“Extrinsic and Intrinsic Immunometabolism Converge: Perspectives on Future Research and Therapeutic Development for Obesity”

Abstract

Purpose of Review:

Research over the past decade has shown that immunologic and metabolic pathways are intricately linked. This burgeoning field of immunometabolism, includes intrinsic and extrinsic pathways, and is known to be associated with obesity-accelerated metabolic disease. Intrinsic immunometabolism includes the study of fuel utilization and bioenergetic pathways that influence immune cell function. Extrinsic immunometabolism includes the study of immune cells and products that influence systemic metabolism.

Recent Findings:

Th2 immunity, macrophage iron handling, adaptive immune memory, and epigenetic regulation of immunity, which are all require intrinsic metabolic changes, play a role in systemic metabolism and metabolic function, linking the two arms of immunometabolism. Together, this suggests that targeting intrinsic immunometabolism can directly affect immune function and ultimately systemic metabolism.

Summary:

We highlight important questions for future basic research that will help improve translational research provide therapeutic targets to help establish new treatments for obesity and associated metabolic disorders.

Introduction

Obesity affects approximately 38% of adults in the United States (US)[1] and increases the risk for nearly every chronic disease, including heart disease, stroke, diabetes, some forms of cancer, and dementia [2]. Roughly $190 billion, or approximately 21% of total healthcare costs, are spent on obesity-related diseases in the US annually [2], and the American Medical Association formally recognized obesity as a disease in 2013. However, there are still very few effective treatments for obesity, as less than 20% of individuals who lose weight are able to maintain ≥10% weight loss for more than a year [3]. Bariatric surgery has a much higher success rate than lifestyle interventions [4], but it is not a feasible solution for every individual. Therefore, additional research is necessary to improve patient health and obesity-related outcomes.

Obesity is a multifaceted disease, associated with environmental, genetic, endocrine, neural, and microbiota-associated risk factors, [reviewed in [5]], as well as functional changes within the brain, adipose tissue (AT), liver, pancreas, skeletal muscle, and intestine. There are many drugs in development to target neurotransmitters, which are involved in appetite regulation and satiety, and GLP-1 and cAMP, which are involved in blood glucose control and insulin action [6]. Additionally, research over the past 15 years suggests that the immune system contributes to the pathogenesis of obesity, and therefore is an emerging target to alleviate health consequences of obesity.

Immune cell presence and function within metabolic tissues is closely linked to systemic glucose and lipid homeostasis, a field of research we refer to as “extrinsic immunometabolism” in this article. Macrophage accumulation in AT of obese mice was first shown in seminal papers published in 2003 [7,8], and by 2013, our field had substantial evidence that obesity effects immune cell populations not only in AT, but also the liver, bone marrow and hypothalamus [as reviewed in [9]]. These immune populations contribute to tissue homeostasis during health; however, shifts in number and phenotype can promote an inflammatory milieu in obesity and can contribute to insulin resistance and glucose intolerance, which together are referred to metabolic dysfunction. Simultaneously, immunologists began to uncover the mechanisms by which changes in intracellular bioenergetic pathways can alter immune cell function [10], a field of research that we refer to as “intrinsic immunometabolism” that has also been specifically linked to obesity-associated inflammation [11**]. Emerging evidence suggests that these to concepts in immunometabolism are interconnected (Figure 1). In this review, we will highlight extrinsic and intrinsic studies of immunometabolism in obesity. Further, we propose future areas of research that can harness both sides of immunometabolism to help identify therapeutic targets for translational use in obesity and other associated metabolic disorders.

Figure 1.

Intrinsic and extrinsic immunometabolic pathways are intricately linked in AT homeostasis and metabolic dysfunction associated with obesity. We propose four distinct areas of research that may provide potential therapeutic targets for the treatment of obesity and associated metabolic disease: Th2 immunity, macrophage iron handling, adaptive memory formation, and epigenetic regulation. Importantly, these targets will likely influence both intrinsic and extrinsic immunometabolism, strengthening the potential likelihood for success as therapeutic targets.

