Key Points

Coronavirus impairs host immunity against secondary bacterial infections.

Coronavirus-induced lysosomal dysfunction impairs bacterial killing.

Targeting lysosomal enzyme cathepsin B limits pyroptotic cell death.

Visual AbstractAbstract

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.

Footnotes

This work was supported by a Parker B. Francis Foundation award and a Catalyst Award from the American Lung Association (L.S.) and by National Institutes of Health Grant HL126094 and U.S. Department of Veterans Affairs Grant BX004661 from the U.S. Department of Defense (C.S.D.C.).

The online version of this article contains supplemental material.

Abbreviations used in this article:

COVID-19coronavirus diseaseLDHlactate dehydrogenaseMHVmouse hepatitis virusMOImultiplicity of infectionPAPseudomonas aeruginosaPIpropidium iodideSARS-CoV-2severe acute respiratory syndrome coronavirus 2SPStreptococcus pneumoniaeReceived March 15, 2022.Accepted July 21, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.