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

Abstract

RationaleInfluenza 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.MethodsMice 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.ResultsCXCL1 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.ConclusionModulation 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.

Effect of preventive or therapeutic treatment with angiotensin 1–7 in a model of bleomycin-induced lung fibrosis in mice

“…The right lung of mice was collected for indirect quantification of mononuclear cells recruitment into the tissue (NAG—n‐acetilglicosaminidase). The left lobe of the lungs was fixed in formalin for further histological analysis …”

Influenza virus-related critical illness: pathophysiology and epidemiology

“…Experiments blocking CXCR1/2 signaling, a key receptor pathway necessary for neutrophil recruitment to the site of inflammation showed protection in murine infections with influenza, Staphylococcus pneumoniae, or combined infections. Given the prominence of secondary bacterial infections (discussed in detail below) in influenza-associated disease, such host-directed therapies may have significant clinical utility [20]. Neutrophils can mediate tissue damage by secreting high levels of tissue remodeling enzymes such as MMPs, but also amplify inflammation by secreting extracellular traps (NETs).…”

The Annexin A1/FPR2 pathway controls the inflammatory response and bacterial dissemination in experimental pneumococcal pneumonia

“…8 Indeed, the modulation of inflammation is suggested as an important strategy to treat severe pneumonia. 4,9 During inflammation, the production of endogenous proresolving mediators coordinates the termination of the response favoring the return of the affected tissue to homeostasis. Proresolving mediators, in contrast to anti-inflammatory molecules, reduce inflammation without compromising the host defenses against pathogens.…”