Immune Response to Flu & Pneumonia: Infection Order Matters | New Study Reveals

Why bacterial infections following influenza can be particularly severe is a question gaining sharper focus thanks to new research into how our immune systems respond to sequential versus simultaneous infections. A study published in Frontiers in Immunology reveals that the body’s defense mechanisms react particularly differently when viruses and bacteria infect at the same time, compared to when infection occurs one after the other. Understanding this distinction is crucial, as secondary bacterial pneumonia is a significant complication of influenza, contributing to severe illness and even death.

Researchers investigated how macrophages – essential cells of the immune system – behave when faced with both the influenza A virus and Streptococcus pneumoniae, a leading cause of bacterial pneumonia following the flu. The findings highlight that the order of infection dramatically influences which pathogen ‘wins’ the initial immune battle, and the severity of the overall illness.

Immune Response Varies Based on Infection Order

The study demonstrates that when viruses and bacteria infect simultaneously (a coinfection), macrophages activate an inflammatory program very similar to that triggered by the bacteria alone. In this scenario, the bacterial signal dominates the immune response, leading to a strong activation of inflammatory pathways dependent on NF-κB. This means the immune system essentially prioritizes fighting the bacteria, even in the presence of the virus.

Still, when infection occurs sequentially (a superinfection), where influenza virus infects first, followed by the bacteria, the macrophages have already been ‘programmed’ by the virus. This ‘viral priming’ alters the immune response, causing it to be dominated by the virus, which then influences the subsequent reaction to the bacteria. This phenomenon can amplify inflammatory responses associated with lung damage and respiratory complications. Researchers found that this altered macrophage behavior is a key factor in the increased severity of secondary bacterial infections.

Javier Arranz Herrero, the first author of the study, explains that the order in which pathogens arrive determines which microorganism ‘dominates’ the immune response. This finding helps explain why bacterial infections following influenza can be particularly dangerous. It underscores the importance of considering not only which pathogens are present, but similarly the order in which they infect the body.

Validating Findings with Porcine Models

To further validate their findings, the researchers utilized macrophages derived from pigs. What we have is a relevant model given that pigs develop a respiratory illness very similar to that seen in humans when infected with swine influenza virus and Streptococcus suis, a pathogen closely related to S. Pneumoniae. This allowed for a more translational approach to understanding the complex interplay between viral and bacterial infections.

Jordi Ochando, director of the Unit of Transplant Immunity at the National Center for Microbiology of the ISCIII, explains that in simultaneous coinfection models, macrophages are quickly reprogrammed by S. Pneumoniae, diverting their activity towards antibacterial routes. However, when the virus infects first, followed by the bacteria, the macrophages are ‘marked’ by an antiviral imprint generated by the initial interaction with the virus. This alters their subsequent response to the bacteria and modifies the inflammatory course.

This functional divergence, observed through transcriptional profiles and analysis of immune responses via cytokine secretion, provides further insight into why some combinations of influenza and pneumococcus result in particularly severe outcomes, while others follow different clinical trajectories. Cytokines are signaling molecules that play a crucial role in coordinating the immune response.

Age and Macrophage Response

The study also explored how age influences the macrophage response to these coinfections, a critical consideration given that coinfections affect children, adults, and the elderly differently. Researchers compared macrophages from young (1-week-old), adult (12-week-old), and aged (40-week-old) mice. The results showed significant differences in the response between the different macrophage types, and that this response also varied depending on whether infection occurred simultaneously or sequentially.

Estanislao Nistal Villán, director of the Oneflu Porcine Influenza Laboratory and coordinator of the Virology and Innate Immunity Group at the CEU San Pablo University Pharmacy Faculty, noted the substantial differences in response among the various macrophage types and how that response shifted based on the timing of infection.

Implications for Therapeutic Strategies

The research suggests that understanding how macrophage responses are reprogrammed during coinfections could help design new therapeutic strategies to prevent or treat respiratory complications associated with influenza. The findings emphasize the require to consider the timing of infection when developing interventions. For example, strategies that boost the initial antiviral response might help ‘prime’ the immune system to better combat subsequent bacterial infections.

This study is part of a broader collaborative scientific effort involving institutions in Spain and internationally, including the Severo Ochoa Molecular Biology Center-CSIC, the National Institute for Public Health and the Environment in the Netherlands, and Mount Sinai’s Icahn School of Medicine in the United States. Frontiers published the research, adding to a growing body of evidence on the complex interplay between viral and bacterial infections.

Further research is needed to fully elucidate the mechanisms underlying these observed differences and to translate these findings into effective clinical interventions. Ongoing surveillance of influenza and pneumococcal infections, coupled with continued investigation into the immune response, will be crucial for improving our ability to prevent and treat these potentially life-threatening conditions. ScienceDirect.com provides additional resources on the immunology of influenza-associated bacterial pneumonia.

Individuals at high risk of influenza complications – including young children, older adults, pregnant women, and those with underlying health conditions – should prioritize annual influenza vaccination. Consult with a healthcare professional for personalized advice on influenza prevention and treatment. Nature also reports on how allergic inflammation can alter the lung microbiome and impact co-infection risks.