Cysteinyl Maresins Reprogram Macrophages to Protect Mice from Streptococcus pneumoniae after Influenza A Virus Infection
Luciana P. Tavares,
Thayse R. Brüggemann,
Rafael M. Rezende,
Marina G. Machado,
R. Elaine Cagnina,
Ashley E. Shay,
Cristiana C. Garcia,
Julie Nijmeh,
Mauro M. Teixeira,
Bruce D. Levy
Affiliations
Luciana P. Tavares
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Thayse R. Brüggemann
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Rafael M. Rezende
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Marina G. Machado
Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
R. Elaine Cagnina
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Ashley E. Shay
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Cristiana C. Garcia
Laboratório de Vírus Respiratórios e do Sarampo, Instituto Oswaldo Cruz (Fiocruz), Rio de Janeiro, Rio de Janeiro, Brazil
Julie Nijmeh
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Mauro M. Teixeira
Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Bruce D. Levy
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
ABSTRACT Influenza A virus (IAV) infections are a leading cause of mortality worldwide. Excess mortality during IAV epidemics and pandemics is attributable to secondary bacterial infections, particularly pneumonia caused by Streptococcus pneumoniae. Resident alveolar macrophages (rAMs) are early responders to respiratory infections that coordinate initial host defense responses. Maresin conjugates in tissue regeneration (MCTRs) are recently elucidated cysteinyl maresins that are produced by and act on macrophages. Roles for MCTRs in responses to respiratory infections remain to be determined. Here, IAV infection led to transient decreases in rAM numbers. Repopulated lung macrophages displayed transcriptional alterations 21 days post-IAV with prolonged susceptibility to secondary pneumococcal infection. Administration of a mix of MCTR1 to 3 or MCTR3 alone post-IAV decreased lung inflammation and bacterial load 48 and 72 h after secondary pneumococcal infection. MCTR-exposed rAMs had increased migration and phagocytosis of Streptococcus pneumoniae, reduced secretion of CXCL1, and a reversion toward baseline levels of several IAV-induced pneumonia susceptibility genes. Together, MCTRs counter regulated post-IAV changes in rAMs to promote a rapid return of bacteria host defense. IMPORTANCE Secondary bacterial pneumonia is a serious and common complication of IAV infection, leading to excess morbidity and mortality. New host-directed approaches are needed to complement antibiotics to better address this important global infectious disease. Here, we show that harnessing endogenous resolution mechanisms for inflammation by exogenous administration of a family of specialized proresolving mediators (i.e., cys-MCTRs) increased macrophage resilience mechanisms after IAV to protect against secondary infection from Streptococcus pneumoniae.
