Coronavirus Lung Infection Impairs Host Immunity against Secondary Bacterial Infection by Promoting Lysosomal Dysfunction

Abstract

Postviral bacterial infections are a major health care challenge in coronavirus infections, including COVID-19; however, the coronavirus-specific mechanisms of increased host susceptibility to secondary infections remain unknown. In humans, coronaviruses, including SARS-CoV-2, infect lung immune cells, including alveolar macrophages, a phenotype poorly replicated in mouse models of SARS-CoV-2. To overcome this, we used a mouse model of native murine β-coronavirus that infects both immune and structural cells to investigate coronavirus-enhanced susceptibility to bacterial infections. Our data show that coronavirus infection impairs the host ability to clear invading bacterial pathogens and potentiates lung tissue damage in mice. Mechanistically, coronavirus limits the bacterial killing ability of macrophages by impairing lysosomal acidification and fusion with engulfed bacteria. In addition, coronavirus-induced lysosomal dysfunction promotes pyroptotic cell death and the release of IL-1β. Inhibition of cathepsin B decreased cell death and IL-1β release and promoted bacterial clearance in mice with postcoronavirus bacterial infection.

Postinfluenza Environment Reduces Aspergillus fumigatus Conidium Clearance and Facilitates Invasive Aspergillosis In Vivo

“…ROS-independent conidial clearance in both macrophages and neutrophils requires phagolysosome maturation to create an acidic environment, which is necessary for conidial killing ( 51 , 52 ). A recent study also showed that betacoronavirus infection can lead to lysosome destruction, affect its acidification, and reduce bacterial clearance in the macrophage ( 53 ). To assess phagolysosome maturation in the neutrophils and monocytes within the IAV- Af -superinfected lungs, we used pHrodo-zymosan staining.…”

“…To investigate the upstream signal that may drive defective fungal clearance in the IAV- Af superinfection mice in our model, we examined antifungal gene expression in isolated immune cells. Based on viral-bacterial superinfection literature, we expected to observe an anti-inflammatory gene expression profile after IAV infection and during early fungal infection ( 53 – 56 ). However, we observed that immune cells from IAV- Af superinfection mice displayed increased inflammatory gene transcript levels and decreased anti-inflammatory cytokine gene transcript levels ( Fig.…”

Post-Influenza Environment ReducesAspergillus fumigatusConidia Clearance and Facilitates Invasive AspergillosisIn Vivo

“…ROS-independent conidial clearance in both macrophages and neutrophils requires phagolysosome maturation to create an acidic environment which is necessary for conidial killing (56, 57). A recent study also showed that β-coronavirus infection can lead to lysosome destruction, affect its acidification, and reduce bacterial clearance in macrophage (58). To assess phagolysosome maturation in the neutrophils and monocytes within the IAV- Af superinfected lungs, we used pHrodo-Zymosan staining.…”

“…To investigate the upstream signal that drives defective fungal clearance in the IAV- Af superinfection mice in our model, we examined antifungal gene expression in isolated immune cells. Based on viral-bacterial superinfection literature, we expected to observe an antiinflammatory expression profile after IAV infection and during early fungal infection (58–61). However, we observed that immune cells from IAV- Af superinfection mice displayed increased inflammatory gene transcript levels and decreased anti-inflammatory cytokine gene transcript levels (Fig.…”

Concurrent targeting of glycolysis in bacteria and host cell inflammation in septic arthritis

“…Pseudomonas aeruginosa strain PA01 was grown in tryptic soy broth (TSB; BD Biosciences, catalog no. 211825) at 37°C overnight as shown in our publication (Peng et al , 2022 ), and Streptococcus pneumoniae strain TIGER4 was purchased from ATCC and grown in a humidified incubator with 5% CO 2 in Todd Hewitt broth (THB; BD Biosciences, catalog no. 249240).…”