Extrinsic Immunometabolism

There has been a substantial body of work published in the area of extrinsic immunometabolism. While this review will focus on AT, it should be noted that immune cells are also present in other metabolic organs such as muscle, liver, brain and pancreas, where they likely play an important role in systemic metabolic homeostasis. Additionally, we want to emphasize that resident immune cells in the AT can contribute to both AT homeostasis and metabolic disease, which have been nicely summarized in many reviews [12–14]. In healthy AT, there is an abundance of cells with regulatory functions associated with Th2 immunity, including M2 macrophages, invariant natural killer T cell (iNKT)s, innate lymphoid cell (ILC2)s, T regulatory (Treg) cells, T helper (Th)2s cells, and eosinophils. These cell types are traditionally associated with protection against parasites, but are elevated in lean AT and are considered protective against metabolic dysfunction [14]. Following weight gain with high fat diet (HFD)-feeding and in genetically obese models, the Th2-associated cells are reduced and there is an influx of Th1-associated cells. M1 macrophages, Th1 cells, CD8+ T cells, dendritic cells (DCs), and neutrophils infiltrate and expand, contributing to metabolic dysfunction. Interestingly, myeloid derived suppressor cells (MDSCs), which are typically associated with anti-inflammatory effects, increase with weight gain to limit metabolic dysfunction associated with obesity; however, this feedback is not enough to prevent worsened glucose tolerance and insulin resistance (IR) [15]. AT macrophages (ATM)s have received the most attention in the literature [16] and have recently been characterized to have a “metabolically activated” (MMe) phenotype in obesity [17], which is essentially inflammatory. However, both pro- and anti-inflammatory signaling pathways are activated in these cells, which may explain the chronic non-resolving inflammation in obesity. Additionally, recent work has begun to classify the expression pattern of additional populations, such AT DCs, which also accumulate with obesity and contribute to IR [18].

Much of the data above has been discovered by modulating immune populations in knockout mice or transgenic mice. Drug therapies which target chemokines, cytokines, and their receptors have also been used to target specific immune populations of interest. One of the most commonly studied pathways is chemokine receptor 2 (CCR2). Disrupting monocyte chemoattractant protein 1 (MCP-1, also called CCL2)-mediated macrophage infiltration into the AT is associated with improved IR after HFD-feeding [19–22]. However, ATM numbers in CCR2-deficient HFD-fed mice do not return to lean values and less promising results have been shown with other chemokine receptor knockouts [23,24], suggesting that multiple pathways may need to be simultaneously targeted for optimal responses. Additionally, a study on the administration of IL-33 recently elucidated protective effects on metabolic function in obesity [25], however administration also drives allergy and asthma. Importantly, recent adoptive transfer experiments of helminth-induced M2 macrophages[26] and B1-B cells [27] and older experiments with Treg cells [28] suggest that immunotherapy can improve metabolic function in obese mice and should be considered as a potential future therapeutic strategy. This suggests that promoting protective Th2-immunity while limiting detrimental Th1-associated inflammation may improve AT function and more generally, systemic metabolism.

The role of immune cells in AT homeostasis and metabolic dysfunction following weight gain is well understood, however the best therapeutic target to reverse HFD-induced changes in inflammatory populations is not known. Moreover, immune cell populations change in response to weight loss, and may provide further insight into metabolic function with weight gain. Following HFD-induced obesity, weight loss initially accompanies a lipolysis-mediated increase in ATMs and then a decrease with reduced AT mass and a normalization in glucose tolerance [29,30]. However CD11c+ ATMs were still elevated up to 6 months post weight loss and insulin sensitivity was not completely normalized [31]. More work is needed to address the mechanism by which weight loss changes immune cells abundance and how these changes contribute to metabolic function. Potential strategies to modulate immune cell metabolism and relatedly, immune function, are discussed below.

