Pertussis Toxin, Aiding and Abetting Influenza

Pertussis, or whooping cough, is bad. In infants, it can kill or lead to neurological impairment or other permanent injuries. In adults, the 100-day cough can range from a persistent annoyance to bone-wracking agony. As bacteria go, it's a pretty nasty one. Less than two years ago, an outbreak in California resulted in the deaths of 10 babies. In the mid- to late-1970s, vaccination rates plummeted in many countries after reports of neurological damage following immunization, leaving the immunocompromised at much greater risk. The reports were ultimately mistaken. We are currently seeing another downward trend in vaccine uptake rates, as well as reminders that immunity wanes with time. Outbreaks continue to spread across the United States and other nations as teens and adults fail to get timely boosters and parents opt out of immunizing their children.

Avoiding the agony and loss of time, not to mention possible heartache, that accompanies whooping cough would seem to be a good idea regardless of any other factors. But a new study published in PLoS One hints at another reason to immunize.

A team of researchers from the University of Maryland School of Medicine, led by Dr. Victor Ayala, noted that viral infections, such as influenza, can be complicated by subsequent bacterial infection, leading to life-threatening pneumonia. A number of studies, they state, have looked at possible mechanisms that may contribute to increased severity of disease in these situations, but few studies have examined the reverse situation: a bacterial infection followed by infection with influenza virus. Given that as many as 30% of adult and 16% of infant pertussis patients exhibit evidence of a viral co-infection, Ayala et al. investigated the role that pertussis toxin may play in increasing or decreasing the severity of subsequent respiratory viral infection.

Bordetella pertussis, the bacterium that causes whooping cough, produces a toxin that enables it to evade the host's immune system in order to colonize the host's lung tissues. Pertussis toxin (PT) affects many of the signalling pathways that govern the immune response. Basically, it shuts down cell communication so the body doesn't realize it's under attack.

Imagine, for a moment, that you are a guard. If you see an intruder, your job is to first call for reinforcements, then get a nice, clear picture of the intruder so the enforcers know who to look for when they arrive. So you're sitting there, keeping an eye out. You see something suspicious, and as you reach for the phone to call it in, a sultry, seductive woman (or guy, take your pick) wanders up and latches on to you. She works her charm and your attention is hers to command. You forget about phoning anything in; heck, you can't even remember what the suspicious something you saw even looked like.

That's essentially what PT does. It prevents alveolar macrophages (the front line defenses against things that make it into your lungs) from signalling for help to fend off an invasion of foreign organisms. What's more, PT disrupts the ability of the innate immune system to "teach" T-cells what antigens to look for, a process known as antigen presentation. All of this appears to be a means that B. pertussis evolved to outfox the immune system, at least for a short time.

So what does this have to do with influenza? Ayala and his team, using mouse models, found that infection with B. pertussis prior to influenza infection resulted in much more severe flu than when influenza infection preceded pertussis infection. Hypothesizing that the toxin was the agent responsible for this effect, they set up a series of experiments in specially bred mice. Some were inoculated with wild type B. pertussis, some with B. pertussis lacking PT and others with PBS (phosphate buffered saline), a non-toxic solution acting as an inactive control. All of the mice were then inoculated with influenza virus. In mice affected by PT, the innate immune response was suppressed, allowing the influenza virus to replicate much faster and for a longer period of time than in either of the other groups. The result was a more serious bout of the flu, with significantly increased risk of mortality (PT-treated mice died much sooner than non-PT-treated mice). This only occurred, however, when the mice were inoculated with the influenza virus within several days following pertussis infection.

Ayala et al. hypothesize that the increased lethality may be due to several different factors. PT causes a short-term decrease in cytokines (cell-signaling proteins important for immune function). The resultant large viral load may be the reason that a respiratory viral co-infection is so dangerous. Alternatively, after the early low level, cytokines may increase significantly during later stages of infection, potentially leading to a cytokine storm.

Since this study was in mice, it may be difficult to accurately apply the findings to humans; we can't exactly go around purposefully infecting people with pertussis and influenza. However, it does provide a viable explanation as to why influenza infection (and possibly other respiratory viral infections) concurrent with or shortly after pertussis infection can be so severe. The authors certainly have interesting findings, and more research is needed. Bringing this all back to the issue of vaccination, immunizing against pertussis may not only prevent a survivable, if painful, several months of coughing, but it could potentially reduce the risk of a fatal case of influenza, as well.

Reference
Ayala VI, Teijaro JR, Farber DL, Dorsey SG, Carbonetti NH (2011) Bordetella pertussis Infection Exacerbates Influenza Virus Infection through Pertussis Toxin-Mediated Suppression of Innate Immunity. PLoS One. 2011; 6(4): e19016.