CXCR1/2 Antagonism Is Protective during Influenza and Post-Influenza Pneumococcal Infection.

Luciana P Tavares,Adeline Barthelemy,Cristiana C Garcia,François Trottein,Marina G Machado,Alexandre M Machado,Laura Brandolini,Mauro M Teixeira,Marilda M Siqueira,Lirlândia P De Sousa,Marcello Allegretti,Celso M Queiroz-Junior

doi:10.3389/fimmu.2017.01799

Abstract

Influenza A infections are a leading cause of morbidity and mortality worldwide especially when associated with secondary pneumococcal infections. Inflammation is important to control pathogen proliferation but may also cause tissue injury and death. CXCR1/2 are chemokine receptors relevant for the recruitment of neutrophils. We investigated the role of CXCR1/2 during influenza, pneumococcal, and post-influenza pneumococcal infections. Mice were infected with influenza A virus (IAV) or Streptococcus pneumoniae and then treated daily with the CXCR1/2 antagonist DF2162. To study secondary pneumococcal infection, mice were infected with a sublethal inoculum of IAV then infected with S. pneumoniae 14 days later. DF2162 was given in a therapeutic schedule from days 3 to 6 after influenza infection. Lethality, weight loss, inflammation, virus/bacteria counts, and lung injury were assessed. CXCL1 and CXCL2 were produced at high levels during IAV infection. DF2162 treatment decreased morbidity and this was associated with decreased infiltration of neutrophils in the lungs and reduced pulmonary damage and viral titers. During S. pneumoniae infection, DF2162 treatment decreased neutrophil recruitment, pulmonary damage, and lethality rates, without affecting bacteria burden. Therapeutic treatment with DF2162 during sublethal IAV infection reduced the morbidity associated with virus infection and also decreased the magnitude of inflammation, lung damage, and number of bacteria in the blood of mice subsequently infected with S. pneumoniae. Modulation of the inflammatory response by blocking CXCR1/2 improves disease outcome during respiratory influenza and pneumococcal infections, without compromising the ability of the murine host to deal with infection. Altogether, inhibition of CXCR1/2 may be a valid therapeutic strategy for treating lung infections caused by these pathogens, especially controlling secondary bacterial infection after influenza.

Highlights

The lungs are composed of a myriad of tree-like ramifications that end in intensively vascularized alveoli
Secondary pneumococcal infections are characterized by exacerbated inflammatory responses with massive number of neutrophils recruited into the lungs
The lack of negative regulators of inflammation, such as ST2, has been shown to aggravate secondary pneumococcal infection leading to higher mortality and number of bacteria in the lungs of infected mice [25]

Summary

Introduction

The lungs are composed of a myriad of tree-like ramifications that end in intensively vascularized alveoli. The mucosal surface of the lung is incredibly large (90 m2) and is exposed daily to a high number of particles and microorganisms including pathogens [1]. A great number of physical and biological barriers, including the innate immune system, protect the lungs from a possible infection. Pro-inflammatory cytokines and chemokines are produced by resident immune cells and lung epithelial cells promoting recruitment of neutrophils and the onset of inflammation. This is important to control dissemination and proliferation of microorganisms. The uncontrolled inflammatory response triggered by infection may lead to increased lung damage, morbidity, and mortality [2]

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