Intrinsic Immunometabolism

It is well known that macronutrient catabolism is required for energy production; however, the importance of intrinsic immunometabolism for immune function and systemic metabolism has only recently been investigated (reviewed in [32]). While immune cell metabolites continuously flux through both glycolysis and oxidative phosphorylation (OX PHOS), the relative contribution of each pathway to ATP versus metabolite production influences immune cell differentiation, polarization, and effector function [33,34]. Fatty acid oxidation (FAO) and OX PHOS are primarily used by regulatory and anti-inflammatory cells, including Treg cells, M2 macrophages, and MDSC, while glycolysis is primarily used by inflammatory effector cells, such as Th1 and Th17 cells, M1-like macrophages and DCs [35–38]. OX PHOS is more efficient than glycolysis, producing 32 versus 2 ATPs per glucose molecule; however, glycolysis is often utilized because it can increase ATP availability rapidly, operate under low oxygen tension, and provide pentose phosphate pathway and tricarboxylic acid (TCA) cycle intermediates for the synthesis of nucleotides, amino acids, and lipids [33,35]. Additionally, the metabolites generated can contribute to oxidation-reduction reactions, pro- and anti-oxidant balance, and protein modifications such as acetylation, methylation, prenylation, and palmitoylation. Metabolic enzymes, nutrient sensors, and nutrient transporters are amenable to pharmacological intervention and offer promising opportunities for selective regulation of the immune response. Moreover, because intrinsic metabolism is tightly linked to immune function, targeting intrinsic immunometabolism may offer potential opportunities to improve systemic metabolism.

Healthy, lean AT has an abundance of Treg cells, which primarily utilize FAO and OX PHOS. Lean AT also has an abundance of Th2 cells, M2 macrophages, ILC2s, and eosinophils which utilize glycolysis at a rate similar to Th1 cells and neutrophils; however, they too have elevated glucose oxidation, FAO, and OX PHOS [39*, 40–41]. On the contrary, Th1 cells, M1-like macrophages, and effector CD8+ T cells, which are associated with obesity, primarily utilize glycolysis [42–44]. This suggests that increasing OX PHOS could support healthy AT-associated cells and blunting OX PHOS could support obese AT-associated cells, but very little research has been done to modulate energy metabolism strictly in immune cells in the context of obesity. A few studies have shown that systemic suppression of glycolysis can improve obesity-related metabolic dysfunction in mice. For example, administration of oxamate, which blocks the conversion of pyruvate to lactate and reduces glycolytic flux, resulted in reduced inflammatory cytokine secretion, improved insulin sensitivity, and improved glycemic control in leptin receptor deficient obese mice [45,46]. This effect was observed with oxamate alone as well as when combined with metformin [47]. The mechanism for these results was attributed to reduced plasma lactate, a metabolite known to impair insulin sensitivity; however, it is plausible that immune effects also contributed to improved metabolic function, as both oxamate and metformin can suppress immune cell glycolysis and inflammatory cytokine production [48]. In a second example, HFD fed pyruvate dehydrogenase (PDK2) deficient mice demonstrated improved blood glucose and insulin and reduced weight gain compared with control mice [49]. PDK2 increases the flux of pyruvate through the TCA cycle and indirectly suppresses glycolysis, again suggesting that glycolytic suppression, however these studies could not clarify a role for immune specific metabolic changes. In contrast to studies targeting glycolysis, a recent study of macrophage-specific deficiency in Raptor, part of the mammalian target of rapamycin complex 1 (mTORC1) that promotes OX PHOS, improved glycemic control and blunted inflammatory parameters in the liver and AT of HFD-fed mice. This data supports older studies showing that impingement on FAO and OX PHOS in macrophages generally impairs metabolic health following HFD feeding [50–53]. Together, these studies suggest that blunting glycolysis may be protective against obesity-induced metabolic dysfunction, while blunting FAO and OX PHOS may be detrimental.

There is still a lot to understand about modulating metabolic pathways for therapeutic targeting. A recent study with a global knock out of the glycolytic enzyme pyruvate kinase (PKM2) reported PKM1 compensation [54], suggesting the importance of considering feedback loops when modulating metabolic targets. Furthermore PKM2, as well as the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), have been shown to translocate to the nucleus and alter gene transcription [55,56], suggesting that non-glycolytic functions for target proteins should be better explored to understand the overall impact of these systems. In a myeloid-specific glucose transporter (GLUT)1 deficiency model, GLUT1 deficient BMDMs increased oleate and glutamine metabolism [57*]. These results suggest that other metabolic pathways can compensate when glucose is limited and should be considered when inhibiting any metabolic pathway. Additionally, deficiency of the fatty acid transporter carnitine palmitoyltransferase (Cpt)1b shows opposite effects on weight gain and metabolic dysfunction when mice are fed HFD for 8 weeks versus 7 months [58,59], suggesting that acute versus long term needs may be different for each cell type and that targeting these mediators may induce adaptation or feedback regulation over time. Moreover, it’s recently been reported that the drug etomoxir, which is commonly used to inhibit FAO, has non-specific effects at the concentrations used in many previous immunometabolism studies [60*]. Previous studies suggest that etomoxir treatment inhibits M2 polarization, however this effect happens in the absence of the target enzymes Cpt1 and Cpt2, as shown in a double knockout model. Instead, this recent study showed that the depletion of intracellular free coenzyme A is responsible for the M2 polarizing effects of etomoxir, suggesting that M2 macrophages may be less reliant on FAO than we previously believed.

