Boosting Immunity

If a bacterium invades the bloodstream or deep tissues to sicken a patient, one can say that the sentinel defense functions of our innate immune system have failed. A more holistic definition of antibiotic therapy that centers on understanding correcting the dysfunctional host-pathogen interaction can unlock opportunities for therapeutic discovery.

Raise Up the Defense

While there are many medicines used in clinical medicine today whose purpose is to dial down immune cell activity to treat of inflammatory disorders such as rheumatoid arthritis or multiple sclerosis (eg, corticosteroids, anti-cytokine therapies), the management of serious acute bacterial infections is performed agnostic to immune cell function. However, since the activation states of all immune cells are controlled through intricate pathways that rapidly deploy but promptly counter-regulate inflammatory processes (“accelerators” and “brakes”), opportunities exist to pharmacologically target more effective immune clearance. Host-directed therapies to boost resilience or microbicidal capacities of immune cells may help eradicate difficult pathogens.

Resistance Prevention

An advantage of approaches targeting host factors that enhance immune cell recruitment or bactericidal activity is reduced selective pressure for resistance—the pathogen cannot evolve to combat a drug targeting the host and releasing a combination therapy of natural antimicrobial molecules. These approaches could be useful adjuncts to antibiotics in patients with altered host immunity (eg, cancer chemotherapy or AIDS) or defects in barrier functions (eg, surgical wounds or burns). Finally, these therapies should prove effective against antibiotic-resistant bacteria because these strains depend on the same virulence attributes as their antibiotic-sensitive counterparts to subvert innate immunity and produce disease.

Opportunities and Challenges

Immunotherapy has revolutionized cancer therapy leading to dramatically improved outcomes, successes that can inspire precision medicines to enhance antimicrobial function of innate immune cells for infectious disease indications. Host direct therapies can help cure or prevent deep tissue foci of antibiotic-resistant pathogens with minimal collateral damage on our microbiota. Theoretical concerns exist regarding the pro-inflammatory consequences of immune activating therapy, however uncontrolled antibiotic-resistant infections themselves cause severe deleterious inflammatory effects on the host until effective medical cure is achieved, and that wise host immune pathway targeting can overcome such hurdles.

Boosting HIF-1α to complement antibiotic treatment

A type of drug in clinical development for anemia or inflammatory bowel diseases stabilizes the human immune defense protein HIF-1α and can protect human bladder cells and mice against pathogenic E. coli urinary tract infection, and may thus provide a therapeutic alternative or complement to antibiotic treatment.

Click here to see the PLOS Pathogens paper

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