Effects of Pathogen and Tumor Evasion Techniques on Immune Response in the Context of Critical Care

Abstract

Abbreviations: CD4/CD8: Cluster of Differentiation 4/8; CTLA4: CYTOTOXIC T-Lymphocyte Associated Protein 4; CTL: Cytotoxic Lymphocytes; DNA: Deoxyribonucleic Acid; DC: Dendritic Cells; EBV: Epstein-Barr Virus; CMV: Cytomegalovius; FOXP3: Forkhead Box P3; GAS: Group A Streptococcus; HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; HIV: Human Immunodeficiency Virus; HSV: Herpes Simplex Virus; MHC: major Histocompatibility complex; MDSC: Myeloid-Derived suppressor cell; NK: Natural Killer Cell; PML: Progressive Multifocal Leucoencephalopathy; PDL1: Programmed Cell Death Ligand 1; PsA: Pseudomonas Aeruginosa; TAM: Tumor Associated Macrophages; TAF: Tumor Associated Fibroblasts; TGFB: Transforming Growth Factor Beta; Tim3: T-cell Immunoglobulin and Mucin-Domain Containing-3; SSPE: Subacute Sclerosing Panencephalitis; V(D)J: Variable Diversity Joining

Introduction

Immune responses are dynamically influenced by invading pathogens and by host immune quality. While basic science literature is abundant in recognizing the reciprocation of immune fight with pathogens, which develop assorted sophisticated techniques of evading and modulating the immune response, the embeddement, the translation of this information into clinical thinking is not routinely employed. The comprehension of the phenotype of the invading pathogen regarding the immune deviation enables to a certain extent to predict the character of the immune response. This article serves to highlight the aspect of immune evasion for clinical intensivists. The rarely implemented measurement of immune response may validate the evasion tactics as triggers of immune dysregulation, and more so potentially disclose a preexisting immune deviation that is intrinsic to the host.

Overview

The constitution of sepsis, the most serious and generalized form of infection including the immune response, with profound clinical reverberations, is diverse [1]. There is uncertainty as to how to underpin such diversity clinically, how to interpret and how to customize therapy. Oblivious immune modulation without concluding the individual phenotype of sepsis, with emphasis on the particularization of the invading pathogen may not offer desired results. It is perhaps partly why so many large clinical trials attempting at monosyllabically influence the immune response during sepsis failed to bring benefit. Immune evasion, perceived in a broad term, denoting modulation, suppression and upgrading antibiotic resistance mechanisms is integral to microbial pathogenic mechanisms, it is a way of self-preservation against destruction so that active invasion can continue unharmed [2].

Tumor Immune Evasion

Immune evasion is a popular and newly acclaimed mechanism of tumor growth and propagation. It is the redefinition of original dogma, which argued that self cannot be recognized and attacked. The tumor is perhaps more of a distorted self, presenting neoantigens which undergo recognition mechanisms similar to pathogenic and autoantigens. Cells that are exposed to constant provocation mutate, eventually transform, and become oncogenic. The ultimate outcome is the clinical conclusion of unfortunate, randomly occurring mutations, enhanced by toxic environmental pressures [3]. Transformation and oncogenesis are random events. DNA and retroviruses participating in viral oncogenesis, introducing further stimuli to already preexisting mutagens, particularly during chronic infection, are not primarily interested in oncogenesis, rather in host cell survival to secure ongoing reproduction. They usually carry or incorporate host prooncogens to their own genome, alternatively produce factors that stimulate cell survival and proliferation pathways [4] or produce epigenetic modifications [5]. Frame shift mutations, inducing tumors which are associated with cigarette smoke and irradiation, produce more neoantigens, than single nucleotide mutations, consequently eliciting a more potent immune response, increasing the likelihood of tumor specific or tumor associated antigen presentation and development of antitumor immunity.