New discoveries in intrinsic immunometabolism offer the opportunity to selectively target specific immune cell subsets by modifying the metabolic pathways essential for their function. Recent studies support the need for better mouse models to test deficiency of immune cell-specific pathways. Additionally, these studies support the need to develop more specific pharmacological drugs with fewer off-target effects. Mechanisms to target specific cells would be optimal, as these pathways are utilized in all cell types, and any modulation should be reversible in order to reverse immunosuppression in order to effectively fight bacterial and viral infections as well as cancer. Furthermore, future studies should examine the full impact of immune cell subset metabolic regulation on metabolic function and how modulating these pathways change over time with feedback regulation.

Current Research and Potential Avenues for Therapeutic Development

An enhanced understanding of immune cell networks and metabolic pathways may help us to target immune responses associated with obesity and metabolic dysfunction more effectively. In light of this, there are many ongoing studies that aim to understand and modulate both intrinsic and extrinsic immunometabolism to improve metabolic health. In this section, we will review current and ongoing areas of research that simultaneously impact both extrinsic and intrinsic immunometabolism that we believe are promising areas for therapeutic development.

Th2 immunity and intrinsic immunometabolism

There is substantial evidence for the role of Th2 immunity in AT and metabolic health, yet targets for modulating Th2 immunity are still unclear. While eosinophils are associated with healthy AT and positively correlated with metabolic health in IL-5 transgenic and IL-5 deficient mice [61,62], increasing AT eosinophils via IL-5 injections or via CCR2 deficiency had no effect on metabolic function [20,63], suggesting that eosinophil infiltration alone does not contribute functionally to metabolic health. It’s plausible that eosinophil activation or polarization is required or that AT-associated tissue resident cells are distinct from circulating cells of the same type. Additionally, it’s plausible that that additional cell types, such as ILC2, Th2 cells, or M2 macrophages, are required for improved metabolic function [64]. Targeting Th2 intrinsic immunometabolism may be a therapeutic strategy to influence systemic immunometabolism. Immunometabolism-targeted treatment strategies in autoimmunity and cancer research should be considered for use in obesity-driven metabolic disease to promote Th2 immunity and polarization. In a model of allograft rejection, simultaneously blocking glycolysis and glutamine metabolism prevented the induction of CD4+ and CD8+ effector T cells while promoting the generation of allospecific Treg cells [65], suggesting that inhibiting more than one pathway can be an effective strategy to encourage anti-inflammatory immunometabolism. Additionally, anti-cancer agents and metabolic inhibitors have been conjugated to glucose to selectively deliver the highest concentration of drug to cancer cells that have much higher rates of glucose uptake than surrounding cell populations [66], suggesting that a similar strategy could exert selectivity on immune subsets by affecting the populations with the greatest demand for a particular substrate. Moreover, nanoparticles, glucan-shells, and liposomes can be engineered to express ligands or antibodies to target specific cell types, and carry siRNA or different drugs, as further reviewed here in the context of ATMs [67]. These therapeutics can even induce tissue specificity, as intraperitoneal administration of siRNA encapsulated by glucan shells in obese mice selectively silences genes in epididymal ATMs, whereas macrophages within lung, spleen, kidney, heart, skeletal muscle, subcutaneous adipose, and liver were not targeted [68]. Additional research is needed to determine a full view of metabolic pathways utilization by AT immune cells during obesity. Technologies such as RNA sequencing, proteomics, and phage display [69] can help us to further identify peptides targets for drug delivery.

