Many bacterial infections, especially those that are resistant to antibiotics, in the young, elderly, and immunocompromised, are characterized by runaway inflammation and sepsis. A hallmark of acute microbial infections is the chemokine-mediated recruitment of neutrophils to the infected tissue. Activated neutrophils release granule enzymes/peptides and superoxide for microbial killing. These processes must be highly regulated, as too many neutrophils will result in collateral tissue damage and disease. Such regulation, under conditions of high bacterial loads and/or when antibiotics are ineffective, is detrimental with infection winning the battle. We propose augmenting the host immune response as a viable strategy for containing bacterial infection. We have discovered that the ability of chemokines to exist as monomers and dimers plays an important role in regulating neutrophil function. We will test the hypothesis that exogenously administered chemokine variants, by promoting neutrophil function, enable successful resolution of inflammation and restoration of tissue homeostasis.
In Aim 1, we will test the therapeutic efficacy of a chemokine dimer by optimizing dosage, timing and frequency of administration after infecting mice with a lethal Salmonella Typhimurium (S. Typhimurium) dose in a septicemic model.
In Aim 2, we will determine how successful resolution is restored in chemokine treated mice by characterizing neutrophil and macrophage phenotypes including neutrophil killing activity, and cytokine/chemokine and lipid mediators that serve as benchmarks along the initiation to resolution phase. Our hypothesis, that the host immune response can be skewed for successful resolution of inflammation using engineered chemokines, is novel. Bacterial diseases cause significant morbidity, mortality, and economic burden, and are quickly developing antibiotic resistance. Our study will identify the molecular basis of cellular injury and disease exacerbation, enabling discovery and development of more effective therapeutics to treat infectious diseases, especially those that are associated with multi- antibiotic-resistant pathogens.
A large segment of the population including vulnerable groups, such as the young, old, and immunocompromised, are susceptible to multiple antibiotic-resistant (MAR) microbial infections, resulting in significant morbidity, mortality, and economic burden. Despite a dire need to develop new therapeutics to combat MAR pathogens, there has been very little investment to discover novel therapeutics. Our studies of using engineered chemokines to augment host immune response will advance drug development to treat such MAR pathogen-associated diseases in a clinical setting.
