Modulating MAVS Aggregation to Promote Host Resilience During Bacterial Pneumonia
Abstract
Bacterial infections are leading cause of clinical pneumonia, leading to one million hospitalizations and approximately 50,000 deaths each year in the U.S. alone. After the discovery of antibiotics, the death rate of bacterial lung infections has not significantly improved in the last five decades. The reason of extensive mortality in pneumonia can be attributed to our limited understanding of host mechanisms that allow us to tolerate the infection without causing tissue damage. Despite the clearance of infecting pathogens with the help of antibiotic therapies, the host often succumbs to the infection due to their failure to limit the lung damage or repair it in a timely manner to restore the lung function. Failure to resolve the lung injury can lead to acute respiratory distress syndrome or ARDS where patients would require high levels of oxygen support including mechanical ventilations. The immune system that responds to the removal of the bacteria can sometimes be damaging itself, causing increased and/or prolonged inflammation. This can result in damaging the host lung tissue. In addition, the emergence of multidrug-resistant pathogens poses significant threat of further increasing death rates due to bacterial pneumonia. Targeting the host rather than pathogen to promote the host tolerance (also called host resilience) is a promising option, given it can be effective against wide range of pathogens and not susceptible to generating drug-resistant pathogens. However, most of the efforts to limit the inflammatory response to promote infection tolerance have produced mixed results due to a delicate interplay between host inflammatory response and pathogen clearance. In the current study, we have identified a novel molecule named MAVS that is best known for its antiviral activity to play a key role in promoting the harmful host inflammatory and damage response when challenged with bacterial lung infection. Not much is known about the role of MAVS and bacterial infections. Inhibiting this protein using either genetic or pharmacologic approaches provided the host with the ability to withstand the bacterial infection. Surprisingly, despite limited inflammatory response, MAVS blockade did not lead to overgrowth of bacteria in our studies, making it an ideal target to promote host resilience. This approach targeting the MAVS pathway can work handily with antibiotics in the management of bacterial lung infections and preventing lung injury. Our mechanistic studies using mouse model of infection show that upon infection with bacteria MAVS makes multimeric aggregates to form high order protein structures that are absent in the uninfected lungs. We will focus on Pseudomonas aeruginosa (PA) bacteria given it is a common cause of pneumonia. We confirmed this multimeric aggregation of MAVS in the tracheal aspirates obtained from clinically confirmed bacterial pneumonia subjects compared to uninfected human subjects that were on ventilator for non-pulmonary illnesses. We further discovered that a protein, known to play key role in mitochondrial health, known as PINK1, plays an inhibitory role on MAVS. In this proposal, we will investigate molecular and cellular mechanisms to understand how MAVS inhibition promotes the host tolerance to infections without compromising the antibacterial host immunity. We will utilize cellular, molecular, and mouse models of bacterial infection along with genetically modified pathogens to investigate these mechanisms. We will further confirm these findings in human samples obtained from hospitalized patients with or without bacterial infections, healthy human cells, and healthy human lungs that were infected with bacteria to decipher these mechanisms. Cutting-edge technologies like CyTOF and single cell RNA sequencing will be used to gain detailed mechanistic insights into MAVS-mediated host resilience mechanisms in the host. We will achieve this by following specific aims: In Aim 1, we will charact
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211078
Entities
People
- Min-Jong Kang
Organizations
- United States Army
- Yale University