Host-informed therapies for the treatment of pneumococcal pneumonia

Abstract

Over the past two decades, traditional antimicrobial strategies have lost efficacy due to a rapid rise in antibiotic resistance and limited success in developing new antibiotics. Rather than relying on therapeutics solely targeting the bacterial pathogen, therapies are emerging that simultaneously focus on host responses. Here, we describe the most promising 'host-informed therapies' (HITs) in two categories: those that aid patients with fully functional immune systems, and those that aid patients with perturbed immune processes. Using Streptococcus pneumoniae, the leading cause of bacterial pneumonia, as a case study, we show HITs as an attractive option for supplementing infection management. However, to broaden their applicability and design new strategies, targeted research and clinical trials will be essential. The host response is integral to disease outcomeThe introduction of vaccines and antimicrobials are among the most important strategies that have enabled us to drastically curb the spread and impact of infectious diseases. However, several challenges have impeded their continued efficacy, including the rapid rise of antibiotic resistance, the largely unsuccessful efforts to identify novel classes of antibiotics, and the limited antigenic breadth of vaccines. Rather than relying on therapeutic strategies that solely focus on bacterial killing, growth inhibition, and infection eradication, treatment strategies are emerging that modulate the host, particularly the immune system. These therapies are focused on enhancing the host response and/or defenses against the infection, with the potential to significantly improve disease outcome and host health.

Arginine-mediated gut microbiome remodeling promotes host pulmonary immune defense against nontuberculous mycobacterial infection

“…Due to significant limitations in using current antibiotics and the increasing incidence of antibiotic resistance in pathogenic infections over the last two decades, there are urgent medical needs to develop novel host-directed therapeutics against infectious diseases. 60–62 NTM infections are often fatal in immunocompromised patients and treatment is particularly challenging because of multiple antibiotic resistance. 61 , 62 Importantly, we found that B. pseudolongum administration reduced in vivo bacterial loads during pulmonary infections with multidrug-resistant clinical strains of Mabc.…”

Blocking HXA3-mediated neutrophil elastase release duringS. pneumoniaelung infection limits pulmonary epithelial barrier disruption and bacteremia

“…Epithelial cell supernatants were generated from B6 ALI monolayers infected with 1×10 7 WT or Δply S. pneumoniae for 1 hour at 37°C with 5% CO 2 , and then placed in 24-well receiving plates containing HBSS with Ca 2+ and Mg 2+ in the apical chamber for an additional 2 hours to allow for HXA 3 generation. The apical chamber supernatants were then collected and transferred to new Transwells with ALI monolayers for PMN transmigration assays.…”

“…Vaccination and antimicrobials are first-line strategies in combating pneumococcal diseases. However, the rapid rise of antibiotic resistance and the limited antigenic breadth of effective vaccines have fueled interest in treatment strategies that focus on diminishing tissue-destructive host immune responses (4)(5)(6)(7).…”

Screening under infection-relevant conditions reveals chemical sensitivity in multidrug resistant invasive non-typhoidal Salmonella (iNTS)

“…Host-directed therapeutics comprise chemical agents that either enhance protective host functions or blunt inflammatory processes that cause damage. 44 Apart from studies focusing on host-directed therapies as treatments for tuberculosis 44 and pneumococcal pneumonia, 45 host-directed therapies have been relatively underexplored adjuncts to anti-infective therapy. The success and promise of host-directed therapies to modulate innate immune functions in other therapeutic areas including transplantation, autoimmune diseases, and cancer 46,47 warrants a critical exploration of their potential against drug-resistant infections such as those caused by iNTS.…”