Macrophage Iron Handling

Targeting macrophage iron handling may also be a therapeutic strategy to influence both intrinsic and extrinsic immunometabolism. Our lab has recently discovered a population of ATMs with high iron content in lean AT [70]. Coined “MFe^hi” cells, these iron handling cells can take in, store, and release iron in response to environmental demands, similar to iron handling Kupffer cells in the liver [71,72]. Additionally, MFe^hi cells have similar gene expression to M2 macrophages and are reduced with HFD-feeding, which suggests they may play a role in metabolic function [70–72]. In general, iron metabolism in macrophages reduces the expression of genes associated with antigen presentation while increasing gene expression for antioxidant and glucose metabolism proteins [73], and iron is well known for its role within iron-sulfur clusters, re-dox reactions, and enzyme function in the mitochondria [74]. Based on these studies, it is possible that iron handling in macrophages may impact intrinsic immunometabolism and therefore polarization and effector function. Moreover, MFe^hi macrophages may prevent iron overload and oxidative stress in adipocytes [75], which in turn improves systemic metabolic function. Iron chelation and intravenous iron treatments have been shown to play a direct role on tumor-associated macrophage polarization and indirectly impacting cancer survival [76], suggesting that targeting macrophage iron handling and polarization may also be an effective target for extrinsic metabolism. Future studies should determine how iron handling in macrophages is regulated, the effects on intrinsic metabolism, and how therapeutic drugs could target these pathways to improve metabolic function.

Adaptive Immune Memory

Macrophages are considered a major player in extrinsic immunometabolism; however, T cell populations are also altered in obesity and weight cycling (WC), which is defined by repeated cycles of weight gain and loss that impairs metabolic function beyond that of obesity alone. Our lab has recently shown that CD8+ and CD8+ memory T cells are elevated in the AT after HFD-feeding in mice, and that CD4+, CD8+, and CD8+ memory T cells are even further increased with WC [30]. The role of CD4+ T cells in WC has also recently supported by another group [77**]. This data suggests that the immune system recognizes weight gain in a manner similar to its recognition of pathogens and develops an adaptive memory response that may affect subsequent bouts of weight gain. Additionally, we recently found that T cells isolated from HFD-fed mice have reduced TCR diversity and increased clonality, with TCR-CDR3 regions enriched for positively charged and less polar amino acids [78**], further supporting the role for antigenic memory. These regions can recognize isolevuglandins, gamma reactive ketoaldehyde and isoprostenoid derivatives, suggesting these may be relevant neoantigens in AT. T cells have been well characterized in light of intrinsic immunometabolism, and bioenergetic pathways contribute to polarization, memory development, and proliferation, suggesting that future therapeutics may target both intrinsic and extrinsic immunometabolism.

There are many promising mechanisms by which T cell memory development in the AT could be bunted to reduce AT inflammation and metabolic dysfunction. First, blocking antigen presentation may ameliorate initial memory formation. Dendritic cells, macrophages, and adipocytes reside in AT and upregulate MHCII in obesity [79,80], and a recent study showed that adipocyte-specific MHCII deficiency improves insulin sensitivity in HFD-fed mice [81]. This suggests that targeting MHCII interactions in the AT may reduce memory formation. Second, modulating checkpoint co-inhibitory interactions have been successful in animal models of obesity-associated inflammation and metabolic dysfunction as well as in humans for lupus, Crone’s disease, and transplant rejection. However, long-term treatment targeting general co-inhibitory molecules can leave patients susceptible to bacterial and viral infections, as well as cancer [82]. A recent study showed that the interaction between CD40-TNF receptor-associated factor (TRAF) 2/3/5 is protective against metabolic dysfunction and inflammation associated with obesity; while, the CD40-TRAF6 pathway contributes to the detrimental consequences of obesity [83]. Administration of an inhibitor of the CD40-TRAF6 interaction improved IR in mice, suggesting that specific co-inhibitory interactions and/or blocking co-stimulatory interactions in the AT may be plausible targets to modulate T cell activation and memory formation.

Finally, Treg immunotherapy has potential use in transplant patients, graft versus host disease, and autoimmunity, and could be expanded to metabolic diseases. Ex vivo expanded Tregs have been shown to polarize M2 macrophages more effectively than freshly isolated Treg cells [84*], and progenitor populations can be differentiated and expanded ex vivo using anti-CD3/CD28 beads, IL-2 and rapamycin [85]. The ThRIL clinical trial at King’s College London is currently studying Treg immunotherapy to prevent organ transplant rejection while minimizing long-term immunosuppression, and if successful, may have potential use in obesity- and WC- related metabolic dysfunction. Interestingly, AT Tregs have been shown to have distinct TCR repertoires from both the lymph cells and conventional AT T cells and express high levels of PPARy [86,87]. Using this technique in AT would require selective isolation and expansion of the AT Tregs or their direct progenitors. Future research should elucidate additional AT antigens and determine the best mechanism to target adaptive memory formation to improve metabolic function in obesity.

