown. Here we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin, and instead increases levels of circulating IL-10. IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia and cardiac triglyceride accumulation, allowing for metabolic reprogramming of the heart. Our work reveals a beneficial "off-target" effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential.

CD4+ T cells regulate sickness-induced anorexia and fat wasting during a chronic parasitic infection.

Infections cause catabolism of fat and muscle stores. Traditionally, studies have focused on understanding how the innate immune system contributes to energy stores wasting, while the role of the adaptive immune system remains elusive. In the present study, we examine the role of the adaptive immune response in adipose tissue wasting and cachexia using a murine model of the chronic parasitic infection Trypanosoma brucei, the causative agent of sleeping sickness. We find that the wasting response occurs in two phases, with the first stage involving fat wasting caused by CD4+ T cell-induced anorexia and a second anorexia-independent cachectic stage that is dependent on CD8+ T cells. Fat wasting has no impact on host antibody-mediated resistance defenses or survival, while later-stage muscle wasting contributes to disease-tolerance defenses. Our work reveals a decoupling of adaptive immune-mediated resistance from the catabolic response during infection.

Cooperation between physiological defenses and immune resistance produces asymptomatic carriage of a lethal bacterial pathogen.

Animals evolved two defense strategies to survive infections. Antagonistic strategies include immune resistance mechanisms that operate to kill invading pathogens. Cooperative or physiological defenses mediate host adaptation to the infected state, limiting physiological damage and disease, without killing the pathogen, and have been shown to cause asymptomatic carriage and transmission of lethal pathogens. Here, we demonstrate that physiological defenses cooperate with the adaptive immune response to generate long-term asymptomatic carriage of the lethal enteric murine pathogen, Citrobacter rodentium. Asymptomatic carriage of genetically virulent C. rodentium provided immune resistance against subsequent infections. Immune protection was dependent on systemic antibody responses and pathogen virulence behavior rather than the recognition of specific virulent antigens. Last, we demonstrate that an avirulent strain of C. rodentium in the field has background mutations in genes that are important for LPS structure. Our work reveals insight into how asymptomatic infections can arise mechanistically with immune resistance, mediating exclusion of phenotypically virulent enteric pathogen to promote asymptomatic carriage.

Cachexia: A systemic consequence of progressive, unresolved disease.

Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.

Age-dependent roles of cardiac remodeling in sepsis defense and pathogenesis.

Disease tolerance is a defense strategy essential for survival of infections, limiting physiological damage without killing the pathogen. The disease course and pathology a pathogen may cause can change over the lifespan of a host due to the structural and functional physiological changes that accumulate with age. Since successful disease tolerance responses require the host to engage mechanisms that are compatible with the disease course and pathology caused by an infection, we predicted that this defense strategy would change with age. Animals infected with a lethal dose 50 (LD50) of a pathogen often display distinct health and sickness trajectories due to differences in disease tolerance, and thus can be used to delineate tolerance mechanisms. Using a polymicrobial sepsis model, we found that despite having the same LD50, old and young susceptible mice exhibited distinct disease courses. Young survivors employed a cardioprotective mechanism via FoxO1-mediated regulation of the ubiquitin-proteosome system that was necessary for survival and protection from cardiomegaly. This same mechanism was a driver of sepsis pathogenesis in aged hosts, causing catabolic remodeling of the heart and death. Our findings have implications for the tailoring of therapy to the age of an infected individual and suggest that disease tolerance alleles may exhibit antagonistic pleiotropy.

Cooperation between physiological defenses and immune resistance produces asymptomatic carriage of a lethal bacterial pathogen.

Animals have evolved two defense strategies to survive infections. Antagonistic strategies include mechanisms of immune resistance that operate to sense and kill invading pathogens. Cooperative or physiological defenses mediate host adaptation to the infected state, limiting physiological damage and disease, without killing the pathogen, and have been shown to cause asymptomatic carriage and transmission of lethal pathogens. Here we demonstrate that physiological defenses cooperate with the adaptive immune response to generate long-term asymptomatic carriage of the lethal enteric murine pathogen, Citrobacter rodentium. Asymptomatic carriage of genetically virulent C. rodentium provided immune resistance against subsequent infections. Host immune protection was dependent on systemic antibody responses and pathogen virulence behavior, rather than the recognition of specific virulent factor antigens. Finally, we demonstrate that an avirulent strain of C. rodentium in the field has background mutations in two genes that are important for LPS structure. Our work reveals novel insight into how asymptomatic infections can arise mechanistically with immune resistance, mediating exclusion of phenotypically virulent enteric pathogen to promote asymptomatic carriage.

