Resistance is futile? Mucosal immune mechanisms in the context of microbial ecology and evolution.
Mucosal Immunol
; 15(6): 1188-1198, 2022 06.
Article
em En
| MEDLINE
| ID: mdl-36329192
ABSTRACT
In the beginning it was simple we injected a protein antigen and studied the immune responses against the purified protein. This elegant toolbox uncovered thousands of mechanisms via which immune cells are activated. However, when we consider immune responses against real infectious threats, this elegant simplification misses half of the story the infectious agents are typically evolving orders-of-magnitude faster than we are. Nowhere is this more pronounced than in the mammalian large intestine. A bacterium representing only 0.1% of the human gut microbiota will have a population size of 109 clones, each actively replicating. Moreover, the evolutionary pressure from other microbes is at least as profound as direct effects of the immune system. Therefore, to really understand intestinal immune mechanisms, we need to understand both the host response and how rapid microbial evolution alters the apparent outcome of the response. In this review we use the examples of intestinal inflammation and secretory immunoglobulin A (SIgA) to highlight what is already known (Fig. 1). Further, we will explore how these interactions can inform immunotherapy and prophylaxis. This has major implications for how we design effective mucosal vaccines against increasingly drug-resistant bacterial pathogens Fig. 1 THE IMMUNE RESPONSE SHAPES THE FITNESS LANDSCAPE IN THE GASTRO-INTESTINAL TRACT. The red arrows depict possible evolutionary paths of a novel colonizer along adaptive peaks in the intestinal fitness landscapes that change with the status of the host immune system. The flat surfaces represent the non-null fitness baselines (values x or y) at which a bacterium can establish at minimum carrying capacity. a In the healthy gut, metabolic competence, resistance to aggressions by competitors and predators, swift adaptation to rapid fluctuations as well as surviving acidic pH and the flow of the intestinal content, represent potent selective pressures and as many opportunities for bacteria to increase fitness by phenotypic or genetic variations. b When pathogens trigger acute inflammation, bacteria must adapt to iron starvation, killing by immune cells and antimicrobial peptides, and oxidative stress, while new metabolic opportunities emerge. c When high-affinity SIgA are produced against a bacterium, e.g., after oral vaccination, escape of SIgA by altering or losing surface epitopes becomes crucial for maximum fitness. However, escaping polyvalent SIgA responses after vaccination with "evolutionary trap" vaccines leads to evolutionary trade-offs A fitness maximum is reached in the vaccinated host gut that represents a major disadvantage for transmission into naïve hosts (fitness diminished below x) (d).
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Vacinas
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Microbioma Gastrointestinal
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article