Influenza virus and S. pneumoniae are the two pathogens that cause the majority of respiratory infections in humans. Although influenza infection alone may cause pneumonia, secondary bacterial pneumonia is a major cause of excess morbidity and mortality during typical influenza pandemics, including the major pandemic of 1918-1919 (Brundage, J. F., “Interactions Between Influenza and Bacterial Respiratory Pathogens: Implications for Pandemic Preparedness,” Lancet Infect Dis 6:303-12 (2006), Stiver, H. G., “The Threat and Prospects for Control of an Influenza Pandemic,” Expert Rev Vaccines 3:35-42 (2004)). Indeed, cultivable pneumococci could be found in more than half of the blood samples obtained from soldiers with influenza during the 1918 pandemic, suggesting that more individuals died from secondary bacterial pneumonia than from the primary virus infection (Spooner et al., “A Bacteriologic Study of the Influenza Epidemic at Camp Devens, Mass.,” Jama 72:155-159 (1919), Hall et al., “The Epidemic of Pneumonia Following Influenza at Camp Logan, Texas,” Jama 71:1986-87 (1918)). The fact that secondary bacterial infections are responsible for a significant proportion of deaths during influenza pandemics has led to a recent call for stockpiling of antibiotics and pneumococcal conjugate vaccine as part of a plan for influenza preparedness (Klugman et al., “Pneumococcal Vaccines and Flu Preparedness,” Science 316:49-50 (2007)).
Several factors have been proposed to be involved in this viral-bacterial synergy, including suppression of neutrophil function (Craft et al., “Effect of Virus Infections on Polymorph Function in Children,” Br Med J 1:1570 (1976), Abramson et al., “Polymorphonuclear Leukocyte Dysfunction During Influenza Virus Infection in Chinchillas,” J Infect Dis 143:836-45 (1981), McNamee et al., “Both Influenza-Induced Neutrophil Dysfunction and Neutrophil-Independent Mechanisms Contribute to Increased Susceptibility to a Secondary Streptococcus Pneumoniae Infection,” Infect Immun 74: 6707-21 (2006)), increased bacterial adherence to epithelia due to upregulation of platelet-activating factor receptor expression (van der Sluijs et al., “Involvement of the Platelet-Activating Factor Receptor in Host Defense Against Streptococcus Pneumoniae During Postinfluenza Pneumonia,” Am J Physiol Lung Cell Mol Physiol 290: L 194-9 (2006), (McCullers et al., “Lethal Synergism Between Influenza Virus and Streptococcus Pneumoniae: Characterization of a Mouse Model and the Role of Platelet-Activating Factor Receptor,” J Infect Dis 186:341-50 (2002)), and induction of inhibitory IL-10 (van der Sluijs et al., “IL-10 is an Important Mediator of the Enhanced Susceptibility to Pneumococcal Pneumonia After Influenza Infection,” J Immunol 172:7603-9 (2004), van der Sluijs et al., “Influenza-Induced Expression of Indoleamine 2,3-dioxygenase Enhances Interleukin-10 Production and Bacterial Outgrowth During Secondary Pneumococcal Pneumonia,” J Infect Dis 193:214-22 (2006)). The fact that increased susceptibility to various bacteria can occur following influenza infection, including S. pneumoniae, H. influenzae, and S. aureus (Brundage, J. F., “Interactions Between Influenza and Bacterial Respiratory Pathogens: Implications for Pandemic Preparedness,” Lancet Infect Dis 6:303-12 (2006)), suggests a general immune defect. In addition, clinical secondary bacterial infections occur at a time when the virus begins to be cleared from the lung and the patient enters the recovery stage (Brundage, J. F., “Interactions Between Influenza and Bacterial Respiratory Pathogens: Implications for Pandemic Preparedness,” Lancet Infect Dis 6:303-12 (2006)). This raises the possibility that the immune response that is induced against viral infection leads to decreased protection against bacterial infection. In the current invention, the innate immune mechanisms in the lung that are responsible for initial removal of pneumococci and the influence of influenza infection on these protective mechanisms have been examined. It was found that IFN-γ produced by T cells in the lung after viral infection inhibits alveolar macrophage-mediated microbial clearance and, consequently, leads to enhanced susceptibility to secondary bacterial infection.
Bacterial infections often follow influenza infection and are responsible for much of the morbidity and mortality associated with influenza. The present invention shows that interferon-γ (IFN-γ) induced by the viral infection dampens the antibacterial responses of lung tissue. IFN-γ-treated alveolar macrophages have lower phagocytic capacity and, thus, are less able to clear bacteria from infected lung tissues. In vitro treatment of alveolar macrophages with IFN-γ leads to down-regulation of the scavenger receptor MARCO, which has been associated before with complement-independent pneumococcal phagocytosis. Mice lacking either IFN-γ or its receptor show enhanced survival after secondary bacterial infection upon influenza virus exposure. Notably, neutralization of IFN-γ in virus-infected wild-type mice results in lower mortality. These findings indicate therapeutic intervention strategies for enhancing innate immunity and limiting the lethality of secondary bacterial infections.
The present invention is directed to overcoming these and other deficiencies in the art.