The phenomenon of pathogen evasion uses conceptually similar strategies to tumor evasion and while tumor specific and associated immunity is a relatively recent concept, it offers important insights and triggers alternative questions regarding the behaviour of the immune system in general. Tumor elicited immunity is triggered upon neoantigen and damage associated molecule presentation on patient’s individual MHCI and II molecules primed in sentinel lymph nodes with the aid of dendritic cells. Originally, the immune involvement in tumors was narrowed to immune cell tumors that arbitrarily undergo frequent gene recombinations, in the VDJ regions for instance, opening opportunity for mistakes culminating potentially in phenotypically diverse pathologies, autoimmunity [6] and immune cell tumors. Similarly, virus- associated tumors [7] representing about 12-20% of all viruses, add to the mutational burden. Among them EBV and CMV stand out for clinicians for widespread colonisation of the adult population, and in later association with increasing prevalence of lymphomas, gastric cancers, glioblastomas, etc [8-10].

The tumor elicited response begins with surveillance, continues with elimination and equilibrium. These are clinically dormant periods that ultimately build up to learned or induced evasion, signaling that a previously capable antitumor immune response becomes bypassed and exhausted [11]. This back-and-forth battle is accompanied with immune selection for tumors that are less immunogenic to safeguard survival. It is likely the balance of cytotoxic and regulatory cells and their activation equilibrium that defines the dormant stage (NK, CD8, Th1, MDSC, Foxp3, CTLA4). Tumors developed multiple ways to evade, slow and ultimately stop the immune response aimed at eliminating faulty cells. There are ways of impaired antigen trafficking to the cell surface, MHC downregulation [12] to evade CD4 helper and CD8 cytotoxic effectors, TAM and TAF associated impairment of NK cell functions [13]. Interferon gamma produced by cytotoxic T cells empowers tumors to PDL1 production and induction of T cell suppressive phenotype. Tumor associated fibroblasts produce a barrier that effector cells cannot breach. Tumors upregulate CTLA-4 to dampen T cells responses. Some tumors produce large amounts of regulatory cytokines: IL-10, and TGFbeta. As per common metabolites, lactic acid and ammonia contribute to immunosuppressive phenotype. Cancer cells may overexpress do not eat me signals, like CD47, to disable phagocytosis by macrophages. While CD8 and CD4Th1 presence is associated with improved outcome, Th17 association decreases survival.

Viral Immune Evasion

Virus infected cells are killed by CTL based on MHCI presented virus peptides. Many viruses disable peptide processing and presentation through proteasome and endoplasmatic reticulum pathways, or remove already attached peptides from MHC groove (adeno, CMV, HSV, HIV, EBV) [14,15]. Others create CTL escape mutants by presenting peptides that are not recognized as foreign (HSV, HBV). CTL escape, as opposed to antibody escape, doesn’t propagate, because MHC composition is relatively unique to the individual. HIV induces FasLigand expression on the surface of CTL and reverse killing assumes. Certain organs are immune privileged in the body to avoid self-damage by killing (eyes, CNS, testes,). In the rare, irreversible sequel of measles infection-SSPE, measles virus particles persist, and within 5-10 years cause progressive, degenerative panencephalitis [16]. Some polyomaviruses can also persist for unknown reasons, and rarely complicate biological therapies. Antia4b1 integrin blockage disabling immune cells from entering the brain may cause progressive multifocal leuco encefalopathy. HBV may persist too, in 5% of adults and 95% of newborns, may lead to T cell exhaustion and decades later to hepatocellular cancer [17]. Parenteral entrance, bypassing barrier immunity is an effective evasion technique. Type I interferons serve as major, universal defense mechanisms for all viruses, including HCV [18]. HCV however developed several counterfeit mechanisms, using non-structural proteins to suppress interferon alpha production, hijacking several intracellular pathways. Chronic hepatitis C infection is characterized by predominance of exhausted CD8+Tim3+PD1+ cells, similarly to tumors [19].