Chronic Leptin Deficiency Improves Tolerance of Physiological Damage and Host-Pathogen Cooperation during Yersinia pseudotuberculosis Infection.

To combat infections, hosts employ a combination of antagonistic and cooperative defense strategies. The former refers to pathogen killing mediated by resistance mechanisms, while the latter refers to physiological defense mechanisms that promote host health during infection independent of pathogen killing, leading to an apparent cooperation between the host and the pathogen. Previous work has shown that Leptin, a pleiotropic hormone that plays a central role in regulating appetite and energy metabolism, is indispensable for resistance mechanisms, while a role for Leptin signaling in cooperative host-pathogen interactions remains unknown. Using a mouse model of Yersinia pseudotuberculosis (Yptb) infection, an emerging pathogen that causes fever, diarrhea, and mesenteric lymphadenitis in humans, we found that the physiological effects of chronic Leptin-signaling deficiency conferred protection from Yptb infection due to increased host-pathogen cooperation rather than greater resistance defenses. The protection against Yptb infection was independent of differences in food consumption, lipolysis, or fat mass. Instead, we found that the chronic absence of Leptin signaling protects from a shift to lipid utilization during infection that contributes to Yptb lethality. Furthermore, we found that the survival advantage conferred by Leptin deficiency was associated with increased liver and kidney damage. Our work reveals an additional level of complexity for the role of Leptin in infection defense and demonstrates that in some contexts, in addition to tolerating the pathogen, tolerating organ damage is more beneficial for survival than preventing the damage.

Virulence triggered allergies: Pseudomonas gets the Las laugh.

The mechanisms of how infectious diseases contribute to allergy remain unanswered. In this issue of Immunity, Agaronyan et al. (2022) show that Pseudomonas aeruginosa drives immune deviation through induction of type 2 immune responses, resulting in niche remodeling that incites allergic responses to innocuous antigens.

Adipose triglyceride lipase mediates lipolysis and lipid mobilization in response to iron-mediated negative energy balance.

Maintenance of energy balance is essential for overall organismal health. Mammals have evolved complex regulatory mechanisms that control energy intake and expenditure. Traditionally, studies have focused on understanding the role of macronutrient physiology in energy balance. In the present study, we examined the role of the essential micronutrient iron in regulating energy balance. We found that a short course of dietary iron caused a negative energy balance resulting in a severe whole body wasting phenotype. This disruption in energy balance was because of impaired intestinal nutrient absorption. In response to dietary iron-induced negative energy balance, adipose triglyceride lipase (ATGL) was necessary for wasting of subcutaneous white adipose tissue and lipid mobilization. Fat-specific ATGL deficiency protected mice from fat wasting, but caused a severe cachectic response in mice when fed iron. Our work reveals a mechanism for micronutrient control of lipolysis that is necessary for regulating mammalian energy balance.

Cooperative defenses during enteropathogenic infection.

During their co-evolution with pathogens, hosts acquired defensive health strategies that allow them to maintain their health or promote recovery when challenged with infections. The cooperative defense system is a largely unexplored branch of these evolved defense strategies. Cooperative defenses limit physiological damage and promote health without having a negative impact on a pathogen's ability to survive and replicate within the host. Here, we review recent discoveries in the new field of cooperative defenses using the model pathogens Citrobacter rodentium and Salmonella enterica. We discuss not only host-encoded but also pathogen-encoded mechanisms of cooperative defenses. Cooperative defenses remain an untapped resource in clinical medicine. With a global pandemic exacerbated by a lack of vaccine access and a worldwide rise in antibiotic resistance, the study of cooperative defenses offers an opportunity to safeguard health in the face of pathogenic infection.

Microbiota control of maternal behavior regulates early postnatal growth of offspring.

Maternal behavior is necessary for optimal development and growth of offspring. The intestinal microbiota has emerged as a critical regulator of growth and development in the early postnatal period life. Here, we describe the identification of an intestinal Escherichia coli strain that is pathogenic to the maternal-offspring system during the early postnatal stage of life and results in growth stunting of the offspring. However, rather than having a direct pathogenic effect on the infant, we found that this particular E. coli strain was pathogenic to the dams by interfering with the maturation of maternal behavior. This resulted in malnourishment of the pups and impaired insulin-like growth factor 1 (IGF-1) signaling, leading to the consequential stunted growth. Our work provides a new understanding of how the microbiota regulates postnatal growth and an additional variable that must be considered when studying the regulation of maternal behavior.

A metabolic handbook for the COVID-19 pandemic.