Epigenetic regulation of immunity and microRNAs (mIRs)

Another emerging field in immunometabolism is the epigenetic control of immunity [88]. Epigenetics changes such as DNA methylation, can have long-lasting effects on hematopoietic lineage commitment and cell differentiation. In contrast, acute changes to covalent histone modifications such as methylation, acetylation, phosphorylation, sumolyation, ubiquitination, and monoaminylation, can impact cell polarization and function. These modifications influence the phenotype, polarization, and activation stage of the cells as well as their metabolic phenotypes. For example, CD4+ and Th2 cells are marked by H3K27me3, a repressive histone modification at the interferon gamma locus, whereas Th1 cells show increased levels of histone H3K4me2, a histone mark associated with actively transcribed chromatin, at the same locus [89]. Monocyte to macrophage differentiation and the development of tolerance or trained immunity are associated with the acquisition of distinct epigenetic signatures (H3K4me1, H3K4me3, and H3K27ac) at promoter and enhancer regions of inflammatory and glycolytic genes [90]. In addition, H3K4me3 is required for M1 macrophage cytokine production and H3K27 demethylation is required for M2 polarization [91]. Furthermore, metabolic pathway utilization can drive epigenetic changes. Glycolysis and β-oxidation increase acetyl-coA availability which can be used by histone acetyltranferase enzymes to promote an open chromatin state and increase transcription. Interestingly, histone deacetylase (HDAC)11 deficient mice are resistant to HFD-induced obesity and have greater glucose tolerance and insulin sensitivity when compared to wild type controls [92], while sirtuin (SIRT)2 deficiency and macrophage-specific SIRT1 deficiency increase weight gain and impair metabolic parameters associated with HFD-feeding [93,94]. This data suggests that specific modulation of epigenetic changes is important, as both HDAC and sirtuin proteins function as deacetylase enzymes. Additional research is needed to determine how obesity affects immune cell histone modifications and what therapeutic targets may be useful to improve metabolic function.

Another element of epigenetics that has being recently explored in obesity is the role of miRs [88]. MiRs are non-coding RNA molecules that bind mRNA and prevent translation. Like epigenetic changes, miRs can simultaneously influence metabolic and inflammatory function. miRs-155 is well known to augment receptor signaling in immune cells and has been shown to increase glycolysis in cancer cells [95–97]. Deletion of miR-155 in female mice protects against HFD-induced obesity[98]; however, there were immune-independent effects on AT beiging and male mice did not demonstrate the same protection [99]. Additionally, miRs can be secreted. MiR-34a has been shown to be secreted from adipocytes, suppress M2 polarization, and worsen metabolic dysfunction [100], suggesting that targeting exosome release could modulate miR delivery and function. Future studies should further examine the contribution of specific miRs to inflammation and metabolic function in obesity. Additionally, researchers can utilize nanoparticle, β-glucan coated, or liposome delivery methods to deliver miR mimics or antagomiRs, antisense oligonucleotides that prevent the interaction of miRNAs with their target mRNAs, to cells of interest in order to target immune cell function and moreover, metabolic function.

Conclusions

Intrinsic immunometabolism is the study of how bioenergetics pathway utilization is linked to inflammatory function, and is closely linked to extrinsic immunometabolism, which is the study of how immune cell distribution and function broadly influences systemic metabolism. Both intrinsic and extrinsic immunometabolism are linked to obesity and metabolic dysfunction. Targeting different areas of intrinsic immune cell metabolism may therefore influence immune function and more largely, metabolic function in obesity. While many studies have been designed to target macrophage metabolism and function in obesity, targeting Th2 immunity, iron-handling, adaptive memory, or epigenetic regulation in immune cells may also be worthwhile targets to better understand immunometabolism and to develop better pharmacological treatments (Figure 1). Future basic science research will help us to better understand which metabolic pathways and controls to target to improve obesity-related inflammatory diseases without dampening host immunity against pathogens like bacteria and viruses.