A new study coordinated by CEU USP and published in Frontiers in Immunology reveals that the immune system responds very differently when viruses and bacteria infect simultaneously compared to when infection occurs sequentially. Researchers analysed how macrophages, key cells of the immune system, react to infection by the influenza virus (Influenza A) and the bacterium Streptococcus pneumoniae, one of the leading causes of bacterial pneumonia following influenza.
“The study shows that the order in which pathogens arrive determines which microorganism ‘dominates’ the immune response,” explains Javier Arranz Herrero, first author of the study. In this regard, he notes that “when viruses and bacteria infect simultaneously (coinfection), macrophages activate an inflammatory programme very similar to that induced by the bacterium alone. In this situation, the bacterial signal dominates the immune response, triggering strong activation of NF-?B-dependent inflammatory pathways.”
By contrast, when infection occurs sequentially (superinfection), with the influenza virus infecting first and the bacterium later, macrophages have already been “programmed” by the virus. In this scenario, the immune response is dominated by the virus, which conditions the subsequent reaction to the bacterium. This phenomenon of “viral priming” alters macrophage behaviour and may amplify inflammatory responses associated with lung damage and respiratory complications.
These findings help explain why secondary bacterial infections following influenza can be particularly severe and highlight the importance of considering not only which pathogens are present, but also the order in which they infect the host.
The researchers point out that understanding how macrophage responses are reprogrammed during coinfections could help design new therapeutic strategies to prevent or treat respiratory complications associated with influenza.
“In models of simultaneous coinfection, macrophages are rapidly reprogrammed by S. pneumoniae, which redirects their activity towards antibacterial pathways,” explains Jordi Ochando, head of the Transplant Immunity Unit at the National Centre for Microbiology of the Carlos III Health Institute. “By contrast, when the virus infects first and the bacterium follows later, macrophages are ‘marked’ by an antiviral imprint generated by the initial interaction with the virus. This alters their subsequent response to the bacterium and modifies the inflammatory course.”
This functional divergence, observed experimentally through transcriptional profiling and immune response analysis 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.
The researchers validated their findings using pig-derived macrophages, a relevant model since this animal develops a respiratory disease very similar to that of humans when infected with swine influenza viruses and the bacterium Streptococcus suis, a pathogen closely related to S. pneumoniae. The porcine model allowed comparison of the effects of coinfections depending on the viral strain or different serotypes of S. suis.
“This concordance shows that the mechanisms described may behave similarly across different species affected by influenza,” explains César Gutiérrez Martín, from the Department of Animal Health at the Faculty of Veterinary Medicine of the University of León. “It also highlights the value of animal models in translational research to better understand coinfections and develop more effective interventions.”
The study also explores how age influences macrophage responses to these coinfections, a relevant issue given that coinfections affect children, adults, and older people differently. Researchers compared macrophages from young mice (1 week), adult mice (12 weeks), and older mice (40 weeks).
“The results showed that there are significant differences in the response among the different types of macrophages, and that this response also varies depending on whether infection occurs simultaneously or sequentially,” notes Estanislao Nistal Villán, head of the Oneflu Swine Influenza Laboratory and coordinator of the Virology and Innate Immunity Group at the Faculty of Pharmacy of CEU USP.
The study forms part of a broad scientific collaboration involving Spanish and international institutions. These include the group led by Dr Yolanda Revilla at the Severo Ochoa Molecular Biology Centre–CSIC; Dr Elena Pinelli’s team at the Centre for Infectious Disease Control, National Institute for Public Health and the Environment (Bilthoven, the Netherlands), and, in the United States, the group of Dr Adolfo García-Sastre at the Department of Microbiology, Icahn School of Medicine at Mount Sinai.
Access to the article:
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1729086/full