For infectious-disease outbreaks, clinical solutions typically focus on efficient pathogen destruction. However, the COVID-19 pandemic provides a reminder that infectious diseases are complex, multisystem conditions, and a holistic understanding will be necessary to maximize survival. For COVID-19 and all other infectious diseases, metabolic processes are intimately connected to the mechanisms of disease pathogenesis and the resulting pathology and pathophysiology, as well as the host defence response to the infection. Here, I examine the relationship between metabolism and COVID-19. I discuss why preexisting metabolic abnormalities, such as type 2 diabetes and hypertension, may be important risk factors for severe and critical cases of infection, highlighting parallels between the pathophysiology of these metabolic abnormalities and the disease course of COVID-19. I also discuss how metabolism at the cellular, tissue and organ levels might be harnessed to promote defence against the infection, with a focus on disease-tolerance mechanisms, and speculate on the long-term metabolic consequences for survivors of COVID-19.

The Biology of Physiological Health.

The ability to maintain health, or recover to a healthy state after disease, is an active process involving distinct adaptation mechanisms coordinating interactions between all physiological systems of an organism. Studies over the past several decades have assumed the mechanisms of health and disease are essentially inter-changeable, focusing on the elucidation of the mechanisms of disease pathogenesis to enhance health, treat disease, and increase healthspan. Here, I propose that the evolved mechanisms of health are distinct from disease pathogenesis mechanisms and suggest that we develop an understanding of the biology of physiological health. In this Perspective, I provide a definition of, a conceptual framework for, and proposed mechanisms of physiological health to complement our understanding of disease and its treatment.

Microbiota Metabolites in Health and Disease.

Metabolism is one of the strongest drivers of interkingdom interactions-including those between microorganisms and their multicellular hosts. Traditionally thought to fuel energy requirements and provide building blocks for biosynthetic pathways, metabolism is now appreciated for its role in providing metabolites, small-molecule intermediates generated from metabolic processes, to perform various regulatory functions to mediate symbiotic relationships between microbes and their hosts. Here, we review recent advances in our mechanistic understanding of how microbiota-derived metabolites orchestrate and support physiological responses in the host, including immunity, inflammation, defense against infections, and metabolism. Understanding how microbes metabolically communicate with their hosts will provide us an opportunity to better describe how a host interacts with all microbes-beneficial, pathogenic, and commensal-and an opportunity to discover new ways to treat microbial-driven diseases.

Metabolic Adaptations to Infections at the Organismal Level.

Metabolic processes occurring during host-microbiota-pathogen interactions can favorably or negatively influence host survival during infection. Defining the metabolic needs of the three players, the mechanisms through which they acquire nutrients, and whether each participant cooperates or competes with each other to meet their own metabolic demands during infection has the potential to reveal new approaches to treat disease. Here, we review topical findings in organismal metabolism and infection and highlight four emerging lines of investigation: how host-microbiota metabolic partnerships protect against infection; competition for glucose between host and pathogen; significance of infection-induced anorexia; and redefinition of the role of iron during infection. We also discuss how these discoveries shape our understanding of infection biology and their likely therapeutic value.

Host-Pathogen Relationship Advice: Fat Protects against a Broken Heart.

During infection, disease tolerance promotes host health without killing the pathogen. In a recent issue of Cell, Luan et al. (2019) identify GDF15 as a central regulator of disease tolerance of bacterial and viral challenges, while preventing cardiac damage, by mediating downstream cross-organ communication via the sympathetic and metabolic systems.

Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues.

Fatty acid synthase (FASN) predominantly generates straight-chain fatty acids using acetyl-CoA as the initiating substrate. However, monomethyl branched-chain fatty acids (mmBCFAs) are also present in mammals but are thought to be primarily diet derived. Here we demonstrate that mmBCFAs are de novo synthesized via mitochondrial BCAA catabolism, exported to the cytosol by adipose-specific expression of carnitine acetyltransferase (CrAT), and elongated by FASN. Brown fat exhibits the highest BCAA catabolic and mmBCFA synthesis fluxes, whereas these lipids are largely absent from liver and brain. mmBCFA synthesis is also sustained in the absence of microbiota. We identify hypoxia as a potent suppressor of BCAA catabolism that decreases mmBCFA synthesis in obese adipose tissue, such that mmBCFAs are significantly decreased in obese animals. These results identify adipose tissue mmBCFA synthesis as a novel link between BCAA metabolism and lipogenesis, highlighting roles for CrAT and FASN promiscuity influencing acyl-chain diversity in the lipidome.