Biological and clinical implications of a model of surveillance immunity

Abstract

The immune system must identify genuine threats and avoid reacting to harmless microbes because immune responses, while critical for organismal survival, can cause severe damage and use substantial energy resources. Models for immune response initiation have mostly focused on the direct sensing of microorganisms through pattern recognition receptors. Here, we summarize key features of the leading models of immune response initiation and identify issues they fail to solve individually, including how the immune system distinguishes between pathogens and commensals. We hypothesize and argue that surveillance of disruption to organismal homeostasis and core cellular activities is central to detecting and resolving relevant threats effectively, including infection. We propose that hosts use pattern recognition receptors to identify microorganisms and use sensing of homeostasis disruption to assess the level of threat they pose. We predict that both types of information can be integrated through molecular coincidence detectors (such as inflammasomes or others not yet discovered) and used to determine whether to initiate an immune response, its quality, and its magnitude. This conceptual framework may guide the identification of novel targets and therapeutic strategies to improve the progression and outcome of infection, cancer, autoimmunity, and chronic conditions in which inflammation plays a critical role.

Figure 1. Models of innate immune initiation.

(A) Pattern-triggered immunity (PTI). Microbial structural molecules (PAMPs or MAMPs) are directly sensed by PRRs, which can activate transcriptional programs or effectors directly. MAMPs that are not conserved or are unknown to the host may not activate PTI. MAMPs may be shared between virulent and avirulent microorganisms (102). (B) PTI by infidelities (14). This model proposes that PRRs are predominantly byproducts of unsuccessful pathogens that lead to biochemical infidelities. This implies a high pressure on pathogens to minimize unsuccessful events and should result in a lower-than-observed ability to evolve and evade (14). Additionally, live-attenuated vaccines tend to have the highest efficiency and sensing of markers of live pathogens (vita-PAMPs) by the host (103). (C) Danger model (damage recognition) (16). PRRs are activated by sensing host molecular patterns released upon compromised tissues. The relevance of DAMPs in the context of infection has not been fully resolved in this model. (D) Effector-triggered immunity (ETI) (21). Virulence factors are sensed by “guard proteins” directly or indirectly by detecting changes or modifications in host proteins (“guardees”). (E) Surveillance immunity (3). Immune responses are triggered by disruption of core cellular functions or homeostasis parameters through stress pathways. Multiple input pathways synergize to generate an output tailored to the nature and level of threat. However, maladaptive responses cannot be fully avoided. Yellow symbols depict microbial factors; purple symbols depict host factors. HAMPs, homeostasis altering molecular processes.

Figure 2. Patterns of pathogenesis.

The risk level (threat to host system homeostasis) and the magnitude and nature of the immune response that needs to be activated are assessed using direct sensing of microorganisms and additional contextual signals (9). The pathogen must overcome several checkpoints (depicted in columns labeled Checkpoint 1–5) before it poses the highest level of threat, resulting in a vigorous immune response (7). Checkpoint 1: Soluble MAMPs initiate cytokine and chemokine production remotely, while MAMPs on whole microorganisms trigger direct microbicidal responses. Checkpoint 2: Vita-PAMPs, such as bacterial mRNA, indicate live microorganisms capable of growth, multiplication, and invasion and trigger enhanced immune responses by activating PRRs. Checkpoint 3: The need and type of immune response to microbial presence varies according to the tissue’s physiology and microenvironment, ensuring appropriate responses. Systemic threats trigger immediate, strong reactions to prevent severe consequences, while local tissue responses are tightly regulated. At the subcellular level, the strongest immune responses are initiated against agents that invade the cytosol. Checkpoint 4: The degree of invasiveness is critical information for the immune system to distinguish between pathogenic and nonpathogenic microorganisms. While commensal bacteria coexist with the host without causing disease, they can become pathogenic if they breach sterile tissues. Invasive forms of microbes expose specific molecules or morphologies that signal potential threats, leading to more robust immune activation. Commensals can act as facultative pathogens under specific conditions. Commensal bacteria can become invasive due to host factors like immunodeficiency, pregnancy, or treatments altering the microenvironment. The immune system and intact physical barriers are crucial for preventing this switch. Invasiveness can be controlled by inhibiting the quorum-sensing system of microorganisms. Checkpoint 5: Virulence. Microorganisms are classified as pathogens or nonpathogens based on their ability to cause disease, correlating with virulence factors that disrupt host barriers and invade tissues.

Figure 3. Surveillance immunity.

All major groups of pathogens (viruses, bacteria, protozoan parasites, and fungi) trigger stress responses to core homeostatic processes such as DNA damage, replicative stress, mitochondrial dysfunction and proteostatic stress (UPR^mt), translation inhibition and ER proteostatic stress (UPR^er), in addition to direct recognition by PRRs. Direct and indirect sensing of homeostasis disruption and signaling by PRR is integrated and synergizes in the production of immune and homeostasis effectors to tailor effector responses to specific classes of pathogens and level of threat. Both disease resistance (directed against the pathogen) and disease tolerance mechanisms that act on the host (to limit tissue damage, collateral damage, and tissue dysfunction) are activated. ER, endoplasmic reticulum.