To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.
Pneumonia is a disease that is commonly caused by a bacterial infection and results in the lungs becoming inflamed. Pneumonia is a serious condition and can lead to hospitalization and sometimes death. However, women—and other female animals—are less likely than males to get pneumonia and are more likely to survive if they do. Understanding this sex-based difference may help to develop treatments or preventive actions that either reduce the number of people who get pneumonia or help infected patients to recover.
Bacteria from the nose—including those that cause pneumonia—frequently enter the lungs during sleep. Luckily, the body has very robust defense mechanisms against such invasions; the immune system immediately deploys cells called macrophages as a ‘first response’ to devour and kill invading bacteria in the lungs. However, this system is not perfect, particularly if an individual has a weakened immune system or if they are already suffering with a respiratory infection. Indeed, many individuals with severe influenza infections are hospitalized as a result of pneumonia.
Yang et al. studied why females are more able to fend off pneumonia and found that estrogen, the main female sex hormone, boosts the ability of the macrophages to kill bacteria. Treating male mice with estrogen also boosted their immune system's ability to kill off bacteria in the lungs.
Investigating further, Yang et al. found that the estrogen worked by increasing the number of proteins produced from one gene called NOS3. Female mice lacking NOS3 proteins lost their pneumonia-fighting advantage. A widely used class of drugs called statins, which are used to treat cardiovascular disease, boosts the activity of the NOS3 gene. Yang et al. therefore wondered whether treatment with either estrogen or statins might prevent pneumonia, or help patients with pneumonia fight off the infection.
Using a large database of information about healthcare in Denmark, Yang et al. assessed the relationship between taking these drugs and the risk of pneumonia. When several confounding factors (such as unrelated diseases that the patient was suffering from) are taken into account, the data show that the women were less likely to be hospitalized for pneumonia if they were taking statins or estrogens. Those taking both treatments had an even lower risk.
Yang et al. also found that treating mice with statins or an experimental drug that boosts NOS3 activity increased the ability of the animals to fight off pneumonia-causing bacteria—even if they also had influenza—and increased the likelihood that mice already infected with pneumonia would survive. Further studies will be needed to determine if statins or the experimental drug might also help to prevent pneumonia in human patients with influenza.