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

Area of Science:

• Immunology
• Microbiology
• Virology

Background:

• Postviral bacterial infections pose a significant healthcare challenge, particularly in coronavirus disease (COVID-19).
• Mechanisms underlying increased host susceptibility to secondary bacterial infections following coronavirus infection are not fully understood.
• Existing mouse models for SARS-CoV-2 do not accurately replicate the infection of lung immune cells like alveolar macrophages.

Purpose of the Study:

• To investigate the mechanisms by which coronaviruses enhance susceptibility to secondary bacterial infections.
• To utilize a murine beta-coronavirus model that infects both immune and structural cells to study post-coronavirus bacterial infections.
• To identify therapeutic targets for mitigating secondary bacterial infections after coronavirus infection.

Main Methods:

• Employed a mouse model infected with a native murine beta-coronavirus.
• Assessed the host's ability to clear bacterial pathogens post-coronavirus infection.
• Investigated the impact of coronavirus infection on macrophage function, including lysosomal activity and inflammatory responses.
• Evaluated the effect of cathepsin B inhibition on bacterial clearance and host cell death.

Main Results:

• Coronavirus infection in mice impaired the clearance of invading bacteria and exacerbated lung tissue damage.
• Coronaviruses were found to limit the bacterial killing capacity of macrophages by disrupting lysosomal acidification and fusion with bacteria.
• Coronavirus-induced lysosomal dysfunction promoted pyroptotic cell death and the release of Interleukin-1 beta (IL-1β).
• Inhibition of cathepsin B significantly reduced cell death and IL-1β release, while promoting bacterial clearance in mice with post-coronavirus bacterial infection.

Conclusions:

• Coronavirus infection compromises host defense mechanisms, increasing vulnerability to secondary bacterial infections.
• Disruption of macrophage lysosomal function is a key mechanism by which coronaviruses enhance secondary bacterial infections.
• Targeting cathepsin B may represent a viable therapeutic strategy to combat secondary bacterial infections following coronavirus infections.