Bacterial Evasion of the Immune Response

In the bacterial world, persistent cells had been described, albeit in tiny proportions in a quiescent form, with great resilience towards macrophage engulfment and antibiotics [20]. Many bacteria possess sturdy capsules that serve as barriers to complement and antibody mediated opso-phagocytosis. GAS [21] owns a hyaluronic acid-based capsule that prevents opsonisation and serves a molecular mimicry substrate, also a M protein, that limits terminal complement MAC formation and pore forming. GAS virulence functions via toxins, such as streptolysin O leading to massive host cell apoptosis, including host immune cells. GAS is able to dismantle IgG molecules. Beyond these versatile tricks tackling the innate and adaptive immune response, bacteria may hide intracellularly, may form biofilms or survive dormant in persistent cells, to hide from antibiotics that do not have capability to penetrate cells. A hallmark example is Staphylococcus aureus, that forms biofilms on prosthetic surfaces, or if ultimately can nor resist engulfment using quorum sensing mechanisms, it hides intracellularly particularly during chronic osteomyelitis and contributes to bone resolution [22]. Pseudomonas Aeruginosa (PsA) [23] is notorious for hiding beneath biofilms, extracellular polymeric substances, which are structures built by bacteria, a highly impermeable habitat to antibiotics and immune targeting. In these biofilms, PsA alters its own phenotype to become more resistant to killing, its persistence triggers ongoing inflammation and tissue damage. PsA in biofilms produce rhamnolipids, leading to neutrophil death. During sepsis, T cell phenotypes gradually become exhausted, characterized by high Tim-3, PD-1, and CTLA-4 expression, reminiscent of tumor associated T cell phenotypes [24,25] Certain bacteria deploy superantigens to circumvent antigen presentation, they bind to MHC directly and induce massive T cell activation and cytokine storm.

Neutrophils are the most abundant and significant immediate first line defense in bacterial infection. Arising and replenished from the bone marrow the transmigrate from blood to effect site based on chemotactic bacterial and host mediated inflammatory trigger, they phagocytose upon pattern recognition receptor, complement and immunoglobulin opsonisation, they kill by using reactive oxygen species, azurophilic protease enzymes and by NET formation [26]. NET formation is a suicide mission of neutrophils to tackle a huge variety of pathogens. It is a form of self-consuming event, with liberation of nucleolar and cytoplasmatic content, entrapment of pathogens, and ultimately neutrophil cell death. Bacteria deploy various mechanisms to inhibit NET formation and function, inhibition of IL-8 production, by engagement with inhibitory SIGLEC receptors, NET degradation by DNAses (PsA), inhibition of reactive oxygen species formation (Klebiella pneumoniae), aggregation of extracellular DNA and NET escape (Staphylococcus aureus) [27,28]. The concluding immune response may lack neutrophil stimulation, with impaired phagocytosis, and NET functionality, diminished transmigration, uninvited survival inside macrophages, mast cells, overall T or B suppression or inhibition of memory, and recall responses.

Conclusions

ICU patients frequently struggle with life threatening infections like sepsis due to underlying comorbid conditions or pre-existing immune dysregulation. Pathogens will perhaps never stop developing evasion mechanisms. They employ diverse mechanisms to evade, deviate and suppress the immune response. These sophisticated mechanisms, similarly to tumor escape, were developed upon selective pressure to enhance survival. Clinically it is impossible and irrelevant to scrutinize them, the concluding changes in immune response are however measurable to a reasonable extent. For clinical intensivists the priority is to recognize this aspect of disease pathogenesis as a fundamental step to understand pathogenesis and in the future perhaps to implement, targeted and measured therapies based on immune response dynamics and property. The potential measures of prevention are of utmost concern. It is particularly interesting to realize how certain features and logics are intertwined between autoimmunity, infection and tumor.

Acknowledgments

This work was only possible thanks to the diligent teaching of Prof. Vincent Racaniello and Assoc. Prof. Brianne Barker.

Conflicting Interest

None.

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