Integrated Signaling Pathways Mediate Bordetella Immunomodulation, Persistence, and Transmission

Abstract

The mammalian immune system includes a sophisticated array of antimicrobial mechanisms. However, successful pathogens have developed subversive strategies to detect, modulate, and/or evade immune control and clearance. Independent disciplines study host immunology and bacterial pathogenesis, but interkingdom signaling between bacteria and host during natural infection remains poorly understood. An efficient natural host infection system has revealed complex communication between Bordetella spp. and mice, identified novel regulatory mechanisms and demonstrated that bordetellae can respond to microenvironment and inflammatory status cues. Understanding these bacterial signaling pathways and the complex network of them that allows precisely timed expression of numerous immunomodulatory factors will serve as a paradigm for other organisms lacking such a powerful experimental infection system.

Enhancement of immune response against Bordetella spp. by disrupting immunomodulation

“…Despite their divergent ecological strategies and niches, these species share a large set of genes whose products mediate interactions with the host, modulating host immunity in various ways to optimize their success. The importance of their many immunomodulatory mechanisms is only beginning to be appreciated 10 .…”

Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections

“…Bordetellae harbor multiple mechanisms that allow them to modulate the host immune response (1,70,71). Some of the proteins that these organisms utilize to manipulate immune cells include adenylate cyclase toxin (ACT), a pore forming protein that leads to the deregulation of cAMP levels within target cells (72,73); type 3 secretion system (T3SS), a needlelike structure that injects toxins within mammalian cells (74-76); a type 6 secretion system that uses a phage-like mechanism to inject molecules (77); pertussis toxin (PTX), which prevents G proteins from interacting with G protein-coupled receptors on the cell membrane and therefore interfering with intracellular communication (78-80); and filamentous hemagglutinin (FHA), which binds signaling receptors, enables adhesion to epithelial cells and interferes with cytokine production (81, 82).…”

“…To persist in such an environment, bacteria must find a way to survive this onslaught of antibacterials. The strategy of resisting them all may be exceedingly challenging or impossible; instead, most of the best-studied pathogens have mechanisms that allow them to evade the full effects of host defenses (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In this review, we will consider examples of novel approaches in vaccine and therapeutic development that have been guided by the better understanding of bacterial immunomodulatory abilities.…”

Computational Health Engineering Applied to Model Infectious Diseases and Antimicrobial Resistance Spread

“…The mammalian immune system is a sophisticated, complex, and well-orchestrated network of cells and antimicrobial molecules operating at different levels to protect it against disease [59][60][61]. Initially, the immune response is innately effective against "new threats".…”

“…The adaptive immunity responsible for the memory response includes cellular and humoral immune responses. Unfortunately, successful pathogens have developed subversive strategies to exploit, modulate, and/or evade immune control and clearance [59], including evolutionarily optimized protein structures that bind with high specificity to protein-like hosts [62]. In addition, the immune response is highly specific to host and pathogen, hence why everyone has a unique immune system and will respond differently to immune challenges, such as infection or sepsis.…”