When the flu strikes, the real danger often comes from an unseen collaborator.
When we think of the deadliest flu pandemics in history, from the 1918 Spanish flu to the 2009 H1N1 outbreak, we often picture the influenza virus as the sole villain. However, the grim reality is that many of these millions of deaths were actually caused by a dangerous partnership. While the virus weakens the body's defenses, bacteria like Streptococcus pneumoniae and Staphylococcus aureus seize the opportunity to launch a devastating secondary attack. This phenomenon has puzzled scientists for decades. How does a viral infection open the door for seemingly unrelated bacterial invaders? The answer may lie at the cellular level, within the very cells the virus first occupies.
Influenza A virus (IAV) infections are known to predispose infected individuals to severe bacterial infections of the respiratory tract. During co-infection, viral and bacterial proteins interact in ways that can dramatically alter disease outcomes, promoting bacterial colonisation, immune evasion, and significant tissue damage 2 .
The respiratory tract is normally protected by a sophisticated defense system. Ciliated epithelial cells act as a physical barrier, constantly moving mucus and trapped pathogens out of the airways. When influenza virus breaches these defenses, it initiates a cascade of cellular changes.
Ciliated epithelial cells form a protective barrier with a functional "mucociliary elevator" that removes pathogens from the airways.
Viral replication damages cilia, disrupting the mucociliary elevator and creating opportunities for bacterial invasion.
The virus primarily targets airway epithelial cells, with its surface glycoproteins—hemagglutinin (HA) and neuraminidase (NA)—playing crucial roles in infection and spread 2 .
The damage begins during viral replication. As new virus particles bud from respiratory epithelial cells, they cause substantial damage, including clumping and subsequent erosion of the delicate cilia. This disruption to the "mucociliary elevator"—the body's natural escalator for removing pathogens—paves the way for bacterial invasion 2 . The scene is now set for a secondary bacterial infection to take hold.
To understand exactly how influenza infection makes our cells more vulnerable to bacterial attack, scientists have turned to laboratory models using HEp-2 cells, a human epithelial cell line valuable for studying respiratory infections. A pivotal series of experiments conducted in 1999 provided crucial insights into this dangerous relationship 1 7 .
Researchers designed a systematic approach to compare how bacteria interact with both healthy and influenza-infected cells:
HEp-2 cells were grown into confluent monolayers and divided into two groups. One group was infected with human influenza A virus, while the other served as an uninfected control 7 .
Using flow cytometry, scientists investigated whether influenza infection altered the expression of specific cell surface antigens that could act as bacterial receptors 1 .
Additional experiments examined how treating cells with neuraminidase alone affected bacterial binding, testing the importance of this enzyme independently 1 .
The findings were striking. Across multiple experiments, influenza A virus-infected HEp-2 cells showed significantly increased binding of all bacterial isolates tested compared to uninfected cells. This was true regardless of the bacterial species' surface characteristics, suggesting a broad mechanism of enhanced vulnerability 1 7 .
When researchers delved deeper into which cellular receptors were involved, they discovered that infection did not change the expression of certain Lewis antigens. Instead, there were significant increases in binding of monoclonal antibodies to CD14 and CD18, cell surface antigens known to act as receptors for bacteria 1 . Furthermore, when cells were treated with antibodies to block these receptors, binding of Neisseria meningitidis was significantly reduced, confirming their functional role in the enhanced bacterial adherence 1 .
| Bacterial Species | Binding to Infected Cells | Binding to Uninfected Cells |
|---|---|---|
| Neisseria meningitidis | Significantly Increased | Baseline |
| Haemophilus influenzae | Significantly Increased | Baseline |
| Moraxella catarrhalis | Significantly Increased | Baseline |
| Staphylococcus aureus | Significantly Increased | Baseline |
| Streptococcus pneumoniae | Significantly Increased | Baseline |
| Cell Surface Antigen | Change After Influenza Infection | Potential Role in Bacterial Adhesion |
|---|---|---|
| CD14 | Significant Increase | Receptor for bacterial components; blocking it reduces meningococcal binding |
| CD18 | Significant Increase | Receptor for bacteria; blocking it reduces meningococcal binding |
| Lewisb | No Significant Change | Not a major factor in this mechanism |
| Lewisx | No Significant Change | Not a major factor in this mechanism |
| H type 2 | No Significant Change | Not a major factor in this mechanism |
Beyond the cellular changes observed in the HEp-2 experiments, more recent research has uncovered an even more complex picture involving direct molecular interactions between viral and bacterial proteins 2 .
From pathogens like Streptococcus pneumoniae (NanA, NanB, NanC) further desialylate host cells and can use sialic acids as a carbon source 2 .
Can directly bind to bacterial surface proteins, "dragging" bacteria into host cells during viral entry 8 .
Meanwhile, Bacterial Surface Proteins such as pneumococcal surface protein A (PspA) and M protein of Streptococcus pyogenes have evolved to exploit the altered environment of the virus-infected cell, enhancing immune evasion during co-infection 2 .
| Molecule | Origin | Function in Co-infection |
|---|---|---|
| Neuraminidase (NA) | Influenza Virus | Cleaves sialic acids, exposing bacterial receptors on host cells |
| Hemagglutinin (HA) | Influenza Virus | Can directly bind some bacteria, promoting their internalization |
| NanA, NanB, NanC | Streptococcus pneumoniae | Bacterial neuraminidases that further expose host cell receptors |
| PspA & PspK | Streptococcus pneumoniae | Surface proteins that modulate immune system, enhancing evasion |
| M Protein | Streptococcus pyogenes | Binds to host tissues and modulates immune responses |
Understanding these complex interactions requires specialized laboratory tools. Here are some essential components used in this field of research:
A powerful technology that analyzes the physical and chemical characteristics of cells or particles in a fluid as they pass through at least one laser, used here to quantify bacterial binding and detect cell surface antigens 1 .
Used experimentally to treat cells independently of whole virus infection, helping researchers distinguish the specific effects of this enzyme from other viral components 1 .
Laboratory-produced antibodies that target specific cell surface antigens (like CD14 and CD18), allowing researchers to identify receptor changes and block their function to test hypotheses 1 .
During the 2009 H1N1 pandemic, approximately 30% of cases involved bacterial co-infection with high mortality 2 .
The implications of this research extend far beyond laboratory curiosity. Similarly, secondary bacterial pneumonia was responsible for the majority of the estimated 50 million deaths during the 1918 influenza pandemic 2 .
Secondary bacterial pneumonia caused most deaths in the 1918 Spanish flu pandemic, highlighting the deadly synergy between influenza and bacteria.
Understanding these mechanisms opens promising avenues for interventions targeting the collaborative processes between virus and bacteria.
Understanding these mechanisms opens promising avenues for therapeutic interventions. Targeting the collaborative processes between virus and bacteria—such as developing inhibitors against bacterial neuraminidases or blocking the specific receptor interactions enhanced by viral infection—could potentially mitigate the severity of secondary bacterial infections 2 .
As research continues to unravel the complex dialogue between influenza virus and bacteria, one thing becomes increasingly clear: in the battle against respiratory infections, we must account for both the primary invader and the opportunistic allies it recruits. The secret handshake between flu and bacteria, once revealed, may finally be interrupted.
Acknowledgement: This article was developed based on scientific research findings from peer-reviewed journals including FEMS Immunology and Medical Microbiology, PMC, and other scholarly sources.