Research in the McCullers lab focuses on the pathogenesis and immunology underlying co-infections between pathogens. We are interested in how viral or parasitic infections modulate both innate and adaptive immunity of their hosts in ways that benefit bacteria. The primary organisms we study include influenza viruses, Streptococcus pneumoniae, and Staphylococcus aureus. Projects are available for prospective students and postdoctoral fellows exploring the host-pathogen interface in several areas including virology, bacterial pathogenesis, immunology, and vaccinology.
Why we study secondary bacterial infections:
Death following influenza occurs via one of three distinct mechanisms. In a very small number of cases, viral-induced acute lung injury is severe enough to kill the host. More frequently, this lung injury is mild and resolves after a period of time, during which co-pathogens such as bacteria may take advantage of changes in innate immunity and physical damage to the lung to cause fatal infections. In hosts who are compromised by co-morbidities such as pre-existing chronic heart or lung disease, the increased physiologic load during influenza may cause the host to succumb to underlying pathologies. In most inter-pandemic influenza seasons, it is this latter mechanism that predominates, and most deaths occur in the elderly. Mortality directly from viral effects may strike any age group and has historically been the province of only a select few highly pathogenic influenza viruses, such as the 1918 pandemic strain and the H5N1 strains of avian origin currently circulating in Asia, Europe, and Africa.
Although secondary bacterial pneumonia as a cause of deaths has been appreciated since the 1803 pandemic struck Europe, this association came into sharp focus in 1918. Our societal memory of 1918 is of the virus that triggered 40-50 million deaths worldwide, but contemporary investigations and careful reconstructions suggest that bacterial super-infections were responsible for the majority of fatal cases. The descendents of that virus now circulate in an adapted and weakened form, and neither the primary viral deaths nor secondary bacterial fatalities that were hallmarks of the Spanish Flu occur with regularity in the present day. The specter of a new pandemic with another highly pathogenic strain, however, suggests we need to better understand both of these mechanisms of killing before a novel virus enters the population. The emergence of the novel H1N1 swine-origin pandemic has opened several new research avenues to explore this important interaction on both clinical and basic levels.
The role of the inflammatory response:
Influenza is a highly inflammatory disease, and secondary bacterial infections amplify this process. One of the paradoxes apparent in the study of secondary bacterial infections is, “Why is the inflammatory response supporting and worsening bacterial infections rather than helping to clear them”? Recent data suggest that the adaptive immune response to influenza virus promotes a robust inflammatory response to secondary challengers, but at the same time cripples the ability of innate immune effectors such as macrophages to deal with these pathogens. The result is severe pneumonia and its accompanying immunopathogenic effects, coupled with unrestrained bacterial growth. Our lab is interested in the viral and bacterial virulence factors that promote inflammation, and the effects that severe inflammation has on the host. A particular focus at present is the viral cytotoxin PB1-F2 and the broad array of cytotoxins produced by S. pneumoniae and S. aureus. A better understanding of the effects of influenza viruses on acute lung injury and wound healing and how these promote bacterial mediated disease will help direct strategies to improve therapy.
Treatment of severe lung infections:
Bacterial pneumonia after influenza infection typically presents at a more advanced stage, has complex features including multi-lobar involvement and bacteremia, and targets the frail and the elderly. For these reasons and because of the contribution of the virus itself to the pathogenesis, secondary bacterial pneumonia is more difficult to treat and the case fatality rate is higher. In addition, pre-clinical studies suggest that an over-exuberant host inflammatory response contributes to the severity of the illness and to treatment failures. The use of cell wall active antibiotics may be a contributing factor to these poor outcomes. The antibiotics most commonly used in clinical practice rapidly lyse organisms like Streptococcus pneumoniae causing release of pathogen associated molecular patterns (PAMPs) such as pneumolysin, cell wall, and bacterial DNA that act as triggers for inflammatory pathways, This problem may be exacerbated by the propensity of highly pathogenic influenza viruses such as the 1918 strain or the H5N1 strains currently infecting people in Asia and Europe to cause massive cytokine release. Since secondary bacterial infections account for a significant proportion of the deaths that occur during circulation of virulent strains, it is critical that we develop more effective treatment regimens before the next highly pathogenic influenza virus enters the population from avian sources. Our lab investigates the effectiveness of current and novel antibiotic treatment strategies in models relevant to severe lung infections.
Improving existing vaccines and developing new approaches are priorities for the control of respiratory pathogens. Our laboratory seeks to achieve a better understanding of the immune correlates of protection against these pathogens so better vaccines can be designed. To attain this goal, we study a variety of vaccine approaches and explore the influence of co-infections such as viruses or worms on the development of adaptive immunity. Our studies are translational in nature, including both pre-clinical models of pneumonia and otitis media as well as human studies. We are particularly interested in exploring the specific immune defects that underlie poor responsiveness to vaccines in children with chronic illnesses or immunodeficiency. We hope to use the information gained in these studies to predict which patients might benefit from which type of vaccine approach, allowing us to tailor our efforts to individual subjects. Studies are ongoing examining differences in immune responses to the H1N1 swine-origin influenza virus vaccine.
We have discovered that the immune modulation engendered by chronic worm infection impairs the ability of the host to respond appropriately to bacterial pathogens. We are currently exploring the mechanistic basis of the immune deficits that lead to this phenotype. In addition, we are exploring the impact of chronic worm infections on adaptive responses in the context of vaccination against common respiratory tract pathogens such as influenza viruses and S. pneumoniae and studying whether eradication of worms from the host can reverse the changes in host immunity we observe. These studies may have profound implications for prevention and treatment of common diseases in developing countries.