Protective Microbiota: From Localized to Long-Reaching Co-Immunity

Abstract

Resident microbiota do not just shape host immunity, they can also contribute to host protection against pathogens and infectious diseases. Previous reviews of the protective roles of the microbiota have focused exclusively on colonization resistance localized within a microenvironment. This review shows that the protection against pathogens also involves the mitigation of pathogenic impact without eliminating the pathogens (i.e., "disease tolerance") and the containment of microorganisms to prevent pathogenic spread. Protective microorganisms can have an impact beyond their niche, interfering with the entry, establishment, growth, and spread of pathogenic microorganisms. More fundamentally, we propose a series of conceptual clarifications in support of the idea of a "co-immunity," where an organism is protected by both its own immune system and components of its microbiota.

Keywords: colonization resistance; containment; disease tolerance; host–microbiota symbiosis; infectious diseases; microbial ecology; pathogens.

Figure 1

An expanded view of microbe-conferred protection. Microorganisms can protect the host in different ways, depending on the mode of protection (direct ecological and indirect host-mediated), the effects of protection (colonization resistance against pathogenic establishment and growth, containment of pathogens and their effects, and disease tolerance of pathogens while suppressing their negative effects), and the range of protection (localized or long-reaching, with the latter further divided into protection that is systemic or from one locale to another locale). All three aspects of protection can occur in combination. Long-reaching protection, for instance, involves both direct (ecological) and indirect (host-mediated) modes of protection that result in colonization resistance, containment, or disease tolerance effects.

Figure 2

Stages of pathogen invasion and the obstacles presented by resident communities. Colonization resistance, containment, and disease tolerance present obstacles to different stages of the invasion process. Colonization resistance disrupts the establishment and growth of pathogens, the containment of pathogens prevents their spread into other tissues, and disease tolerance suppresses the negative effects of pathogens without decreasing their load.

Figure 3

Localized microbe-conferred protection against pathogen invasion. Alien pathogens invade the host by entering a host site, establishing a growing colony, exerting negative effects on the host. When conditions are ripe, they can spread to a different host site, in this case, through the epithelium or endothelium barrier. Protective microorganisms can challenge pathogen invasion at any of the four stages, by disrupting entry, preventing or destroying colony establishment and growth, by suppressing pathogenic effects, or by preventing spread into other tissues.

Figure 4

The overlapping mechanisms of colonization resistance, containment, and disease tolerance. Colonization resistance, containment, and disease tolerance are distinct effects on invading pathogens, disrupting their growth and establishment, their spread, and their negative effects, respectively. Nevertheless, the mechanisms underlying these effects can overlap, deployed at different times and stages with different outcomes. Antimicrobial peptides, for instance, prevent the translocation of microorganisms as part of the mucus barrier and disrupt the establishment and growth of pathogens. Another example is the disruption of a pathogenic biofilm, which may destroy the establishment of the colony as well as prevent it from adhering and translocating gut lumen.

Figure 5

Long-reaching microbe-conferred protection against pathogens. The multiple pathways of long-reaching protection include: local-to-local protection against pathogens at a distal site by protective microorganisms at another site (e.g., gut to lung, upper respiratory tract to lower respiratory tract, and small intestine to large intestine) (left), local-to-systemic protection from one site to pathogens across the body (e.g., systemic protection from gut microbiota) (center) and systemic-to-systemic protection by microorganisms that are distributed systemically (e.g., protective viruses or bacteria that circulate through the blood stream or the lymphatic system, or reside in multiple locations) (right).